Recent Advances of Using Hybrid Nanocarriers

www.MaterialsViews.
com
Drug Delivery
Recent Advances of Using Hybrid Nanocarriers in

Remotely Controlled Therapeutic Delivery
Zibiao Li, Enyi Ye, David, Rajamani Lakshminarayanan, and Xian Jun Loh*
From the Contents
1. Introduction ...............................................2
The development of hybrid biomaterials has been
2. Stimuli for Remote Trigger ...........................2 attracting great attention in the design of materials for
biomedicine. The nanosized level of inorganic and
3. Remote Triggers Versus In Situ Stimuli.........3
organic or even bioactive components can be combined
4. Structures of Hybrid Nanovehicles ..............4 into a single material by this approach, which has
created entirely new advanced compositions with truly
5. Mechanisms of Remote Trigger Release .....17 unique properties for drug delivery. The recent advances
6. Concerns and Limitations .........................21
in using hybrid nanovehicles as remotely controlled
therapeutic delivery carriers are summarized with
7. Conclusion and Future Perspective ...........22 respect to different nanostructures, including hybrid
host–guest nanoconjugates, micelles, nanogels, core–shell
nanoparticles, liposomes, mesoporous silica, and hollow
nanoconstructions. In addition, the controlled release
of guest molecules from these hybrid nanovehicles in
response to various remote stimuli such as alternating
magnetic ﬁeld, near infrared, or ultrasound triggers
is further summarized to introduce the different
mechanisms of remotely triggered release behavior.
Through proper chemical functionalization, the hybrid
nanovehicle system can be further endowed with many
new properties toward speciﬁc biomedical applications.
small 2016, © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.small-journal.com 1
DOI: 10.1002/smll.201601129
reviews
www.MaterialsViews.com
[11]
1. Introduction different aspects. For example, the design considerations
of various remotely controlled drug delivery carriers were
We have seen rapid development of various nanovehicles as discussed by Duguet et al. in their review article.[12] Timko
drug delivery systems (DDS) in the past few decades. Particu- and Kohane reviewed different types of materials as clin-
larly hybrid nanovehicles incorporating organic and inorganic ical devices developed for remotely triggered drug delivery,
molecules into a nanocontainer have attracted great interest. which include magnetically activated membranes, UV-
These hybrid nanovehicles are designed such that they can be triggered polymers, thermosensitive liposomes (TSLs), and
controlled by remote stimuli.[1] These remotely triggered DDSs microchips.[6d] The same research group also summarized the
have enticed a lot of researchers’ attention, as they have a great fabrication and physical triggering mechanism of remotely
potential in becoming the ideal DDS, which is preferably an triggerable DDS from the view of chemistry and mate-
active drug carrier so as to make it possible to regulate and rials science behind triggered release systems.[7] Among the
control the drug release behavior.[2] An ideal DDS must also be various the triggers under the definition of remote stimuli,
biocompatible, highly stable against various colloidal interac- light, ultrasound, and magnetic field are the most appealing
tions, able to encapsulate the drug effectively without leakage ones in the future development of DDSs because of their
or denaturation, and finally able to escape mononuclear phago- facile accessibility and easy manipulation, as well as less side
cyte system (MPS).[3] One possible application of such hybrid effects. Thus far, nanostructured carriers with the responsive-
nanovehicles as remotely triggered/controlled DDS is to con- ness to each of the respective stimulus have been extensively
tain anticancer chemotherapeutic reagents and to transport reviewed for remotely controlled drug release.[5e,6c,9a,c,13]
them to the cancer/tumor populated regions effectively.[4] Such In this review, we present some of the strategies that have
DDS has great potential to overcome the shortcomings of the been recently attempted by researchers in order to develop
traditional chemotherapeutic procedure—the most prominent hybrid nanovehicles for remotely triggered therapeutic deliv-
of all is the toxic side effect of the chemotherapeutic reagents eries, including drug, gene (DNA and siRNA) delivery, and
to the surrounding noncancerous cells. Thus, by using remotely synergistic therapeutic effect induced from the combined use
triggered DDS, it is possible to deliver higher payload of of different remote triggers. Special focus is emphasized on
chemotherapeutic reagents to the cancerous regions, without the most extensively studied stimuli for remotely triggered
any “leaks” to the surrounding healthy cells during the trans- system design such as near infrared (NIR) light, ultrasound,
port. Once the DDS has reached the cancerous regions, the and alternating magnetic field (AMF), followed by the dif-
clinicians can apply appropriate stimuli to trigger a controlled ferent nanostructures of the hybrid vehicles fabrication and
drug release in that region.[2a,5] This DDS is also beneficial in their trigger mechanisms. The structure and organization of
such a way that a pulsatile drug release can be administered the present review is significantly different from the angle
manually, thus giving a higher degree of control on the drug of previously reported reviews which are dealing with indi-
administration pattern.[2b,6] Besides being able to be triggered vidual remote trigger or specific drug delivery applications,
remotely, these DDSs also benefit from their nanosize. Com- as well as those pioneer reviews focusing on remote-stimuli-
pare to larger devices which can cause embolic phenomena, the driven single component or hybrid systems of remotely con-
hybrid nanocarriers are more suitable for intravenous admin- trolled devices with largely varied dimensions. The insights to
istration and have better systemic distribution.[7] In addition, the underlying challenges and possibly future perspectives of
Matsumura and co-workers reported that nanoparticles have using hybrid nanocarriers in remotely controlled therapeutic
the ability to spontaneously gather in some pathological sites delivery are also provided at the end of this review.
such as tumors.[8] This is owing to the enhanced permeability
and retention (EPR) effect, which occurs when nanoparticles
undergo extravasation through the “leaky” and disjointed neo- 2. Stimuli for Remote Trigger
vasculatures inside the tumorous tissues, and finally accumulate
within the interstitial tumor space.[2a,6a,9] As a result of this EPR For the applications of drug release in the human
effect, nanoparticles can be passively targeted toward tumorous body, the stimuli for remote trigger have to meet certain
regions, potentially increasing the efficiency and effectiveness criteria, including biocompatibility, nontoxicity, and ease
of drug transport process. However, integrating different com-
ponents and driving them to self-assemble into a hybrid nano- Dr. Z. Li, Dr. E. Ye, Prof. X. J. Loh
vehicle may pose many challenges. Institute of Materials Research and Engineering (IMRE)
A*STAR
There have been efforts to design hybrid devices in order
2 Fusionopolis Way. Innovis, #08-03
to synergistically combine different functions or strengths of Singapore 138634, Singapore
the individual components; or even to compensate for the E-mail: lohxj@imre.a-star.edu.sg
weaknesses of one another.[10] Many have experimented on David, Prof. X. J. Loh
the combination between organic substances such as stimuli- Department of Materials Science and Engineering
responsive, and biodegradable polymers; and inorganic sub- National University of Singapore
stances such as gold, maghemite, silica nanoparticles, and 9 Engineering Drive 1, Singapore 117576, Singapore
upconversion nanocrystals to form remotely controlled drug R. Lakshminarayanan, Prof. X. J. Loh
delivery devices. Due to their good biocompatibility and bio- Singapore Eye Research Institute
11 Third Hospital Avenue, Singapore 168751, Singapore
availability, these types of remotely controlled materials have
been extensively explored for biomedical applications in DOI: 10.1002/smll.201601129
2 www.small-journal.com © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim small 2016,
DOI: 10.1002/smll.201601129
of application. In this section, some strategies to stimulate

remote trigger of hybrid nanovehicles will be presented. Li Zibiao obtained his Ph.D. in 2014 from
National University of Singapore. Currently,
he is working as a research scientist at the
2.1. NIR Light Institute of Materials Research and Engi-
neering, A*STAR, Singapore. His research
interests are focused on biodegradable
Electromagnetic waves such as light is a promising stimuli
and functional polymeric materials design,
for remote trigger applications as it can be applied to human structural properties investigations and
body with great spatial and temporal precision.[14] NIR light their hybrid fabrications for biomedical and
is utilized because its wavelength is within a biologically- consumer care applications.
friendly range (650–950 nm), which lead to minimal light
absorption by the human body.[2c,6a,15] This is because blood
and tissues are transparent within NIR light wavelength.[16]
As such, NIR light is able to enter tissues safely and in
greater depth.[2b,5b,d] NIR light can be used to stimulate plas- Xian Jun Loh is the program manager of the
monic metallic nanoparticles, for instance gold nanoparticles A*STAR Personal Care Programme and an
assistant professor at the National University
(GNPs).[17] GNPs show strong absorption to NIR light owing
of Singapore (NUS). His main research
to the surface plasmon resonance (SPR) oscillations.[5a] interests are in the design of supramolecu-
These nanoparticles can transform optical energy from lar and stimuli-responsive polymers and
NIR light into thermal energy effectively, known as photo- hydrogels for biomedical and personal care
thermal heating or photothermia.[18] Furthermore, GNPs are applications.
biocompatible, easily fabricated, and modified with various
host–carrier molecules, and effectively bound with guest
molecules.[17] GNPs also benefit from the EPR mechanism,
rendering it suitable to target tumorous regions.[19] With
NIR-induced photothermia, tumor ablation via heat stress
and thermo-induced release of therapeutic molecules can be
achieved.[2c,5b,20]
2.3. AMF
2.2. Ultrasound AMF is able to produce local heating around magnetic nano-
particles, like iron oxide nanoparticles (IONPs) (maghemite
Similar to the NIR stimuli, exposure of ultrasound will lead or magnetite) through hysteresis losses, Neel relaxation, or
to a temperature increase (ultrasound hyperthermia) due Brownian relaxation.[25] The transformation of electromag-
to absorption of ultrasonic energy.[6c] Focused and directed netic energy from an external high-frequency field to heat is
ultrasound has great spatial and temporal precision, as well known as magnetic hyperthermia.[26] The local heating pro-
as a greater penetration depth than NIR light.[21] Focused duced may be utilized to induce heat stress on tumor cells,
ultrasound can also produce physical force onto the target, as causing them to undergo intracellular as well as extracellular
utilized in kidney stone shattering application for instance.[22] degradation.[26d,27] However, in order to achieve efficient
Both ultrasound hyperthermia and physical impact could be tumor ablation, high concentration of magnetic nanoparti-
utilized to trigger the release of drug molecules from hybrid cles needs to accumulate at the tumorous regions to achieve
nanoparticles which incorporate thermoresponsive sub- homogenous and efficient heating. As such, many efforts
stances. Furthermore, application of ultrasound onto cells can have been diverted to utilization of this local heating feature
increase membrane permeability and improve the penetra- as stimuli for remote trigger of DDS. Magnetic nanovehicles
tion ability of nanovehicles into the cells. As such, ultrasound can be hybridized with thermoresponsive materials which can
has promising potential in enhancing therapeutic efficiency be designed to encapsulate therapeutic molecules and release
of DDS.[23] of the payloads upon exposure to AMF.[28] AMF itself is non-
There are two types of ultrasound that can be utilized toxic and easy to be applied onto the human body, making it
as stimulus for remote trigger, namely low-frequency and a suitable stimulus for remotely triggered DDS applications.
high-frequency ultrasound.[24] Low-frequency ultrasound can
induce molecular rearrangement of lipid molecules to form
temporal pores, resulting in enhanced permeability and the 3. Remote Triggers Versus In Situ Stimuli
subsequent increase in drug release rate. On the other hand,
high-frequency ultrasound can induce vigorous structural DDSs development has evolved from macroscopic con-
oscillations which may lead to cavity or even destruction of trolled drug delivery devices and implants since the early
the nanovehicles when the local stress exceeds the ultimate 1960s, to the current nanotechnology era of targeted nano-
strength of the particle. Therefore, different types of ultra- carriers.[29] However, it still poses great challenges to clini-
sound can be used depending on which release mechanism cians everywhere. For example, in cancer therapy, the most
is desired. critical requirements for DDSs are: (i) the capabilities of the
DOI: 10.1002/smll.201601129
reviews
designed carriers to encapsulate sufficient amount of chemo- loaded and released upon exposure of appropriate stimuli. In
therapeutic agents and, (ii) transport them to the tumor loca- this section, several structures of hybrid nanovehicles will be
tions effectively without drug leakage or denaturation, and discussed.
(iii) release the anticancer drugs in a control manner for dis-
eases cure.[4] The efficient transportation of drugs to targeted
regions could eliminate the toxic side effect of the chemo- 4.1. Hybrid Host–Guest Conjugated Nanostructures
therapeutic reagents to the surrounding noncancerous cells,
which is one the most prominent side effects in cancer chem- One of the simplest strategies to bind guest drug molecules
otherapy.[30] In addition, the controlled release could enable to the nanostructures is to form a host–guest conjugate
the drugs to work at their optimum efficacy by maintaining by directly “attaching” the drug molecules onto the host
the drugs at above the therapeutic concentration for prede- nanostructure through permanent covalent bonds or inter-
fined periods of time.[31] Previous studies have manifested the molecular interactions such as van der Waals’ forces and
use of both remote and the internal stimuli for on-demand dipole–dipole attraction forces. One example of such struc-
drug release.[32] Specifically, the pathological microenviron- ture would be the direct conjugation of sulfur-bearing DNA
ment changes along the disease sites such as pH, concen- molecules onto gold GNPs via strong AuS bonding.[36]
tration of glucose and reductive reagents, and the presence AuS bonding is so strong that extensive NIR irradiation
of specific enzyme were used as in vivo stimuli to trigger is needed to produce higher local temperature to break the
the demand drug release.[33] For example, the pHs in tumor AuS bond so as to release the therapeutic DNA molecules.
tissue are lower than normal tissues. The changes in pH are This may result in drawbacks as higher local heating often
also encountered once the drug carriers enter cells where pH causes the GNPs to alter their shapes and the drug mol-
can drop as low as 5.0–6.0 in endosomes and 4.0–5.0 in lys- ecules to undergo thermo-induced degradation, ultimately
osomes. The acidic environment in endosomal and lysosomal resulting in decreased drug delivery efficiency. In order to
compartments can be exploited as an internal stimulus to solve this issue, current studies utilize a new method in which
trigger pH-sensitive drug release.[34] Furthermore, the intra- a single-stranded DNA (ssDNA) is only released upon the
cellular concentration of reducing glutathione is known to be dehybridization of a double-stranded DNA (dsDNA). This
substantially higher than that in the cellular exterior (≈10 mm hybrid nanosystem is produced by firstly combining one
vs ≈2 μm). These extreme conditions provide opportunities ssDNA to a thiol-end group. Then, another ssDNA, which
for tumor-targeted drug delivery.[33] Despite of the potential is therapeutically active, is hybridized with the thiol-func-
of using the in vivo pathological triggers in controlled drug tionalized ssDNA by Watson–Crick base-pairing method to
release, such a kind of release properties is still executed in a form a dsDNA. The dehybridization process of this dsDNA
passive manner. In addition, the control over the dose, timing to release the therapeutic ssDNA requires much less energy
and duration of the drug release by using this method are than cleaving of AuS bond, thus less intense NIR light can
also facing great challenges. In contrast, the remote triggers be utilized to release the therapeutic DNA molecules.[37]
mediated drug delivery devices could enable the patient or For example, Halas and co-workers recently demon-
physician to control the timing and dose of drug release to strated light-induced release of ssDNA from SiO2@Au based
precisely match the physiological needs over a proper period core–shell complex (Figure 1).[37a,38] In this configuration, the
and within specific sites. Such remotely controlled devices Au nanoshells (NS) with plasmon resonance wavelength at
could increase patient compliance, maximize therapeutic 800 nm were coated with dsDNA, where one strand of the
effectiveness and minimize the side effects.[35] Most impor- dsDNA possessed a terminal thiol moiety that was used for
tantly, these manually introduced remote stimuli are facile to attachment to the NS surface. This thiolated sense sequences
access, easy to manipulate and less side effects. Moreover, this was further employed as a host molecule to hybridize the com-
approach is also superior in pulsatile or self-regulated drug plementary DNA cargo sequence. Upon laser illumination,
release which requires the repeat administration and higher
degree of control on the drug release behavior.[5f] Whilst the
fundamental understanding and the functions of the remote
triggers in DDSs are well understood, there are still practical
points and concerns that need to be addressed. The concerns
and strategies to overcome the limitations of remote stimuli
controlled DDSs will be discussed in Section 6.
4. Structures of Hybrid Nanovehicles

In the process of designing hybrid nanovehicles for remote
drug release applications, one should take into account dif- Figure 1. Schematic of light-controlled release of ssDNA from SiO2@Au
based NSs. Green sequences are the thiolated sense sequences bound
ferent features of the nanocomponents and how to incor-
to the Au NS surface; red sequences are the antisense sequences,
porate these features into a working device by creatively released when NSs are illuminated with NIR light at their plasmon
forming functional connections among them. Furthermore, resonant frequency. Adapted with permission.[37a] Copyright 2011,
one should also consider how the drugs can be effectively American Chemical Society.
DOI: 10.1002/smll.201601129
the antisense sequences sequence was released by dehy- mechanisms are not mutually exclusive and can be controlled
bridization, whereas the thiolated sense sequences remained by adjusting laser power and ionic strength. For example, the
bounded to the Au surface. The coverage of dsDNA on Au release results showed that it favors denaturation over AuS
NS surfaces was quantified and shown to correspond closely cleavage mechanism to an extent of more than six-to-one
to packing densities obtainable on planar Au films. By quan- when the decorated particles were irradiated in 200 × 10−3 m
tifying the surface coverage of dsDNA, the percentage of NaOAc with a pulsed 532 nm laser. The use of a pulsed laser
ssDNA released for the thermal and the light-induced release could facilitate the release process occurred within minutes
process were approximately 90% and 50%, respectively. The and both the antisense and the sense strands are not chemi-
dramatic differences between thermal and light-induced cally modified during photo-triggered release.[39]
processes on plasmon-resonant nanoparticle surfaces in this In addition to spherical GNPs, gold nanorods also
study not only provides a promising potential for light-con- exhibit strong absorption bands in the near-infrared region,
trolled gene release for gene therapy, it also provides a new in which the absorbed light energy is converted into heat by
and exciting context in understanding of light-actuating nan- gold nanorods. Hence, the on-demand thermal conversion
oparticle complexes.[38] behavior of gold nanorods could be used as controllers of a
In order to further improve the photo-triggered release drug-release system which is responsive to the near-infrared
efficiency of ssDNA from dsDNA–GNP conjugates, Branda light irradiation. To this end, Niidome and co-workers
and co-workers examined the conjugates’ response to pulsed recently formulated gold nanorods with dsDNA attached
irradiation under varying conditions. It is important to dif- on the nanorods surface. It showed that when the dsDNA-
ferentiate that the effects of laser power and salt content on modified gold nanorods were irradiated by near-infrared
the amount of ssDNA released through a denaturation pro- light, the photothermal effect could cause the release of
cess instead of AuS bond cleavage. The extent of release the ssDNA from gold nanorods. Depends on the power and
attributed to both processes were quantified and compared exposure time of light irradiation, the amount of released
by preparing the two different dsDNA–nanoparticle con- ssDNA were varied. In addition, the controlled release
jugates shown in Figure 2. The first conjugate is comprised of ssDNA from the nanorods was also demonstrated in
of a fluorescently labeled antisense oligonucleotide hybrid- tumors in a mice model, indicating the unique optical char-
ized to a complementary, thiolated sense strand anchored acteristics gold nanorods in medicinal fields.[40] Lee et al.
to the nanoparticle surface by an AuS bond. However, the demonstrated a new remote control switch of gene interfer-
ssDNA attached to the nanoparticle contains the lumines- ence in living cells by using NIR-absorbing gold nanoplas-
cent tag, and its antisense complement is unlabeled in the monic particles as switches (Figure 3).[41] In this study, the
second conjugate. The authors demonstrated that these two optical switches are functionalized with double-stranded
oligonucleotides. At desired times and
at specific intracellular locations, remote
optical excitation is used to liberate
gene-interfering oligonucleotides. Using
this designed system, it is possible to gain
more control and flexibility in genetics,
systems biology, and molecular cell
biology-related studies. For instance, the
gene interference can be programmed at
a desired phase of a cell cycle or a cer-
tain moment after external growth factor
stimulation, making it possible to study
dynamic changes in translational events
and gene expression. Furthermore, with
the fine-tuned optical switches to a wave-
length where cellular photodamage was
minimized, this novel gene-interfering
technique could offer spatial and tem-
poral control, which is otherwise impos-
sible using conventional gene-interfering
techniques.[41]
In addition to the conjugation of DNA
molecules onto GNPs via AuS bonding,
host–guest conjugated nanostructures can
Figure 2. Photothermal release of fluorescently labeled DNA from dsDNA–nanoparticle
also be formed by anchoring drug mol-
conjugates (1 and 2) attached to the surfaces of GNPs. Exposure to pulsed laser irradiation
with 532 nm light elicits release of genetic material by denaturation (paths A and B) or
ecules onto magnetic nanoparticles or
by Au–S bond cleavage (paths C and D), which can be distinguished from one another by gold particles by utilizing thermolabile
selectively labeling one strand within the dsDNA with a luminescent marker. Adapted with covalent bonds, for instance, azo-group
permission.[39] Copyright 2010, American Chemical Society. functionalization.[42]
DOI: 10.1002/smll.201601129
reviews
Figure 3. Concept of gene release by oligonucleotides on a nanoplasmonic carrier-based optical switch (ONCOS) system. a) Thiol-modified sense
oligonucleotides (shown in blue) are attached to GNPs. Antisense oligonucleotides (shown in red) are then hybridized to the sense oligonucleotides.
NIR illumination photothermally heats the gold carriers, causing the double-stranded oligonucleotides to denature at their melting temperature and
the antisense oligonucleotides to be released from the carriers. b) ONCOS-activated gene interference: conjugated GNPs are internalized within
cells. Step 1 illustrates transcription of DNA into mRNA. Step 2a illustrates NIR activation to photothermally heat GNP carriers and release antisense
oligonucleotides within the cells. Step 2b illustrates the binding of the antisense oligonucleotides to mRNA. Step 3 illustrates the digestion of the
heteroduplex mRNA by RNase H enzyme, thus silencing the gene of interest at the translational step. Protein translation is halted in Step 4. Since
old protein is continually degraded and no new protein is being synthesized, a decrease in the overall protein expression occurs. c) Concept of
spatially confining temperature gradient to the surface of the nanorod due to photothermal heating. Adapted with permission.[41] Copyright 2009,
American Chemical Society.
4.2. Hybrid Polymeric Micelle Nanostructures as polymeric micelles.[45] This method will be able to allow
the inorganic nanoparticles to be stable in aqueous solution
Polymer micelles are derived from inter-chain packing of and enhance their biocompatibility. By modifying and con-
macromolecules which are amphiphilic in nature.[10a,43] They trolling the assembly mechanism of amphiphilic copolymers
are widely used in biomedical applications because of their with hydrophobic moieties into micelle nanostructure, we
great drug loading capacity and high cellular uptake efficiency. will able to produce hybrid polymeric micelles consisting of
Their lower critical micellar concentration makes them highly polymer micelles encapsulating both the inorganic nanoparti-
stable in aqueous solution, while their low size disparity, cles and the chemotherapeutic payloads. As a result, stimuli-
hydrophilic corona, and nanolevel size allows them to avoid responsive hybrid polymeric micelles nanovehicles for DDS
rapid elimination by renal clearance and MPS process.[10a,b,44] applications can be obtained.
Furthermore, they possess the tendency to gather at tumorous However, such hybrid nanovehicle system may suffer
regions due to the EPR effect. Hydrophobic drug molecules from some drawbacks due to the dynamic nature of the poly-
such as chemotherapeutics can be loaded at the hydrophobic meric micelles. These polymer micelles are not cross-linked
region at the micelles core. Polymeric micelles can be func- to each other and hence may experience sudden dissociation
tionalized with stimuli-responsive blocks and hybridized with and consequently, premature release of the chemotherapeutic
inorganic molecules such as plasmonic or magnetic nanoparti- payloads.[46] Furthermore, upon release to the human body,
cles. This hybrid system would be able to be responsive to and the polymer micelles may experience dilution which causes
remotely triggered by various external stimuli, for instance, them to be unstable and prone to sudden dissociation and
pH or temperature change, light, redox agents, etc.[10a,11,43a,d] premature drug release. In order to mitigate this problem,
One of the advantages of hybrid polymeric micelles is reversible or non-reversible crosslinks can be introduced to
that the biocompatibility of the inorganic component can stabilize the micelles system in human body.
be improved by masking them with the polymeric micelles. One of the examples of such hybrid nanovehicles is pre-
Inorganic nanoparticles usually need to be stabilized with sented in the paper written by Liu and co-workers.[47] They
surfactants which are often toxic in nature. As such, surface used PEO–PPO–PEO as the amphiphilic surfactant, Fe salts
modification of the inorganic nanoparticles is necessary. One as the inorganic component, and 4-Nitrophenyl chlorofor-
way to do this is by masking them with other biocompat- mate, gelatin and 1-ethyl-3-(3-dimethylaminopropyl) carbo-
ible surfactants or encapsulating them in other vehicles such diimide as the cross-linkers. PEO–PPO–PEO amphiphilic
DOI: 10.1002/smll.201601129
Figure 4. Schematic illustration showing the design of highly tunable PLA stereocomplex coated hybrid micelles and drug delivery to cells. Adapted
with permission.[10b] Copyright 2016, American Chemical Society.
copolymer can form oil-in-water micelles readily with PPO stabilization in aqueous solution.[43b] Recently, our group
as the core and PEO as the corona. Fe salts were intro- reported the fabrication of highly tunable hybrid micelles
duced into the internal water phase of the micelles system via a facile layer-by-layer (LbL) stereocomplex self-assembly
and precipitated into magnetic nanoparticles by alkaline of PLLA and PDLA using silica-coated magnetite (Fe3O4@
hydrolysis method. Due to the presence of the cross-linkers, SiO2) as template (Figure 4). The obtained hybrid NPs with
the resulting hybrid nanovehicles system was highly stable. PLA stereocomplex coatings (Fe3O4@SiO2@SC) was fur-
The micelles system experiences a transition from hydro- ther incorporated with various hydrophilic components in
philic to hydrophobic nature at about 40 °C, which causes the micelle corona by coating different stimuli-responsive
the micelles cores to contract and shrink. The magnetic amphiphilic polymers such as PDLA–PDMAEMA (pH-
nanoparticles allow the nanovehicles system to be able to be responsive) and PDLA–PNIPAAm (temperature-respon-
triggered by AMF application. Magnetic hyperthermia can sive) copolymers.[10b] The superparamagnetic property of
induce coarsening of magnetic nanoparticles encapsulated Fe3O4 in the hybrid micelle core was maintained during the
inside the micelles system as well as core–shell disruption, PLA SC coating process. Through this approach, the hybrid
which can lead to the rupture of the spherical nanovehicles micelles exhibited a well-defined core–shell structure with
and burst release of the contained drug payloads. Yin et al. a mean size of 220–270 nm and possessed high magnetiza-
reported a method for the synthesis of hybrid particles, by tion of 70.8–72.1 emu g−1 [Fe3O4]. The effect of different
chemically conjugating the corona of mixed shell polymeric stimuli on the responsiveness of the hybrid micelles for drug
micelles with GNPs.[48] Poly(ε-caprolactone) (PCL) is a bio- delivery was further investigated using DOX as model drug.
degradable and biocompatible member in polyester family It showed that drug release rates were controlled by pH and
that have been widely employed as biomaterials.[43b–d,49] temperature for Fe3O4@SiO2@SC-D and Fe3O4@SiO2@SC-N
PCL-b-(ethylene glycol) (PCL-b-PEG) and PCL-b-poly(N- hybrid micelles, respectively. This result indicates the func-
isopropylacrylamide) (PCL-b-PNIPAM) were co-assembled tionalization of inorganic Fe3O4@SiO2 particles using PLA
to result in a composite polymer with a PCL core and a stereocomplex coatings was successful. The in vitro viability
mixed shell consisting of PEG and PNIPAM. In situ forma- assay using MCF-7 breast cancer cells also showed that
tion of GNPs was obtained by linking to the thiol groups DOX-loaded micelles possessed higher delivery efficiency.
anchored at the end of PNIPAM chains. Reversible size Considering the good biocompatibility and strong magnetic
changes in the PNIPAM chains triggered by changes in sensitivity, the developed hybrid micelles demonstrated a
temperature can be used to tune the inter-particle distance great potential of control over the drug release at a targeted
of the GNPs. These hybrid polymeric micelles were shown site.[10b]
to have thermoresponsive SPR and very colloidal stability,
which are good characteristics for further exploration of
the system as remotely controlled drug delivery carriers. 4.3. Hybrid Polymeric Nanogels
Neoh and co-workers reported the synthesis of a well-con-
trolled poly(l-lactic acid)-block-poly(poly(ethylene glycol) Nanogels possess great potential in biomedical applications
monomethacrylate) (PLLA-b-PPEGMA) amphiphilic owing to their ability to retain a great amount of fluids when
block copolymer and fabricated them into hybrid micelles they are swollen. They are usually made of hydrophilic and
presence of hydrophobic Fe3O4 NPs.[50] With the presence functional polymers which are crosslinked either physically
of folic acid (FA), the functionalized hybrid micelles were or chemically to form a gel network. Besides its great fluid
rapidly internalized by MCF-7 cancer cells, indicating the retaining ability, nanogels can also be designed to exhibit
potential of using such hybrid micelles in cancer targeting. physiochemical changes upon exposure to stimuli such as
Since PLLA-b-PPEGMA copolymers can be further deco- pH or temperature change. This feature is useful in remotely
rated with other targeting ligands and bioactive molecules, triggered DDS applications, and thus many efforts have been
the as developed hybrid micelles can serve as an effec- put to design hybrid nanovehicles which incorporate poly-
tive carrier for targeted drug delivery to different types of meric nanogels and inorganic nanoparticles such as gold or
cancer.[50] maghemite. One of the methods to synthesize such hybrid
The stereocomplex interaction between PLLA and nanovehicles would be via surface-initiated polymerization
PDLA is also known as a convenient approach for micelle (SIP). It is a “grafting from” strategy which allows effective
DOI: 10.1002/smll.201601129
reviews
immobilization of polymer chains onto inorganic matrix (PVOH-b-PNVCL) copolymers hybridized with maghemite
with one end anchored onto the matrix surface. This method nanoparticles. PVOH-b-PNVCL is thermoresponsive and
allows for greater grafting density as compared to “grafting able to form micelles capable of self-assembly beyond the
to” strategy.[51] Polymeric nanogels can be made of irrevers- lower critical solution temperature (LCST) in aqueous solu-
ibly or reversibly crosslinked polymers. One example of irre- tion. The maghemite nanoparticles are first functionalized
versibly crosslinked hybrid nanogels would be copolymers with boronic acid and then used to form reversible crosslinks
of NIPAM, acrylamide (AAm), and fluorescent carbon dots. with PVOH through boronate-diols bonding. Drug molecules
The copolymers are integrated inside a porous shell made that are hydrophobic in nature can then be loaded in the
of carbon, with iron oxide nanocrystals assembled at the PNVCL domains. The resulting nanogels are thermorespon-
core. This nanogels system can exhibit reversible swelling sive, pH-responsive, as well as glucose-responsive, and the
and shrinking upon temperature change, which results in presence of maghemite nanoparticles renders the nanogels
the change in the physicochemical environment around the capable of being remotely triggered by AMF.[54] Chiang et
NSs and the pore size of the nanogels.[52] This feature can be al. prepared hollow hybrid nanogels by coassembling citric
exploited to achieve a controlled drug release with stimuli acid-coated superparamagnetic iron oxide nanoparticles
such as AMF to induce temperature change onto the hybrid (SPIONs) with the graft copolymer of poly(acrylic acid)
nanogels. However, the degree of control is limited due to and poly(2-methacryloylethyl acrylate) units as the back-
the presence of irreversible crosslinks which hold the nano- bone and poly (ethylene glycol) and PNIPAM as the grafts
gels network intact. Reversibly crosslinked nanogels allow (Figure 5).[55] The resultant hollow nanogels maintained their
for higher degree of control of the drug release behaviors. structural integrity as the pH was changed. The superpara-
One example would be nanogels made of Au–Ag nanorods magnetic particles were confined within the pH responsive
system hybridized with DNA crosslinked polymer shells thin gel layer and this remarkably enhances the transverse
which can be made from polyacrylamide and designed to relaxivity and renders the MR imaging highly pH adjustable.
contain anticancer drugs. The nanorods can be designed to pH and temperature responsive drug release was also dem-
be able to target tumor cells by functionalizing it with tar- onstrated. This work shows that the hollow inorganic/organic
geting moieties of aptamers (Aps). This nanogels system hybrid nanogels could potentially be used as a multimodal
can be triggered to unload the contained drugs upon expo- theranostic vehicle functionalized to endow guidable delivery
sure to NIR light which produce photothermia effect that of stimuli mediated diagnostic imaging and hyperthermia/
results in a rapid de-crosslinking of the nanogels system.[53] chemotherapies.
Another example would be reversibly crosslinked nanogels Guarrotxena and Quijada-Garrido reported a versa-
made of poly(vinyl alcohol)-b-poly(N-vinylcaprolactam) tile method to produce monodisperse hybrid nanogels by
Figure 5. a) Concentration-dependent relaxation rate (1/T2) of the citric acid-coated SPIONs and magnetic hybrid nanogels at different pH values.
b) T2-weighted MR images of the hybrid nanogels at 37 °C and various pH values. c) T2-weighted MR images of HeLa cells incubated with hybrid
nanogels at different concentrations for 1 h. Adapted with permission.[55] Copyright 2013, American Chemical Society.
DOI: 10.1002/smll.201601129
Le Guevel and co-workers demonstrated the fabrica-

tion of monodisperse and stable nanogels using cationic
polymer-mediated gold nanocluster (Au NCs) self-assembly
(Figure 7).[57] The designed hybrid nanogel system showed
enhanced cellular drug delivery and efficient fluorescence
detection. The size of the obtained nanogels was 100–150 nm
with positive surface charge. The swelling and shrinking
properties of the nanogels were responsible to pH change of
Figure 6. Schematic depiction of the buildup of Au@P(MEO2MA) core–
the solution. Interestingly, the cross-linking process led to a
shell hybrid nanogels: i) ligand exchange of the citrate by P(MEO2MA- fourfold fluorescence enhancement of the encapsulated Au
co-AcSEMA) copolymer and ii) crosslinking polymerization of MEO2MA NCs compared to free Au NCs. The versatility of polymer
around the Au@P(MEO2MA-co-AcSEMA) copolymer coated AuNP. mediated hybrid nanogel approach was demonstrated by dif-
Adapted with permission.[56] Copyright 2016, American Chemical ferent cationic polyelectrolytes, including poly(allyl amine
Society. hydrochloride) (PAH) and polyethylenimine (PEI). In vitro
cell culture was carried out using human monocytic cell
embedding single plasmonic Au NPs into thermoresponsive model. The results indicated strongly enhanced uptake of the
and biocompatible polymer shells (Figure 6).[56] During the nanogels compared to free Au NCs in endocytic compart-
fabrication process, the Au NPs was first encapsulated with ments. The enhanced drug delivery was also demonstrated
2-(2-methoxyethoxy)ethyl methacrylate) (MEO2MA) based by loading peptides or antibodies in the nanogels during
polymer bearing thioacetate groups and subsequently gel- the cell culture. The results obtained from the fluorescence
wrapped by poly(MEO2MA) in the presence of cross-linker. microscopy and flow cytometry showed a strongly enhanced
The shell thickness in the range of 3–5 nm and size in the biomolecule uptake of 1.7-fold for peptides and 6.5-fold
range of 20–100 nm were controlled by varying the amounts for antibodies, respectively, with a clear colocalization of
and sequence of sodium dodecyl sulfate (SDS) added into the nanogel carrier and the biomolecules. This novel hybrid
the system. The obtained hybrid nanogels showed size change nanogel strategy provides new insights to design new DDS
at the temperature induced volume phase transition (VPTT) for improved theranostic applications.[57]
of the polymer shell and a red shift of the localized surface
plasmon resonance (LSPR) maximum with increasing tem-
perature. This approach paves the way to rational design and 4.4. Inorganic–Organic Core–Corona Nanostructures
modulation of the optical and swelling properties of ther-
moresponsive Au@P(MEO2MA) core–shell hybrid nanogels For this structure, organic macromolecules are immobi-
in order to adapt them to advanced biotechnological applica- lized onto inorganic nanoparticles surface both covalently
tions such as smart delivery systems of active molecules and (via the “grafting from” or “grafting to” techniques) and
disease therapy, diagnosis, and prognosis. non-covalently (via the “grafting to” technique).[11] For the
Figure 7. Scheme of the synthesis of self-assembled hybrid nanogels using a cationic polymer (PAH) as a cross-linking agent and Au NCs stabilized
by GSH. The designed hybrid nanogel system showed enhanced cellular drug delivery and efficient fluorescence detection in cell culture. Adapted
with permission.[57] Copyright 2016, American Chemical Society.
DOI: 10.1002/smll.201601129
reviews
non-covalent method, the immobilization method involves the drug release was performed at 25 °C or 37 °C. The outer
intermolecular interactions like van der Waals’ forces or shell of block copolymer renders the modified magnetic
dipole–dipole attraction forces. Stimuli-responsive macro nanoparticles water solubility and thermosensitivity, resulting
molecules can be prepared via controlled radical poly in thermosensitive drug release behavior which could be
merization (CRP) techniques such as atom transfer radical remotely triggered by external AMF. With a similar strategy,
polymerization (ATRP) and reverse addition fragmentation Kohane and co-workers grafted thermoresponsive PNIPAM
transfer (RAFT) polymerization. These stimuli-responsive copolymer unto ligand peptide decorated silica core–gold
macromolecules will then be utilized to create a functional shell nanoparticles.[59] They demonstrated a targeting mech-
polymeric corona around the inorganic cores. Subsequently, anism by using the thermoresponsive copolymer to mask a
drug molecules can be loaded and anchored within the peptide ligand that binds a widely distributed receptor (inte-
corona, causing them to have the ability to be released on grin β1) on the surface of silica core–gold shell nanoparticles.
remote trigger. One such example would be poly(acrylic These hybrid core–corona nanoparticles convert NIR into
acid)-b-poly(vinyl alcohol) (PAA-b-PVOH) conjugated to heat, causing the PNIPAM to collapse thus to expose the
the surface of maghemite nanoparticles by electrostatic inter- ligand peptides for cell binding, making remote triggering
action. This composite nanostructure is responsive to pH possible. Furthermore, it also exploited the photothermal
change, ionic interaction strength, and AMF, thus allowing properties of the plasmonic gold NS to control the binding
for multiple release triggers. Cationic drug molecules can be of nanoparticles to cells. By engineering gold NS with a poly-
easily anchored on the negatively charged PAA segments at l-lysine (PLL) epilayer, Halas and co-workers demonstrated
pH 7, while PVOH improves the colloidal stability of magh- such core–corona nanostructures (NS–PLL) can be used to
emite cores in aqueous medium. It also allows the nanostruc- capture intact single stranded antisense DNA oligonucleo-
ture to escape the MPS clearance. tides or siRNA molecules, and controlled release of the cap-
In an earlier report, He and co-workers modified Fe3O4 tured species can be achieved by CW NIR laser irradiation
superparamagnetic nanoparticles with a dendritic-linear at 800 nm.[60]
triblock copolymer, and demonstrate their drug release Yu et al. reported a method to prepare a multistimuli-
properties.[58] Initially, oleic acid/oleylamine capped Fe3O4 controlled drug carrier by coating bovine serum albumin
superparamagnetic nanoparticles were prepared, and then (BSA) on Fe5C2 nanoparticles.[61] As illustrated in Figure 8,
PAMAM-type dedron (propargyl-D2.0) was introduced to carbon coated iron carbide nanoparticles serve as magnetic
replace oleic acid/oleylamine on the surface of magnetic resonance imaging and light absorbing agents, DOX as anti-
nanoparticles. Following by a two-step copper-mediated cancer drug was loaded through electrostatic interaction unto
ATRP, PDMAEMA and PNIPAM were grown unto the the surface of Fe5C2 nanoparticles, coating with BSA make
nanoparticles surfaces to form core–corona structure. The these hybrid nanocarriers water-dispersible and biocompat-
characteristic superparamagnetic behavior of these mag- ible. When exposed to NIR irradiation (808 nm, 0.8 W cm−2),
netic nanoparticles was confirmed by magnetization meas- Fe5C2 in the core absorbed the light and convert it into heat
urements. In addition, they used doxorubicin (DOX) as an to trigger the release of DOX to kill the cancer cells. Further-
anticancer drug model, which was then introduced into the more, these hybrid nanocarriers are also responsive the pH
dendritic copolymer shell of the modified nanoparticles, and and magnetic field, by lowering the pH value, the release of
Figure 8. Schematic illustration of multistimuli-regulated photochemothermal cancer therapy remotely controlled via BSA-functionalized Fe5C2
nanoparticles. Adapted with permission.[62] Copyright 2016, American Chemical Society.
DOI: 10.1002/smll.201601129
Figure 9. Schematic illustration of the process for preparing NaYF4:Yb,Tm UCN-Ce6 for photodynamic cancer therapy. Adapted with permission.[67]
Copyright 2015, DOVE Medical Press.
the drugs can be enhanced; guided by a magnetic field, the MCF-7 cancer cells using the established colorimetric MTT
drug delivery from these nanocarriers can be targeted. Both assay for quantification; as a result, such hybrid nanoparticles
in vitro and in vivo investigations confirmed the therapeutic were proved to be biocompatible. As illustrated in Figure 9,
effect comes from synergistic contribution of photothermal UCNs converted absorbed 980 nm laser light into UV light,
effect and released anticancer drug. Such drug delivery plat- activating the attached Ce6 to produce reactive oxygen spe-
form is thus proved to be promising drug carrier to be con- cies (ROS) to kill the cancer cells. Such ROS were further
trolled by multiple stimuli for effective cancer therapy. proved to be mainly singlet O2. By adjusting the laser power
Upconverting nanocrystals (UCNs) responsive to NIR and UCN-Ce6 dosage, the PDT efficacy of these hybrid
light are also promising for remote triggered applications.[63] nanovehicles can be further fine-tuned.
With their intrinsic nature, UCNs absorb multiple photons
of NIR light and convert them into light with higher energy
(visible or UV light).[64] As mentioned, NIR light offers 4.5. Hybrid Liposomal Nanostructures
deeper tissue penetration than UV light or visible light,
making UCNs useful for in vivo applications. Zhang and co- Liposomes are structures which are made of one continuous
workers explored the applications of UCNs as remote trigger bilayer of phospholipids that separates the inner aqueous
to activate biomolecules in deep tissue.[65] As is reported medium from the outer environment. Phospholipids are moi-
in this work, gene was caged the silica shell on UCNs. With eties which possess a nonpolar tail (hydrophobic in nature),
such design, the embedded DNA/siRNA molecules were and a polar head (hydrophilic in nature), causing them to
protected against enzymatic environment in vivo, minimizing be amphiphilic in nature. These phospholipids are able to
any unnecessary loss of the loaded biomolecules. Using spontaneously exhibit self-assembly in aqueous solution
980 nm laser as the external trigger, they successfully dem- to form liposomes. Liposomes can be used to encapsulate ther-
onstrated the activation and knockdown of green fluores- apeutic payloads and release them upon suitable trigger. One
cent protein (GFP) in tissue phantoms and in vivo in mice. can control the dimensions and properties of liposomes by
With such hybrid nanovehicles, the embedded gene can be changing the concentration of phospholipids, pH, and tem-
released by NIR light as remote trigger. Another promising perature, as well as modifying the nature and tail length of
application of UCNs is photodynamic therapy (PDT), using the phospholipids.[68] For example, the lipids can be modi-
the emitted UV light converted from the absorbed NIR light fied to possess a hydrophilic head made of PEG. When
to activate the attached photosensitizers (PSs).[66] By con- these lipids self-assemble, the resulting liposomes structure
jugating Chlorin e6 (Ce6) onto the amino-modified UCNs, (named as “stealth liposomes”) is endowed with length-
our group recently demonstrated the fabrication of UCN@ ened circulation period and a tendency to accumulate in
SiO2@Ce6 core–shell nanoparticles.[67] In this work, cell via- tumorous regions via the EPR effect.[69] As the inner part of
bility was tested with human breast adenocarcinoma cell line the liposomes is made up of aqueous medium, liposomes are
DOI: 10.1002/smll.201601129
reviews
usually used to encapsulate drugs which are hydrophilic in

nature. These drugs are normally “inserted” into liposomes
via passive entrapment during the formation process of
liposomes. Moreover, liposomes can also encapsulate weakly
alkaline amphiphilic drugs which have been modified to
create insoluble complexes with the aid of transmembrane
gradients or trapping agents.
The use of liposomes in triggered release DDS applica-
tions is evident in the development of TSLs.[70] TSLs are able
to release the encapsulated payloads when they are heated
to a temperature close to their melting point. At this tem-
perature, the phospholipid membrane exhibits a phase tran-
sition from gel to liquid crystalline phase. One example of
TSL is dipalmitoyl glycerophosphocholine (DPPC). DPPC
is able to encapsulate chemotherapeutic drugs and prevent
the release of the payloads into healthy tissue at body tem- Figure 11. Illustration of on-command drug release from the hybrid
perature. Only when it is heated to a temperature around its liposome caused using RF field as trigger. Adapted with permission.[72]
melting point, the encapsulated drugs can then be released Copyright 2012, American Chemical Society.
into the surrounding tissues. Conventional heating process
can be used for such purpose. However, the release behavior and that we should consider both IC50 and apoptotic DNA
under conventional hyperthermia is inconsistent and uncon- rates for clinical application.
trollable due to difficulty in producing and maintaining There are some methods that can be used to miti-
focused and highly precise hyperthermia at specific loca- gate this problem. For example, one could use ultrasound
tions. Another report showed that a good correlation exists to induce hyperthermia and/or physical force onto the
between membrane fluidity of hybrid liposomes and the IC50 liposomes, resulting in higher degree of control in the
for the growth of human colon tumor cells was observed for release behavior.[22] Recently, Peiris et al. developed a hybrid
the first time (Figure 10).[71] In addition, it was shown that liposomes based on multicomponent nanochains to integrate
hybrid liposomes induced apoptosis for human colon tumor the advantages of the molecular and nanoparticle mode of
cells through the activation of caspases. It is also worthy to chemotherapeutics into a single agent. The designed system
note that hybrid liposomes distinguished between human is composed of three magnetic nanospheres and one DOX-
colon tumor cells and normal colon cells, and then fused and loaded liposome with a diameter of 100 nm. The magnetic
accumulated into human colon tumor cells after the treat- particles of the chains were used as a mechanical transducer
ment with hybrid liposomes. Thus, this study demonstrated to transfer radio frequency energy to the drug-loaded lipo-
that growth inhibition and apoptosis for tumor cells by hybrid some membrane (Figure 11). Therefore, when the drug
liposomes provides the possibility of therapy from a view- loaded hybrid liposomes were extravasated to the tumor site,
point of biophysical characteristics of tumor cell membranes RF-induced defects on the liposomal walls liberates drug
molecules into their free form that can efficiently diffuse into
the entire tumor, resulting in a widespread anticancer effect.
Taking under consideration that RF can penetrate deep into
tissues, the authors envisioned that this platform technology
could effectively deliver drugs to primary and metastatic
tumors with all the benefits of reduced side effects and sub-
stantial impact on cancer treatment.[72]
Another method would be by encapsulating inorganic
nanoparticles that can induce hyperthermia upon external
stimuli—GNPs under NIR light or maghemite under AMF
application—inside the liposomes. As such, more specific and
focused hyperthermia can be induced onto the liposomes.
Leung and Romanowski demonstrated that gold-coated
liposomes were able to encapsulate and release of signaling
molecules in an on-demand fashion with a spatial and tem-
poral resolution, leading to activation of individual cells
(Figure 12).[73] During the cell culture, a cell model was
designed to overexpress a certain G-protein coupled receptor
and the CCK2 receptor, and its activation in a single cell was
achieved via the localized ligand release using a model of
Figure 10. Schematic representation of hybrid liposomes and molecules the general process of agonist-mediated receptor activation.
used to assemble the hybrid liposomes. Adapted with permission.[71] When the hybrid liposomes were illuminated at wavelengths
Copyright 2006, Elsevier. corresponding to the plasmon resonance of the gold coating,
DOI: 10.1002/smll.201601129
Figure 12. Schematic drawing of light-induced release from gold-coated hybrid liposomes. Adapted with permission.[73] Copyright 2012, American
Chemical Society.
the content release was triggered. As a demonstration, CCK8 can be employed to modify the liposomes to possess abili-
from gold-coated liposomes was released to activate a single ties to target specific sites, and even imaging capabilities.
selected HEK293/CCK2R cell growing in vitro upon appli- However, the great and promising potential to apply various
cation of a light stimulus. In combination with the spectral modifications to improve the functionality of the liposomes
tunability of plasmon resonant coating, this technology may nanostructures are also associated with higher cost and dif-
allow for multiplexed interrogation of complex and diverse ficulty in their production and quality control processes.
signaling pathways in model or living tissues with unprec-
edented spatial and temporal control.[73] The same research
group also demonstrated focal activation of signaling cas- 4.6. Hybrid Mesoporous Core–Shell Nanostructures
cades by similar gold-coated hybrid liposomes.[74] Based on Silica
Amstad et al. reported magnetic NPs loaded PEGylated
hybrid liposomes that can were used to trigger cargo release Mesoporous silica nanoparticles (MSNs) possess several
by high frequency AMF.[75] In their study, the individually properties which render them ideal molecules to host guest
stabilized iron oxide NPs were hosted in the well-defined moieties.[5b,77] Some of the properties are large surface area
assembled membranes of the liposomes. As a result, these and pore volumes, homogeneous pore distribution, stable
hybrid liposomes were colloidally stable and impermeable at mesoporous nanostructure, regular and modifiable pore sizes,
body temperature. Stable incorporation of NPs into liposome and high drug loading capacity.[5a,78] Furthermore, MSNs have
membranes enabled to use AMF to control timing and dose good hemocompatibility, rendering it suitable and potent for
of repeatedly released cargo by locally heating the membrane. intravenous administration. Nevertheless, guest molecules
The release efficiency was high without increasing the bulk usually can only form weak interactions with the inner
temperature. These properties were shown to relate directly mesoporous cavities, causing frequent premature release of
to the structure and stability of the NP–lipid assemblies. This the payloads. One way to mitigate this problem is to modify
novel delivery system thus creates the possibility to assemble the mesoporous structures by incorporating some sort of
and track versatile and efficient drug delivery vehicles and gating components which can be switched on or off to open
nanoreactors, which can locally release thermally sensitive
cargo with AMF without risking bursts, cargo deactivation
during release or heat induced damage to the environment.
Recently, Corato et al. developed a new liposome formula-
tion combining both magnetic nanoparticles and a PS within
the same nanoplatform, with a view to allow a dual photo-
dynamic and magnetothermal therapy (Figure 13).[76] A high
concentration of magnetic nanoparticles a PS m-THPC were
introduced into the liposome core and lipid bilayer, respec-
tively, through a one-pot synthesis method. The in vitro anti-
tumoral efficacy of the hybrid liposomes showed that each
treatment alone produced similar rates of tumor cell death,
while combined treatments led to complete cell destruction.
In vivo tumor growth in a mouse model was also monitored
after each treatment. The results revealed that Each single
treatment slightly inhibited tumor growth, while their com-
Figure 13. Ultramagnetic photosensitive liposomes with two payloads
bination led to a complete tumor regression, reflecting the
in different localization. Magnetic nanoparticles are confined in the
synergistic potential of the combination of PDT and mag- core, whereas the photosensitizing drug is intercalated in the lipid layer.
netic hyperthermia. This spectacular efficacy of combined Synergistic effect in cancer therapy was achieved by the combination of
magnetic therapy and phototherapy endorses the use of PDT and magnetic hyperthermia. Adapted with permission.[76] Copyright
multiple approaches to cancer therapy.[76] Further approach 2015, American Chemical Society.
DOI: 10.1002/smll.201601129
reviews
or close the cavities. This way, one would have greater degree remote trigger by using the external stimulus of AMF. By
of control on the drug release behavior from the mesoporous coating the iron oxide core with gold, Yeh and co-workers
structures. Some examples of such modifications involve the were able impart the ability of NIR-response in addition to
use of supramolecular assemblies, phase change materials, magnetic field response.[81] They successfully demonstrated
and nanoparticles as the gating components. The resulting the remote triggered drug release of DNA-gated Fe3O4@
system would be able to be triggered using chemical stimuli Au@mSiO2 facilitated by magnetic field accompanied by
such as enzymes, glucose, or reductive agents. However, these NIR irradiation.
trigger methods lack precision in terms of time and space due Another example of such system is hybrid MSN nano
to the nature of the stimuli. In order to improve the spatial vehicles fabricated with maghemite as the core and
and temporal precision of the trigger mechanism, remote mesoporous silica as the shell (γ-Fe2O3@MSNs).[82] This
stimuli such as NIR light, AMF, and ultrasound, can be uti- core–shell nanostructure utilizes phase change molecules
lized. To allow the mesoporous structures to be responsive to (PCMS) such as dodecanoic acid (DA) and 1-tetradecanol
these physical stimuli, incorporation of inorganic nanoparti- (TD) as the gating components. When the surrounding tem-
cles such as GNPs, maghemite and graphitic carbon into the perature is above the melting points of the gating compo-
MSNs system would be necessary.[5c] With the mesopores nents, the encapsulated drug molecules are able to diffuse
gated with stimuli-responsive inorganic nanoparticles, drug out of the mesoporous structure. Therefore, in order to keep
release behavior can be controlled in a more precise fashion. the drug molecules well encapsulated inside the structure,
One example of such system would be iron oxide-loaded the gating components chosen must possess a melting tem-
hollow MSNs.[79] These MSNs were prepared by using perature which is higher than human body temperature.
polymer nanospheres as templates, because of the intrinsic By using maghemite nanoparticles as the core, the temper-
nature of the mesoporous shell, these MSNs exhibit high ature-induced release can then be remotely triggered by
drug loading capacity, rendering them suitable for sustained using AMF application. Xie et al. modified DOX-loaded
drug release. And the encapsulated magnetic IONPs can MSNs with Ap against the epithelial cell adhesion molecule
serve as AMF responsive agents, functioning with two roles (EpCAM) for targeted delivery of DOX to colon cancer
(1) magnetic iron oxide responds to AMF to create hyper- cells (Figure 14).[83] Results showed that EpCAM conju-
thermia which can be used for therapy and (2) the heat from gation increased binding of Ap-MSN-DOX to EpCAM
iron oxide will promote the release of payload from the over-expressing SW620 colon cancer cells but not EpCAM-
mesoporous shell to the surrounding media. By decorating negative Ramos cells, resulting in enhanced cellular uptake
the surface of such MSNs with a thermoresponsive copol- and increased cytotoxicity of the DOX in SW620 cells when
ymer of poly(ethyleneimine)-b-poly(N-isopropylacrylamide), compared to nonAp-modified nanoparticles (MSN-DOX).
Baeza et al. demonstrated that on one hand the thermore- It was also found that Ap-MSN-DOX exhibited significant
sponsive copolymer acts as temperature-responsive gate- inhibition effects on the expression of EpCAM on SW620
keeper for the drugs loaded into MSNs, and on the other cells. These results showed that Ap-MSN-DOX has the
hand the polymeric shell helps to retain proteins.[80] The potential for the targeted delivery of therapeutic agents into
ability of dual release from the MSNs and the polymer shell EpCAM positive colon cancer cells to improve therapeutic
with the synergetic effect of hyperthermia, was realized with index while reducing side effects.
Figure 14. Conceptual design and characterization of nanoparticles. A) Synthetic procedures of MSN-DOX and Ap-MSN-DOX. B) TEM image of MSN.
C) Particle size distribution of MSN. D) Particle size distribution of Ap-MSN. E) Polyacrylamide gel electrophoresis experiment to make sure the
conjugation of Ap to MSN. Adapted with permission.[83] Copyright 2016, Elsevier.
DOI: 10.1002/smll.201601129
4.7. Hybrid Hollow Nanostructures modifications will result in better drug retaining ability for the
gold nanocages structure.
Hollow nanostructures possess great potential in biomedical Besides gold nanocages, gold NSs also hold great poten-
applications due to their distinctive structure which consists tial in DDSs application. These NSs comprise of only a thin
of firm shells that protect the empty internal void spaces spherical gold shell acting as a casing for the empty inner
from the outer environment. This feature allows for highly space. They are made by using template technique which
efficient loading and delivery of drug molecules, and thus its utilizes a hard or soft mold to fabricate the inner void. Gold
potential in DDS applications has been largely studied. These NSs are usually utilized as a coating layer on other nano-
hollow nanostructures can be made of organic or inorganic structures in order to impart the capability of being trig-
molecules. One of the examples of those that are made of gered upon exposure of NIR light. For instance, gold NSs
organic molecules would be liposomes, which have been dis- can be used to coat over silica nanorattle.[87] This hybrid
cussed in Section 4.5. As for those that are made of inorganic hollow nanostructure possesses a hollow structure and mov-
molecules, some examples would include hollow silica NSs able cores (properties of silica nanorattle) as well as modifi-
and gold-based hollow nanostructures. able optical and surface properties (properties of gold NSs).
Hollow silica NSs have distinctive feature of a firm With surface functionalization to attach targeting moieties,
mesoporous shell and empty internal void space. These NSs this hybrid nanostructure would have a high efficiency to
have high surface area, low density, and very large cavity destroy tumor cells, thanks to its targeting ability, small size,
volume, rendering them favorable for drug loading and remotely triggered photothermia, and the chemotherapeutic
delivery applications. Hollow silica NSs are usually synthe- drug molecules loaded inside the nanostructure. Yu et al.
sized by dual-template technique. This technique utilizes a developed an electrostatic approach to absorb Ce6 with the
hard or soft mold template to create the internal void and low pH insertion peptide (pHLIP) onto the surface of hollow
a soft template to produce mesoporous shells.[84] These NSs gold nanospheres (HAuNS), forming HAuNS-pHLIP-Ce6, as
can also be modified in order to impart them with the feature illustrated in Figure 15.[88] Upon irradiation of 670 nm laser
of being able to be triggered by remote stimuli. Hybridiza- at power density of 2 W cm−2, within 5 min, the HAuNS-
tion processes with gold NSs, gold cores, or magnetic cores pHLIP-Ce6 experienced hyperthermia to result in photo-
have been explored in order to realize the potential of hollow thermal therapy (PTT) and release attached peptides and PS.
silica NSs as remotely triggered DDSs. One such example The persistence of NIR irradiation facilitated the successive
would be the hybrid hollow silica nanostructure prepared by PDT arising from ROS generated from Ce6. As a result, a
Zhang and co-workers.[85] The initial step of the fabrication synergistic PTT/PDT treatment can be induced simultane-
involved the solvation process of magnetic nanoparticles and ously by a single NIR laser, making the therapeutic process
hydrophobic drug molecules in oil drops. The solution was simple and remote controllable.
then stabilized by adding PEO–PPO–PEO (Pluronics) and Li and co-workers reported dual-functional HAuNS (≈40 nm
PVA, forming thermosensitive F68/PVA nanocomposites. diameter) capable of mediating both photothermal ablation of
Layers of super-thin mesoporous silica shell were then used cancer cells and NIR triggered drug release.[89] As is shown in
to coat the previously formed nanocomposites, resulting in Figure 16, with the large cavity of the HAuNS, effective surface
the formation of hollow silica nanostructure. Upon exposure area for DOX attachment is significantly increased, resulting in
to AMF, this nanostructure was able to exhibit sizable dimen- 3.5-fold enhancement in DOX payload (as much as 63% DOX
sional shrinkage and its diameter was reduced by beyond by weight can be loaded to PEG-coated HAuNS) compared
ten times. This was owing to the temperature increase which with solid gold nanospheres of the same size. Irradiation with
induced the polymer moieties contained inside the structure NIR laser induced photothermal conversion, which triggered
to undergo hydrophilic/hydrophobic transition. Together with rapid DOX release from DOX-loaded HAuNS. Photothermal
this transition process, the solid mesoporous shell also under- ablation mediated by HAuNS and anticancer activity of DOX
went rupture, which caused the release of the drug molecules released from HAuNS triggered by NIR laser irradiation, signif-
initially loaded inside the nanostructure. icantly enhanced the cell killing. This was proved in the system
On the other hand, gold-based hollow nanostructures gen- of MDA-MB-231 cells incubated with DOX-loaded HAuNS,
erally comprises of gold nanocages and NSs. Despite holding which were then irradiated with NIR light.
great potential in DDSs application, gold nanocages suffer Hybrid hollow nanostructures can also be fabricated by
from a major drawback which stems from the large amount using amphiphilic GNPs.[90] These nanoparticles were cre-
of pores which link the void core to the surrounding envi- ated by hybridizing GNPs with two types of polymer grafts
ronment.[86] These pores allow the drug molecules loaded which have different chemical properties.[91] For example,
inside the nanocages to diffuse to the outer environment with GNPs were functionalized with PMMA which is hydro-
ease, and thus gold nanocages suffer from low drug retaining phobic in nature and PEG which is hydrophilic in nature.[92]
ability. In order to mitigate this problem, some changes need The resulting amphiphilic GNPs were able to exhibit self-
to be made to the nanocages structure—either on the prop- assembly in aqueous solution, resulting in the construction
erties of the outer shell or the inner cavity. Some examples of vesicular nanostructures. These nanostructures were able
of such modifications would be by introducing PNIPAAm- to contain therapeutic payloads and be deconstructed under
based copolymers coating over the gold nanocages, or using NIR light irradiation, thus holding great potential in remotely
gating molecules such as PCMS to cover the pores. These triggered DDSs application.
DOI: 10.1002/smll.201601129
reviews
Figure 15. Schematic representation of HAuNS-pHLIP-Ce6 for synergistic PTT/PDT therapeutics. Adapted with permission.[88] Copyright.
Figure 16. Fabrication and characterization of DOX-loaded HAuNS (DOX@HAuNS). A) Schematic of HAuNS synthesis and TEM images of plain and
DOX-loaded HAuNS (DOX@HAuNS and DOX@PEG_HAuNS). B) Absorption spectra of HAuNS and PEG_HAuNS. C) Absorbance spectra of free DOX
(red), HAuNS (green), and DOX@HAuNS (brown). Inset: Photograph of aqueous solutions of free DOX, HAuNS, and DOX@HAuNS. DOX@HAuNS
displayed absorption peaks characteristic of both DOX and HAuNS. D) Absorbance spectra of initial physical mixture of DOX and HAuNS (purple)
and the complexes of DOX and HAuNS after 24 h of incubation (brown). Inset: Fluorescence spectra of solutions of free DOX (red) and DOX@HAuNS
(brown; excitation at 488 nm) with the same DOX concentration. Significant fluorescence quenching was observed for DOX@HAuNS. Adapted with
permission.[89] Copyright 2016, Elsevier.
DOI: 10.1002/smll.201601129
5. Mechanisms of Remote Trigger Release shown in Figure 17, when the magnetic field is on, SPIONs
tend to orient and approach each other, leading to the hydro-
In Section 2, different stimuli for remote trigger have been phobic cores in the ferrogel to get closer and have stronger
discussed and one common thing that each stimulus has is that interaction. This change would further cause an increase in
upon application, local heating in the form of hyperthermia or the local concentration of IMC (indomethacin), producing
photothermia will be generated. The resulting increase in tem- a large concentration gradient between PPO cores and
perature can affect the integrity and properties of the hybrid water channels in the SPEL, pumping out many more drug
nanostructures in different ways. For example, bond cleavage molecules. Therefore, under the applied field, the release rate
may occur when the temperature is raised to a certain tem- is enhanced due to the constriction of the SPEL.[94]
perature limit.[9b] For certain types of hybrid nanostructures, In Section 4, we have discussed various hybrid nano-
more than one trigger mechanisms may occur upon the tem- vehicles which are modified in such a way so that they can
perature increase. In this section, different mechanisms of the be triggered by remote stimuli. During the remote trigger, it
remote trigger process will be detailed and discussed. is inevitable that the resulting temperature increase would
influence the diffusivity of the drug molecules or permeation
of the nanovehicles. In some cases, enhanced diffusion or per-
5.1. Improved Diffusivity or Permeability meation could be the main mechanism of the release of the
chemotherapeutic payloads from the hybrid nanostructures.
The rise in temperature due to the application of stimuli Some examples of such hybrid nanostructures would be
could lead to an improved diffusion rate of drug molecules hybrid liposomes nanostructures formed by lipids which are
and an increased permeability of the nanostructures. This is not thermoresponsive; mesoporous silica nanoparticles which
because the rise in temperature causes the drug molecules are hybridized with GNPs; and polymer micelles encapsu-
to gain kinetic energy and hence their diffusivity improves. lated with upconversion nanoparticles (UCNP). These nano-
Furthermore, higher temperature can lead to better blood structures are able to release their payloads despite having
circulation at the target area, which allows for better penetra- no thermoresponsive component in the hybrid nanostructure,
tion of the drug molecules into the target sites.[93] As such, and thus it could be hypothesized that the release is facili-
therapeutic efficiency can be improved through such mecha- tated by enhanced permeation or diffusion of drug molecules.
nism. The extent of the hyperthermia or photothermia gener-
ated upon application of stimuli can be controlled by altering
several parameters: the time span of stimuli application; the 5.2. Rupture of Thermo- or Photo-Labile Bonds
frequency and amplitude of the AMF; the wavelength and
intensity of the NIR light laser; and lastly, the intensity, fre- The rise in temperature which occurs upon application of
quency, and resolution of the ultrasound application. By remote stimuli is able to provide sufficient energy to break
controlling these parameters, one could control the extent thermolabile covalent bonds.[9b] This is evident in the trig-
of enhanced diffusion of drug molecules or permeation of gered release of host–guest conjugates nanostructures which
the nanostructures. One example is the drug release from a have been discussed in Section 4.1. In this type of nanostruc-
new type of ferrogel consisting of SPIONs and Pluronic F127 tures, guest molecules are bind with the host (usually inor-
(PF127) copolymer (abbreviated as SPEL). The hydrophobic ganic matrix) by Watson–Crick base pairing which is a type of
drug indomethacin was encapsulated in PPO core of F127 bonding which is relatively unstable in changing temperature.
micelles, which were bridged by the interconnecting aqueous This is because Watson–Crick base pairing is different from
moiety. These interconnected bridges could function as a the conventional covalent bonding or hydrogen bonding in
pathway for diffusion of the encapsulated drug molecules. As such a way that its binding strength is intermediate of that
Figure 17. Schematic illustration of ordered microstructure of thermally induced ferrogels based on Fluronic F124 block copolymers: a) before
applying magnetic field, IMC hydrophobic drug molecules are encapsulated in the hydrophobic core of micelles; b) when magnetic field is on
IONPs orient and approach each other, squeezing the micelles and leading to enhancement of indomethacin release. Adapted with permission.[94]
Copyright 2009, John Wiley and Sons.
DOI: 10.1002/smll.201601129
reviews
of covalent bonds’ and hydrogen bonds’.

As such, local heating generated by the
stimuli application would be sufficient
to break such bonding. Such host–guest
nanostructures are usually used in gene
delivery applications, where DNA strands
are immobilized on inorganic nanoparti-
cles to form host–guest nanoconjugates.
One such example would be Fe3O4@DNA
nanoconjugates.[95] This type of nanovehi-
cles involves the immobilization of ssDNA
onto maghemite nanoparticles, and then Figure 18. Sketch of the functionalized IONPs bearing dye or drug connected through VA057
hybridizing it with another ssDNA to azo molecule to the tails of PEG spacers. An increase in temperature results in increased
form dsDNA. The hybridized dsDNA is cleavage of the azo group and release of the conjugated molecules from the particles.
sensitive to changes in temperature. As Adapted with permission.[96] Copyright 2013, American Chemical Society.
such, when the temperature increases due
to hyperthermia upon AMF application, dsDNA would be nanovehicles. Lastly, selective release can be achieved by
dehybridized into ssDNA and hence releasing the therapeutic binding the drug molecules at various specific distances from
ssDNA into the target sites. The dehybridization temperature the nanoparticles.[42,96]
is dependent on the length of the ssDNA chain as well as the Another type of thermolabile bonding that is prone to
amount of guanine/cytosine pair present in the chain. The bond cleavage upon application of remote stimuli would
temperature increase itself could be controlled by varying be AuS conjugation. As described in Section 4.1, guest
the strength of the AMF. The implication of this is that selec- molecules which have sulfur-containing functional groups
tive triggered release can be achieved by varying the field can be directly anchored onto GNPs through AuS conjuga-
strength—lower field strength would result in lower temper- tion. Upon NIR light irradiation, the resulting photothermia
ature rise which can only provide sufficient energy to over- would provide sufficient energy to overcome the AuS con-
come the weaker interaction between the 12-strand dsDNA jugation, thus releasing the DNA molecules which have been
and maghemite nanoparticles and not the stronger interac- preloaded into the hybrid nanostructures. Furthermore, the
tion between the 24-strand dsDNA and maghemite nanopar- rise in temperature also causes the GNPs to undergo shape
ticles. Therefore, this would be useful in applications where transformation, which also plays a role in the release of the
selective triggered release is necessary. Another type of host– payloads. Similar to AMF applications on maghemite–DNA
guest conjugates that adopts the same trigger mechanism nanoconjugates, selective triggered release can also be
would be oligonucleotides@GNPs nanoconjugates. For this achieved with this nanostructure. This can be done by varying
nanoconjugate, NIR light laser is utilized as the trigger stim- the wavelength of the NIR light irradiation. The GNPs used
ulus. Application of NIR light laser onto GNPs will result in can be modified to have different SPR bands within which
photothermia, which leads to temperature increase. As such, they will be able to exhibit photothermia upon NIR light
the host–guest interactions will be destroyed and the guest irradiation. As such, by irradiating NIR light with suitable
molecules would be released to the surrounding environment. wavelengths which coincides with the SPR band of certain
Guest molecules can also be attached onto GNPs sur- type of GNPs, selective triggered release would be possible.
faces by Diels–Alder reaction. The Diels–Alder reaction is Nanostructures which utilizes photolabile chemical bonds
a type of cycloaddition process between diene and alkene to bind guest molecules onto inorganic nanoparticles can also
groups to create a cycloadduct. This reaction process is adopt similar mechanism as their thermolabile counterparts.
reversible in nature and the reverse reaction is known as For example, cleavage of UV-labile chemical bonds could
retro-Diels–Alder reaction. The Diels–Alder cycloadduct be prompted by using UV light. However, due to the toxic
can be modified to bind with desired drug molecules and the nature of prolonged exposure to UV light as well as the ina-
resulting cycloadduct-drug system can be attached onto the bility of UV light to penetrate deep into the human tissues,
surfaces of GNPs. When NIR light is applied and the tem- the use of UV light as remote trigger stimuli is not feasible.
perature increases to a certain temperature limit, the retro- In light of these limitations, UCNP are used hand in hand
Diels–Alder reaction will occur and drug molecules will be with NIR irradiation in order to enable cleavage of such UV-
released to the surrounding environment. Another method labile bonds. UCNPs are nanoparticles which possess the
to anchor guest molecules onto nanoparticles would be by capability to convert NIR light into electromagnetic waves
utilizing thermolabile azo-group functionalization. When the with different wavelengths such as in visible light, UV, and
temperature increases upon application of stimuli, the ther- NIR regions. As such, by incorporating UCNPs in nanostruc-
molabile azo-groups would be cleaved, resulting in release tures which utilize UV-labile chemical bonding to bind guest
of the therapeutic payloads (Figure 18).[96] It is reported molecules, release of therapeutic payloads would be possible
that by using azo-group as immobilization technique, it is by using NIR light irradiation stimulus.
possible to load and release both hydrophilic and hydro- Nanostructures which adopt this bond cleavage mecha-
phobic drug molecules. Moreover, this technique allows nism are usually easy to fabricate in terms of the immobili-
reduction of mass ratio between the drug molecules and zation technique of the desired payloads. Furthermore, such
DOI: 10.1002/smll.201601129
nanostructures usually possess higher loading capacity and a way that the release can now be switched on or off delib-
higher degree of control over the release behavior. However, erately by controlling the local temperature and period of
there are a few drawbacks that this type of nanovehicles may stimuli application.
experience. One of them would be the inability of the nano- Furthermore, the release can be controlled in a pulsatile
structures to fully encapsulate and quench the chemothera- manner and hence this system can be potentially applied to
peutic payloads, thus raising some concerns over possibility pulsatile drug release mimicking biological rhythm. Besides
of incursion of side toxic effects. Another one would be that TD, polymeric materials which exhibit phase transition upon
bond cleavage often requires high amount of energy and thus temperature change can also be used as the gating compo-
high degree of local heating—this might also induce unde- nents. For example, amphiphilic copolymers based on crys-
sired side effects. Furthermore, there exists a contradictory talline PCL can be utilized to form a phase-changed corona
notion such that in order to form stable host–guest nanocon- acting as gating components. Upon stimuli application, the
jugates, strong covalent bonding would be desirable but in rise in temperature causes the crystalline PCL to undergo
terms of bond cleavage, the opposite would be true. There- fusion, leading to the release of the preloaded drug molecules.
fore, it might be difficult to find the optimum balance. Local Another type of nanostructures which exhibit such
heating may also result in degradation of therapeutic drug release mechanism would be hybrid liposomes nanostruc-
molecules, which will lead to lower therapeutic efficiency. tures which incorporate TSLs. TSLs consists of lipid bilayer
The nanostructures themselves can be affected by the hyper- membrane which exhibit gel-to-liquid crystalline phase tran-
thermia in such a way that they experience shape change or sition above its melting temperature. This gel-to-liquid crys-
even structural degradation. Therefore, further studies need talline phase transition leads to increase in permeability of
to be conducted in order to optimize the design of nanostruc- the membrane layer, thus increasing the ease of diffusion
tures which adopt this type of triggered release mechanism. of the entrapped drug molecules. Therefore, by using TSLs
which melting temperature is slightly higher than human
body temperature, drug release based on phase-changed
5.3. Phase Transition of Phase-Changed Materials material mechanism can be realized via hybridization with
inorganic nanoparticles capable of generating hyperthermia
As previously mentioned in Section 3, gating components or photothermia upon stimuli application.
can be utilized to avoid premature release as well as to allow
drug release upon application of remote stimuli.[1a] These
gating components are usually made of PCMs. One example 5.4. Reversible Thermo-Induced Conformation Transition
of PCMs would be TD which was used as gating components
for γ-Fe2O3@MSNs (Figure 19).[82] TD is highly biocompat- This mechanism involves the conformation transition of thermo-
ible and immiscible with water, rendering it suitable to be responsive polymers at their LCST. Below the LCST, thermo-
used in vivo. Furthermore, TD is able to exhibit rapid and responsive polymer chains exhibit a hydrophilic nature and
reversible solid/fluid phase transition within a small range of dissolve well in the solvent. As such, their chain conforma-
temperature around its melting point. As such, it can restrict tion is such that the end to end distance of the chain is large,
the movements of the preloaded drug molecules in its solid i.e., the chains appear to be uncoiled and extended. This also
state while allowing diffusion of drug molecules when it turns causes the viscosity of the polymer solution to be higher. On
into fluid state above its melting point. This feature allows a the other hand, above the LCST, thermoresponsive polymer
higher degree of control over the release behavior in such chains exhibit a hydrophobic nature and do not dissolve well
in the solvent. As such, the polymer chains
appear to be coiled and compressed, thus
reducing the viscosity of the polymer solu-
tion. This reversible conformation transi-
tion about the LCST can be exploited as
the release mechanism for the loaded drug
payloads. This can be achieved by designing
a hybrid nanostructure which incorporates
such thermoresponsive polymers and inor-
ganic components capable of producing
hyperthermia or photothermia upon expo-
sure to certain stimuli. Drug molecules can
be loaded and encapsulated in such hybrid
nanostructure and upon application of suit-
able stimulus, the resulting hyperthermia
will induce conformation transition of the
thermoresponsive polymer into that of com-
Figure 19. Schematic illustration of the preparation of γ-Fe2O3@MSNPs as drug reservoirs pacted and hydrophobic nature. Such sudden
and subsequent drug release triggered by using TD as phase change materials. Adapted with reduction in polymeric domain sizes will
permission.[82] Copyright 2013, Royal Society of Chemistry. induce the rapid diffusion of the contained
DOI: 10.1002/smll.201601129
reviews
temperature so as to allow for more precise control on the

drug release behavior—better control on the conformation
transition of the polymers. Therefore, thermoresponsive poly-
mers with LCST around 40–45 °C would be highly suitable
for hybrid nanostructures exhibiting reversible conformation
transition as release mechanism.
5.5. Rupture of Nanostructures
In the applications whereby controlled and sustained release

of therapeutic drug molecules is not required, this release
mechanism would be the most reliable one to produce burst
Figure 20. Schematic representation of the release mechanism of release effect on the contained drug molecules. The hybrid
hybrid liposomes upon alternating magnetic field irradiation. Adapted nanostructures encapsulating the drug molecules can be
with permission.[97] Copyright 2011, John Wiley and Sons. exposed to stimuli or impact that causes them to undergo
structural disintegration, resulting in the drug release. Such
drug molecules out of the hybrid nanostructure, resulting in pay- structural rupture can be achieved via physical pressure or
load release. sudden rise in local temperature. For example, by using
This reversible conformation transition can also be high-intensity focused ultrasound (HIFU), both local hyper-
exploited in another way. As mentioned in Section 4.7, hybrid thermia and physical stress can be induced onto the suitable
hollow nanostructures such as gold nanocages can be coated hybrid nanostructures. While the local hyperthermia can
by thermoresponsive polymers which would act as an induce drug release in ways that have been discussed in the
external shell to cover the pores and prevent the contained previous sections, physical stress due to HIFU impact onto
drug molecules from leaking out. However, upon exposure to the nanostructures can lead to cavitation or even structural
NIR light irradiation, the gold nanocages will exhibit photo- rupture if the impacted stress is higher than the yield stress
thermia which will induce the reversible conformation tran- or tensile strength of the nanostructures. When such struc-
sition to the compressed structure. As a result, the external tural rupture occurs, the contained drug molecules would be
shell that acts as the protective layer for the gold nanocages released in a sudden and rapid fashion.
breaks down and the pores would be uncovered, leading to Besides HIFU, this type of release mechanism can also be
the release of the contained drug molecules. On the other achieved on GNPs based nanostructures by using NIR light.
hand, magnetic nanoparticles have been used in hyperthermia Exposure to high intensity NIR light irradiation will lead
treatment in an attempt to realize the specific release from to spontaneous local photothermia, which may significantly
reversible conformation transition of thermoresponsive poly- raise the local temperature. This sudden and large increase
mers. One example is the magnetoresponsive hybrid liposome in temperature may cause both thermal and physical stress
consisting of thermosensitive block copolymers and Fe3O4 onto the gold nanostructures, which may in turn lead to
nanoparticles.[97] As shown in Figure 20, a local temperature structural disruption or even rupture. One example of such
increase of the liposomes was applied to induce the transition GNPs based nanostructures would be liposome@gold nano-
of the thermosensitive block copolymer and then the encapsu- structure which was loaded with dye molecules.[98] This nano-
lated substances were released from the interior of the hybrid structure was exposed to NIR light irradiation in order to
liposomes. In this system, controlled release was caused by trigger the release of the contained dye molecules. The NIR
the localized heat from the Fe3O4 nanoparticles under mag- light irradiation caused structural rupture of the hollow gold
netic stimuli, rather than the rupture of the capsules. NSs and the dye molecules were released. The ruptured gold
It is important to note that the reversible nature of this NSs will tend to agglomerate to form chunks of gold parti-
conformation transition would allow a certain degree of con- cles. Therefore, this study has proved the release mechanism
trol on the drug release behavior as the thermoresponsive which involves structural rupture of the nanostructures in
polymers are able to act as some sort of control valves for order to release the contained cargo molecules.
the drug release. In essence, one would be able to control NIR light irradiation can also be used to remotely trigger
the drug dosage released at the desired timings, simply by drug release from hybrid micelle nanostructures. By incor-
manipulating the parameter of the stimuli applications such porating photolabile moieties such as o-nitrobenzyl group
as intensity/amplitude and period of exposure. Furthermore, into the hybrid micelle nanostructures, one can use NIR light
in order to achieve such controllable drug release behavior, irradiation to trigger the structural rupture of the micelle
it would be best if the thermoresponsive polymers used in nanostructures, thus releasing the contained drug molecules.
the hybrid nanostructures have a LCST which is above the One example of such nanostructures would be micelle nano-
human body temperature. This is because one would prefer structures which are comprised of amphiphilic copolymer
the hybrid nanostructures to be able to contain the drug functionalized with o-nitrobenzyl group and UCNPs.[99]
without any leak or premature release even when they have o-nitrobenzyl group is photolabile in such a way that expo-
already been administered inside the human body. Further- sure to UV light would result in bond cleavages on the func-
more, the LCST should not be too close to the human body tional group. UCNPs are capable of converting NIR light
DOI: 10.1002/smll.201601129
controlled DDS with significant cancer-

killing properties.[44a,100c]
6. Concerns and Limitations

DDSs capable of being remotely triggered
by external stimuli would present a series
of benefits over the conventional DDSs.
Conventional DDSs lack the ability to
be controlled at a higher degree, which
include the spatial and temporal preci-
sion of which the drug molecules should
be released at. Remotely triggered DDSs
would be able to offer higher degree of
control and efficiency, as well as reduced
undesirable side effects and premature
leak of the contained drug molecules.
In the situations whereby drug adminis-
tration is required to be periodical and
exact, remotely triggered DDSs would
Figure 21. Schematic illustration of remote-controlled drug release mediated by the rupture of be very useful. For example, for treat-
CB based pseudorotaxanes nanostructure in magnetic-responsive hybrid mesoporous silica ment that requires drug administration
hybrid nanoparticles. Adapted with permission.[100c] Copyright 2012, American Chemical which matches the biological rhythm of
Society. the human body. This way, not only could
the therapeutic efficiency be improved,
irradiation into electromagnetic waves of wavelengths com- but adverse effects such as overdose could also be avoided.
parable to UV light. As such, by exposing the nanostructure However, as described in the above sections, different
to NIR light, conversion to UV light and subsequent bond designs and mechanisms of triggered release have their own
cleavage on the o-nitrobenzyl group would occur, resulting in limitations and drawbacks. For instance, premature release
the structural rupture and dissociation of the micelle nano- of the contained drug molecules may not be totally pre-
structures and subsequent payload release. This strategy vented in some of the hybrid nanostructure designs, simply
can also work on hybrid nanostructures which incorporate due to the nature of thermodynamic diffusion from high
thermolabile moieties, by replacing NIR light stimulus with concentration to low concentration regions. This may result
AMF application. A similar result of structural rupture of the in adverse side effects if the contained drug molecules are
hybrid nanostructures would be obtained. toxic in nature. Nonetheless, there are also some strategies
In addition, the remotely controlled drug release in cancer to minimize the premature release such as putting a barrier
therapy using magnetic field or light irradiations as respective to prevent the drug molecules from diffusing out. To ensure
triggers to crush the supramolecular nanostructure between a minimal premature release, hybrid nanostructures should
specific host and guest materials were also achieved.[100] be equipped with strong barriers. However, the stronger
For example, pseudorotaxanes formed between N-(6-N- the barrier is, the higher the energy required to overcome
aminohexyl)aminomethyltriethoxysilane and cucurbit[6]uril this barrier to allow payload release upon stimuli applica-
(CB[6]) was designed as gatekeepers on the surface of tion. Therefore, to achieve optimal therapeutic efficiency, the
zinc-doped iron oxide incorporated mesoporous silica capability of the hybrid carrier to trap the cargo molecules
nanoparticles for controlled release of encapsulated drugs and their interaction strength should be well-balanced with
(Figure 21).[100c] The drug release results, using rhodamine energy and intensity of the trigger applied. Exposure to high
B and DOX were used as model drugs, showed that the amount of energy—thermal energy for instance—would
magnetic nanocrystals could generate local internal heating be detrimental to the surrounding body tissues. Some of
when the hybrid nanoparticles were placed in an oscillating the detrimental effects would include epidermal burn and
magnetic field, which further caused the pseudorotaxanes to death of surrounding healthy tissues.[101] This concern is par-
disassemble and facilitate the opening of the nanovalves for ticularly apposite in patient-controlled devices, where the
cargo release. For instance, a single magnetic pulse resulted patient may choose to activate the device repeatedly.[35] The
in 40% rhodamine B dye release from the SNPs. Additionally, strategies to address this safety issue include design of the
the feasibility of such system as a controlled drug delivery delivery vehicles with higher on-state kinetics, which would
carrier in cancer cells was also demonstrated. Breast cancer require shorter irradiation times. This is of a particular con-
cells MDA-MB-231 incubated with DOX-loaded SNPs and sideration in the case of devices that will be placed deep
exposed to an oscillating magnetic field resulted in 37% cell within tissues, which will absorb or scatter a substantial por-
lysis. This was reportedly higher than 16% cell lysis of the tion of the energy.[102] Furthermore, it is necessary to design
nanoparticles without drug loading, indicating an externally the therapeutic materials with a lower on-state irradiation
DOI: 10.1002/smll.201601129
reviews
threshold and choose the pulsed laser source that can heat considered is the production of biocompatible particles from
the devices but causes less tissue damage.[6b] Therefore, fur- certified laboratories. Furthermore, there needs to be a stand-
ther studies need to be done to discover new ways to over- ardized test for the evaluation of the long term safety of these
come this problem—new methods and strategies to create nanovehicles in vivo. From the moment of administration, to
a nanovehicle which has high therapeutic efficiency and the foreign body reaction, circulation and the eventual accu-
loading capacity, yet can be triggered with small amount of mulation in the body organs, the fate of the particles need to
hyperthermia and without side effects. As for ultrasound, be carefully examined.
one important shortcoming is the strong attenuation effect
by human tissues through both scattering and absorption,
which prevents the deep penetration of high frequency 7. Conclusion and Future Perspective
ultrasound into the body. This is a drawback for the use of
frequency ultrasound as the trigger for drug delivery.[103] The All in all, this review paper has presented the basic princi-
ultrasound attenuation energy will convert into local heat. In ples of remotely triggered hybrid nanovehicles as DDSs
the situation of the thermal effect is not the activating effect which include the type of stimuli usable for remote trigger
for remotely ultrasound-triggered drug release, this heating agents as well as the different mechanisms behind the pay-
factor must be seriously considered as it may destroy the load release upon application of remote trigger. Furthermore,
healthy and vital tissues. The cavitation effect induced from some of the designs of hybrid nanovehicles have also been
ultrasound in the medium and tissue may cause the same presented, ranging from simple host–guest conjugates to the
undesired local heating issues.[3b] This problem could be pos- more complicated GNPs based nanostructures which utilize
sibly resolved by designing new material system with more gating components to safely encapsulate the cargo molecules.
ultrasound-sensitive properties.[13d] In addition, most of Some of the concerns and limitations have also been dis-
the therapeutic efficiency of the current remotely triggered cussed, highlighting that such DDS technology still requires
hybrid nanovehicle systems was evaluated using a typical advanced studies in order to minimize the potential adverse
in vitro cell culture method, the in vivo efficiency would be effects and improve its efficiency. Advancement in biomed-
dependent on lots of parameters. For example, the biological ical knowledge results in more demanding criteria for an
factors such as tumor vascularization and perfusion should effective DDS, for example, DDS that is capable of releasing
be carefully considered in cancer treatment because they drug in certain predetermined intervals to mimic the biolog-
paly modulate not only the drug uptake within the tumors ical rhythm of human body. Remotely triggered nanovehicles
but may also strongly vary between patients even for the present some interesting features that can be exploited to
same tumor type.[2a,12] satisfy the therapeutic needs of today’s world.
Another concern about such remotely triggered nano- For the remote triggered DDS to become practical for
vehicles is their targeting efficacy. This concern applies for clinical translation, necessary considerations must be taken
most, if not all, DDSs that are being studied today. The dif- into account in designing such systems. For examples, the
ficulty in designing a DDS that is capable of targeting spe- “on”-state release rate should be tunable to ensure the dose
cific types of cells has hold back the advancement in the released would be therapeutically effective (i.e., not too low
DDSs technology today. Some efforts have been made to to be non-effective, nor too high to be cytotoxic). The gap
improve the targeting efficacy. For example, nanostructures between “on” and “off” states much be as large as possible,
can be designed to incorporate targeting moieties such as in other words, the “off” state leakage should be oppressed as
targeting ligands which are only expressed in tumorous low as possible. At the same time, the viability of the loaded
cells and not healthy cells. However, healthy cells are drug should be maintained especially in the case of long-term
capable of constitutive expression of ligands which makes drug release. In addition to reproducible “on” states of drug
it possible for them to have the same ligand expression. As release, the duration and rate of release of an ideal remote
a result, nanostructures with such targeting ligands can also triggered release system should be determined by the dura-
be absorbed by healthy cells, resulting in reduced overall tion and magnitude of the remote trigger. Moreover, the
therapeutic efficiency or even cytotoxicity if the toxic drug side effects of the triggering mechanism together with the
molecules are used. Another method is by using external released nanoparticles and toxicity of any possible degrada-
stimuli as guiding agent. For example, the movement path- tion products must be carefully accessed.
ways of the magnetic nanoparticles can be directed by From the view of the materials responsive to
external magnetic field to reach the desired target areas. remote trigger, we note that most research focused on
However, the type of magnetic field required for the gold nanorods,[105] and UCN absorbing 980 nm NIR
guiding agent is different from AMF, rendering remote light.[64b,65,99,106] However, gold nanorods will change their
trigger unachievable.[104] As such, further studies need to shape upon NIR laser irradiation eventually become spheres
be done to discover new methods to improve the targeting which could not absorb NIR light effectively.[107] Thus, we do
efficacy of DDSs in general. anticipate that stable anisotropic gold nanocrystals would
From the different fabrication techniques highlighted, attract more attention in the future. Moreover, multifunc-
there are numerous preferences and detriments of the dif- tional inorganic nanomaterials would be more preferred,
ferent strategies of synthesizing the nanoparticles. Moving e.g., materials with magnetic core and plasmonic shell will
from lab to industry, there is a need to further scale-up render the hybrid nanovehicles response to multiple stimuli,
the different procedures. Another aspect that needs to be making them theranostic and synergistic. For UCN, most
DOI: 10.1002/smll.201601129
existing UCNs are excited by 980 nm lasers, where water also [10] a) Z. Li, B. H. Tan, G. Jin, K. Li, C. He, Polym. Chem. 2014,
has strong absorbance; the 980 nm excitation heats up water 5, 6740; b) Z. Li, D. Yuan, G. Jin, B. H. Tan, C. He, ACS
resulting in unnecessary tissue heating. We also anticipate Appl. Mater. Interfaces 2016, 8, 1842; c) H. C. Guo,
E. Ye, Z. Li, M.-Y. Han, X. J. Loh, Mater. Sci. Eng. C 2016,
that UCNs excited by NIR at other wavelength (e.g., 800 nm)
DOI: 10.1016/j.msec.2016.01.093.
would be an ideal option, since it will reduce unnecessary [11] S. Ganta, H. Devalapally, A. Shahiwala, M. Amiji, J. Controlled
tissue heating without sacrificing any characteristics of NIR Release 2008, 126, 187.
trigger. It is also worthy to emphasize that most of the cur- [12] J. Liu, C. Detrembleur, S. Mornet, C. Jerome, E. Duguet, J. Mater.
rent DDSs fall short in targeting abilities. This is another Chem. B 2015, 3, 6117.
important aspect to improve to make the remote triggered [13] a) C. S. Brazel, Pharm. Res. 2009, 26, 644; b) M. Marguet,
C. Bonduelle, S. Lecommandoux, Chem. Soc. Rev. 2013, 42,
DDS clinically practical. More efforts would be put into the
512; c) S. Lal, S. E. Clare, N. J. Halas, Acc. Chem. Res. 2008, 41,
design of new functional polymers, modification and bio-con- 1842; d) Y.-Z. Zhao, L.-N. Du, C.-T. Lu, Y.-G. Jin, S.-P. Ge, Int. J.
jugation strategies to meet the needs. Nanomed. 2013, 8, 1621.
Finally, we do believe that with further studies and opti- [14] a) X. Sun, C. Wang, M. Gao, A. Hu, Z. Liu, Adv. Funct. Mater.
mizations of design parameters, the future where smart DDSs 2015, 25, 2386; b) L. L. K. Viitala, S. Pajari, T. Lajunen,
are being widely used to cure diseases around the world, L.-S. Kontturi, T. Laaksonen, P. Kuosmanen, T. Viitala, A. O. Urtti,
would not be too far away. L. Murtomäki, Langmuir 2016, 32, 4554; c) C. B. Highley,
M. Kim, D. Lee, J. A. Burdick, Nanomedicine 2016, 11, 1579.
[15] P. Zhang, Z. He, C. Wang, J. Chen, J. Zhao, X. Zhu, C.-Z. Li,
Q. Min, J.-J. Zhu, ACS Nano 2014, 9, 789.
[16] N. Fomina, J. Sankaranarayanan, A. Almutairi, Adv. Drug Delivery
Rev. 2012, 64, 1005.
Acknowledgements [17] H. Jang, Y.-K. Kim, H. Huh, D.-H. Min, ACS Nano 2014, 8, 467.
[18] M. Reismann, J. C. Bretschneider, G. v. Plessen, U. Simon, Small
Z.L. and E.Y. contributed equally to this work. 2008, 4, 607.
[19] P. Zhang, C. Wang, J. Zhao, A. Xiao, Q. Shen, L. Li, J. Li, J. Zhang,
Q. Min, J. Chen, ACS Nano 2016, 10, 3637.
[20] Z. Li, Y. Hu, K. A. Howard, T. Jiang, X. Fan, Z. Miao, Y. Sun,
[1] a) J. Liu, C. Detrembleur, M. C. De Pauw-Gillet, S. Mornet, F. Besenbacher, M. Yu, ACS Nano 2016, 10, 986.
C. Jerome, E. Duguet, Small 2015, 11, 2323; b) W.-K. Fong, [21] B. Geers, H. Dewitte, S. C. De Smedt, I. Lentacker, J. Controlled
T. L. Hanley, B. Thierry, A. Hawley, B. J. Boyd, C. B. Landersdorfer, Release 2012, 164, 248.
J. Controlled Release 2016, 228, 67. [22] X. Liang, J. Gao, L. Jiang, J. Luo, L. Jing, X. Li, Y. Jin, Z. Dai, ACS
[2] a) I. Brigger, C. Dubernet, P. Couvreur, Adv. Drug Delivery Rev. Nano 2015, 9, 1280.
2012, 64, 24; b) H. Wang, P. Agarwal, S. Zhao, J. Yu, X. Lu, X. He, [23] a) M. A. Elkhodiry, C. C. Momah, S. R. Suwaidi, D. Gadalla,
Adv. Mater. 2016, 28, 347; c) Z. Meng, F. Wei, R. Wang, M. Xia, A. M. Martins, R. F. Vitor, G. A. Husseini, J. Nanosci. Nanotechnol.
Z. Chen, H. Wang, M. Zhu, Adv. Mater. 2016, 28, 245; d) D. Luo, 2016, 16, 1; b) E. C. de Oliveira Guirro, D. d. F. de Angelis,
K. A. Carter, A. Razi, J. Geng, S. Shao, D. Giraldo, U. Sunar, N. T. A. de Sousa, R. R. de Jesus Guirro, Ultrason. Sonochem.
J. Ortega, J. F. Lovell, Biomaterials 2016, 75, 193. 2016, 32, 284.
[3] a) A. Rösler, G. W. Vandermeulen, H.-A. Klok, Adv. Drug Delivery [24] H. Xia, Y. Zhao, R. Tong, Therapeutic Ultrasound, Springer, NY,
Rev. 2012, 64, 270; b) H. Xia, Y. Zhao, R. Tong, Adv. Exp. Med. USA 2016, pp. 365–384.
Biol. 2016, 880, 365. [25] a) S. Mornet, S. Vasseur, F. Grasset, P. Veverka, G. Goglio,
[4] N. Rapoport, Prog. Polym. Sci. 2007, 32, 962. A. Demourgues, J. Portier, E. Pollert, E. Duguet, Prog. Solid State
[5] a) Y. Li, T. Wen, R. Zhao, X. Liu, T. Ji, H. Wang, X. Shi, J. Shi, Chem. 2006, 34, 237; b) L. Deng, Q. Li, S. a. Al-Rehili, H. Omar,
J. Wei, Y. Zhao, ACS Nano 2014, 8, 11529; b) R. Lv, P. Yang, A. Almalik, A. Alshamsan, J. Zhang, N. M. Khashab, ACS Appl.
F. He, S. Gai, C. Li, Y. Dai, G. Yang, J. Lin, ACS Nano 2015, 9, Mater. Interfaces 2016, 8, 6859.
1630; c) Y. Wang, K. Wang, R. Zhang, X. Liu, X. Yan, J. Wang, [26] a) R. Hergt, S. Dutz, R. Müller, M. Zeisberger, J. Phys. Condens.
E. Wagner, R. Huang, ACS Nano 2014, 8, 7870; d) H.-C. Yen, Matter 2006, 18, S2919; b) J.-P. Fortin, C. Wilhelm, J. Servais,
H. Cabral, P. Mi, K. Toh, Y. Matsumoto, X. Liu, H. Koori, A. Kim, C. Ménager, J.-C. Bacri, F. Gazeau, J. Am. Chem. Soc. 2007,
K. Miyazaki, Y. Miura, ACS Nano 2014, 8, 11591; e) T.-Y. Liu, 129, 2628; c) F. Sonvico, S. Mornet, S. Vasseur, C. Dubernet,
M.-Y. Wu, M.-H. Lin, F.-Y. Yang, Acta Biomater. 2013, 9, 5453; D. Jaillard, J. Degrouard, J. Hoebeke, E. Duguet, P. Colombo,
f) A. Chan, R. P. Orme, R. A. Fricker, P. Roach, Adv. Drug Delivery P. Couvreur, Bioconj. Chem. 2005, 16, 1181; d) Y. Haik,
Rev. 2013, 65, 497. V. Mohite, C. Chen, Nature 2016, 4, 5.0.
[6] a) M. L. Viger, M. Grossman, N. Fomina, A. Almutairi, Adv. [27] a) A. Espinosa, R. Di Corato, J. Kolosnjaj-Tabi, P. Flaud,
Mater. 2013, 25, 3733; b) M. Sawa, K. Awazu, T. Takahashi, T. Pellegrino, C. Wilhelm, ACS Nano 2016, 10, 2436; b) P. T. Yin,
H. Sakaguchi, H. Horiike, M. Ohji, Y. Tano, Br. J. Ophthalmol. S. Shah, N. J. Pasquale, O. B. Garbuzenko, T. Minko, K.-B. Lee,
2004, 88, 826; c) A. Schroeder, J. Kost, Y. Barenholz, Chem. Biomaterials 2016, 81, 46; c) H. Bi, S. Ma, Q. Li, X. Han, J. Mater.
Phys. Lipids 2009, 162, 1; d) B. P. Timko, D. S. Kohane, Clin. Chem. B 2016, 4, 3269.
Ther. 2012, 34, S25. [28] a) A. Hervault, A. E. Dunn, M. Lim, C. Boyer, D. Mott,
[7] B. P. Timko, T. Dvir, D. S. Kohane, Adv. Mater. 2010, 22, 4925. S. Maenosono, N. T. Thanh, Nanoscale 2016, 8, 12152;
[8] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, J. Controlled b) Z. Al-Ahmady, K. Kostarelos, Chem. Rev. 2016, 116, 3883.
Release 2000, 65, 271. [29] a) A. S. Hoffman, J Controlled Release 2008, 132, 153;
[9] a) A. M. Alkilany, S. E. Lohse, C. J. Murphy, Acc. Chem. Res. b) M. Karimi, A. Ghasemi, P. Sahandi Zangabad, R. Rahighi,
2012, 46, 650; b) G. Jalani, R. Naccache, D. H. Rosenzweig, S. M. Moosavi Basri, H. Mirshekari, M. Amiri, Z. Shafaei Pishabad,
L. Haglund, F. Vetrone, M. Cerruti, J. Am. Chem. Soc. 2015; A. Aslani, M. Bozorgomid, D. Ghosh, A. Beyzavi, A. Vaseghi,
c) T.-Y. Liu, S.-H. Hu, D.-M. Liu, S.-Y. Chen, I.-W. Chen, Nano A. R. Aref, L. Haghani, S. Bahrami, M. R. Hamblin, Chem. Soc.
Today 2009, 4, 52. Rev. 2016, 45, 1457.
DOI: 10.1002/smll.201601129
reviews
[30] a) A. Chan, R. P. Orme, R. A. Fricker, P. Roach, Adv. Drug Delivery [50] F. Hu, K. G. Neoh, E. T. Kang, Macromol. Rapid Commun. 2009,
Rev. 2013, 65, 497; b) D. Bhattacharya, B. Behera, S. K. Sahu, 30, 609.
R. Ananthakrishnan, T. K. Maiti, P. Pramanik, New J. Chem. [51] E. Ju, Z. Li, Z. Liu, J. Ren, X. Qu, ACS Appl. Mater. Interfaces
2016, 40, 545. 2014, 6, 4364.
[31] X. J. Loh, J. Li, Expert Opin. Ther. Patents 2007, 17, 965. [52] H. Wang, J. Yi, S. Mukherjee, P. Banerjee, S. Zhou, Nanoscale
[32] a) T. Lajunen, L.-S. Kontturi, L. Viitala, M. Manna, 2014, 6, 13001.
O. Cramariuc, T. Róg, A. Bunker, T. Laaksonen, T. Viitala, [53] H. Kang, A. C. Trondoli, G. Zhu, Y. Chen, Y.-J. Chang,
L. Murtomäki, Mol. Pharm. 2016, 13, 2095; b) M. E. Muroski, H. Liu, Y.-F. Huang, X. Zhang, W. Tan, ACS Nano 2011, 5,
R. A. Morshed, Y. Cheng, T. Vemulkar, R. Mansell, Y. Han, 5094.
L. Zhang, K. S. Aboody, R. P. Cowburn, M. S. Lesniak, PloS One [54] J. Liu, C. Detrembleur, A. Debuigne, M.-C. De Pauw-Gillet,
2016, 11, e0145129; c) W. Zhang, F. Wang, Y. Wang, J. Wang, S. Mornet, L. Vander Elst, S. Laurent, E. Duguet, C. Jérôme,
Y. Yu, S. Guo, R. Chen, D. Zhou, J. Controlled Release 2016, 232, J. Mater. Chem. B 2014, 2, 1009.
9; d) Q. Feng, Y. Zhang, W. Zhang, X. Shan, Y. Yuan, H. Zhang, [55] W.-H. Chiang, V. T. Ho, H.-H. Chen, W.-C. Huang, Y.-F. Huang,
L. Hou, Z. Zhang, Acta Biomater. 2016, 38, 129; e) X. Wang, S.-C. Lin, C.-S. Chern, H.-C. Chiu, Langmuir 2013, 29, 6434.
C. Wang, Q. Zhang, Y. Cheng, Chem. Commun. 2016, 52, 978; [56] N. Guarrotxena, I. Quijada-Garrido, Chem. Mater. 2016, 28,
f) C. Ding, Y. Liu, T. Wang, J. Fu, J. Mater. Chem. B 2016, 4, 2819. 1402.
[33] Y. Shao, W. Huang, C. Shi, S. T. Atkinson, J. Luo, Ther. Deliv. [57] A. Yahia-Ammar, D. Sierra, F. Merola, N. Hildebrandt,
2012, 3, 1409. X. Le Guevel, ACS Nano 2016, 10, 2591.
[34] a) E. S. Lee, Z. Gao, Y. H. Bae, J. Controlled Release 2008, 132, [58] X. Wu, X. He, L. Zhong, S. Lin, D. Wang, X. Zhu, D. Yan, J. Mater.
164; b) Z. Liu, N. Zhang, Curr. Pharm. Des. 2012, 18, 3442. Chem. 2011, 21, 13611.
[35] B. P. Timko, D. S. Kohane, Expert Opin. Drug Delivery 2014, 11, [59] A. Barhoumi, W. Wang, D. Zurakowski, R. S. Langer,
1681. D. S. Kohane, Nano Lett. 2014, 14, 3697.
[36] a) P. K. Jain, W. Qian, M. A. El-Sayed, J. Am. Chem. Soc. 2006, [60] R. Huschka, A. Barhoumi, Q. Liu, J. A. Roth, L. Ji, N. J. Halas, ACS
128, 2426; b) T.-Y. Liu, S.-H. Hu, T.-Y. Liu, D.-M. Liu, S.-Y. Chen, Nano 2012, 6, 7681.
Langmuir 2006, 22, 5974. [61] J. Yu, Y. Ju, L. Zhao, X. Chu, W. Yang, Y. Tian, F. Sheng, J. Lin,
[37] a) R. Huschka, J. Zuloaga, M. W. Knight, L. V. Brown, F. Liu, Y. Dong, ACS Nano 2016, 10, 159.
P. Nordlander, N. J. Halas, J. Am. Chem. Soc. 2011, 133, 12247; [62] J. Yu, Y. Ju, L. Zhao, X. Chu, W. Yang, Y. Tian, F. Sheng, J. Lin,
b) M. Chen, P. Qiu, X. He, K. Wang, S. Chen, S. Yang, X. Ye, F. Liu, Y. Dong, Y. Hou, ACS Nano 2016, 10, 159.
J. Mater. Chem. B 2014, 2, 3204. [63] H. Wang, R.-l. Han, L.-m. Yang, J.-h. Shi, Z.-j. Liu, Y. Hu,
[38] A. Barhoumi, R. Huschka, R. Bardhan, M. W. Knight, N. J. Halas, Y. Wang, S.-j. Liu, Y. Gan, ACS Appl. Mater. Interfaces 2016, 8,
Chem. Phys. Lett. 2009, 482, 171. 4416.
[39] L. Poon, W. Zandberg, D. Hsiao, Z. Erno, D. Sen, B. D. Gates, [64] a) Q. Q. Dou, H. C. Guo, E. Ye, Mater. Sci. Eng. C 2014, 45, 635;
N. R. Branda, ACS Nano 2010, 4, 6395. b) J. Liu, W. Bu, L. Pan, J. Shi, Angew. Chem. Int. Ed. 2013, 52,
[40] S. Yamashita, H. Fukushima, Y. Akiyama, Y. Niidome, T. Mori, 4375.
Y. Katayama, T. Niidome, Biorg. Med. Chem. 2011, 19, 2130. [65] M. K. G. Jayakumar, N. M. Idris, Y. Zhang, Proc. Natl. Acad. Sci.
[41] S. E. Lee, G. L. Liu, F. Kim, L. P. Lee, Nano Lett. 2009, 9, 2012, 109, 8483.
562. [66] S. S. Lucky, N. Muhammad Idris, Z. Li, K. Huang, K. C. Soo,
[42] A. Riedinger, P. Guardia, A. Curcio, M. A. Garcia, R. Cingolani, Y. Zhang, ACS Nano 2015, 9, 191.
L. Manna, T. Pellegrino, Nano Lett. 2013, 13, 2399. [67] Q. Dou, C. Teng, E. Ye, X. Loh, Int. J. Nanomed. 2015, 10,
[43] a) X. Fan, Z. Wang, D. Yuan, Y. Sun, Z. Li, C. He, Polym. Chem. 419.
2014, 5, 4069; b) Z. Li, D. Yuan, X. Fan, B. H. Tan, C. He, Lang- [68] W. J. Mulder, G. J. Strijkers, G. A. van Tilborg, A. W. Griffioen,
muir 2015, 31, 2321; c) Z. Li, Z. Zhang, K. L. Liu, X. Ni, J. Li, K. Nicolay, NMR Biomed. 2006, 19, 142.
Biomacromolecules 2012, 13, 3977; d) Z. Li, H. Yin, Z. Zhang, [69] H. Fattahi, S. Laurent, F. Liu, N. Arsalani, L. V. Elst, R. N. Muller,
K. L. Liu, J. Li, Biomacromolecules 2012, 13, 3162; e) Z. Li, Nanomedicine 2011, 6, 529.
B. H. Tan, T. Lin, C. He, Prog. Polym. Sci. 2016, DOI: 10.1016/j. [70] K.-J. Chen, E.-Y. Chaung, S.-P. Wey, K.-J. Lin, F. Cheng, C.-C. Lin,
progpolymsci.2016.1005.1003. H.-L. Liu, H.-W. Tseng, C.-P. Liu, M.-C. Wei, ACS Nano 2014, 8,
[44] a) A. A. Karim, Q. Dou, Z. Li, X. J. Loh, Chem. Asian J. 2016, 5105.
11, 1300; b) Z. Li, L. W. Swee, Mater. Sci. Eng.: C 2016, [71] Y. Komizu, Y. Matsumoto, R. Ueoka, Bioorg. Med. Chem. Lett.
DOI: 10.1016/j.msec.2016.03.039. 2006, 16, 6131.
[45] A. Hervault, N. T. K. Thanh, Nanoscale 2014, 6, 11553. [72] P. M. Peiris, L. Bauer, R. Toy, E. Tran, J. Pansky, E. Doolittle,
[46] a) C. K. Liu, Q. Dou, S. S. Liow, J. N. Kumar, X. J. Loh, Aust. E. Schmidt, E. Hayden, A. Mayer, R. A. Keri, M. A. Griswold,
J. Chem. 2015, 69, 363; b) X. J. Loh, S. J. Ong, Y. T. Tung, E. Karathanasis, ACS Nano 2012, 6, 4157.
H. T. Choo, Polym. Chem. 2013, 4, 2564; c) X. J. Loh, S. J. Ong, [73] S. J. Leung, M. Romanowski, ACS Nano 2012, 6, 9383.
Y. T. Tung, H. T. Choo, Macromol. Biosci. 2013, 13, 1092; [74] G. V. Orsinger, J. D. Williams, M. Romanowski, ACS Nano 2014,
d) X. J. Loh, S. J. Ong, Y. T. Tung, H. T. Choo, Mater. Sci. Eng. 8, 6151.
C-Mater. Biol. Appl. 2013, 33, 4545; e) X. J. Loh, J. Appl. Polym. [75] E. Amstad, J. Kohlbrecher, E. Muller, T. Schweizer, M. Textor,
Sci. 2013, 127, 992. E. Reimhult, Nano Lett. 2011, 11, 1664.
[47] T. Y. Liu, K. H. Liu, D. M. Liu, S. Y. Chen, I. W. Chen, Adv. Funct. [76] R. Di Corato, G. Béalle, J. Kolosnjaj-Tabi, A. Espinosa,
Mater. 2009, 19, 616. O. Clément, A. K. A. Silva, C. Ménager, C. Wilhelm, ACS Nano
[48] T. Yin, X. Liu, J. Z. Wang, Y. L. An, Z. K. Zhang, L. Q. Shi, RSC Adv. 2015, 9, 2904.
2015, 5, 47458. [77] D. Yuan, Z. Li, W. Thitsartarn, X. Fan, J. Sun, H. Li, C. He, J. Mater.
[49] a) Z. Li, X. J. Loh, Chem. Soc. Rev. 2015, 44, 2865; b) Z. Li, Chem. C 2015, 3, 3708.
B. H. Tan, Mater Sci Eng C 2014, 45, 620; c) Z. Li, J. Li, J. Phys. [78] D. Wang, S. Wu, Langmuir 2016, 32, 632.
Chem. B 2013, 117, 14763; d) Z. Li, X. Yang, L. Wu, Z. Chen, [79] F. Lu, A. Popa, S. Zhou, J.-J. Zhu, A. C. S. Samia, Chem. Commun.
Y. Lin, K. Xu, G.-Q. Chen, J. Biomater. Sci. Polym. Ed. 2009, 20, 2013, 49, 11436.
1179; e) Z. Li, S. Cheng, S. Li, Q. Liu, K. Xu, G.-Q. Chen, Polym. [80] A. Baeza, E. Guisasola, E. Ruiz-Hernández, M. Vallet-Regí, Chem.
Int. 2008, 57, 887. Mater. 2012, 24, 517.
DOI: 10.1002/smll.201601129
[81] W.-P. Li, P.-Y. Liao, C.-H. Su, C.-S. Yeh, J. Am. Chem. Soc. 2014, T.-H. Wu, H. Wang, W.-Y. Lin, M. Ohashi, P.-Y. Chiou, H.-R. Tseng,
136, 10062. Angew. Chem. Int. Ed. 2010, 49, 3777; c) C. R. Thomas,
[82] J. Liu, C. Detrembleur, M.-C. De Pauw-Gillet, S. Mornet, L. V. Elst, D. P. Ferris, J.-H. Lee, E. Choi, M. H. Cho, E. S. Kim, J. F. Stoddart,
S. Laurent, C. Jérôme, E. Duguet, J. Mater. Chem. B 2014, 2, 59. J.-S. Shin, J. Cheon, J. I. Zink, J. Am. Chem. Soc. 2010, 132,
[83] X. Xie, F. Li, H. Zhang, Y. Lu, S. Lian, H. Lin, Y. Gao, L. Jia, Eur. J. 10623; d) J. Croissant, J. I. Zink, J. Am. Chem. Soc. 2012, 134,
Pharm. Sci. 2016, 83, 28. 7628.
[84] F. Tang, L. Li, D. Chen, Adv. Mater. 2012, 24, 1504. [101] B. P. Timko, M. Arruebo, S. A. Shankarappa, J. B. McAlvin,
[85] W. Xiao, W.-H. Chen, X.-D. Xu, C. Li, J. Zhang, R.-X. Zhuo, O. S. Okonkwo, B. Mizrahi, C. F. Stefanescu, L. Gomez, J. Zhu,
X.-Z. Zhang, Adv. Mater. 2011, 23, 3526. A. Zhu, PNAS 2014, 111, 1349.
[86] Y. Sun, B. T. Mayers, Y. Xia, Nano Lett. 2002, 2, 481. [102] D. S. Kohane, R. Langer, Chem. Sci. 2010, 1, 441.
[87] H. Liu, T. Liu, X. Wu, L. Li, L. Tan, D. Chen, F. Tang, Adv. Mater. [103] C. P. Phenix, M. Togtema, S. Pichardo, I. Zehbe, L. Curiel,
2012, 24, 755. J. Pharm. Pharm. Sci. 2014, 17, 136.
[88] M. Yu, F. Guo, J. Wang, F. Tan, N. Li, Biomaterials 2016, 79, 25. [104] O. Veiseh, J. W. Gunn, M. Zhang, Adv. Drug Delivery Rev. 2010,
[89] J. You, G. Zhang, C. Li, ACS Nano 2010, 4, 1033. 62, 284.
[90] J. Wei, K. Niikura, T. Higuchi, T. Kimura, H. Mitomo, H. Jinnai, [105] a) A. Agarwal, M. A. Mackey, M. A. El-Sayed, R. V. Bellamkonda,
Y. Joti, Y. Bessho, Y. Nishino, Y. Matsuo, J. Am. Chem. Soc. 2016, ACS Nano 2011, 5, 4919; b) C.-C. Chen, Y.-P. Lin, C.-W. Wang,
138, 3274. H.-C. Tzeng, C.-H. Wu, Y.-C. Chen, C.-P. Chen, L.-C. Chen,
[91] Y. Ren, R. Wang, L. Gao, K. Li, X. Zhou, H. Guo, C. Liu, D. Han, Y.-C. Wu, J. Am. Chem. Soc. 2006, 128, 3709; c) J. Huang,
J. Tian, Q. Ye, J. Controlled Release 2016, 228, 74. K. S. Jackson, C. J. Murphy, Nano Lett. 2012, 12, 2982;
[92] J. Song, J. Zhou, H. Duan, J. Am. Chem. Soc. 2012, 134, d) J. C. Y. Kah, J. Chen, A. Zubieta, K. Hamad-Schifferli, ACS
13458. Nano 2012, 6, 6730; e) T. Kawano, Y. Niidome, T. Mori,
[93] E. Oude Blenke, E. Mastrobattista, R. M. Schiffelers, Expert Y. Katayama, T. Niidome, Bioconj. Chem. 2009, 20, 209; f) J. Liu,
Opin. Drug Delivery 2013, 10, 1399. C. Detrembleur, M.-C. De Pauw-Gillet, S. Mornet, E. Duguet,
[94] J. Qin, I. Asempah, S. Laurent, A. Fornara, R. N. Muller, C. Jérôme, Polym. Chem. 2014, 5, 799; g) Y. Zhong, C. Wang,
M. Muhammed, Adv. Mater. 2009, 21, 1354. L. Cheng, F. Meng, Z. Zhong, Z. Liu, Biomacromolecules 2013,
[95] A. M. Derfus, G. von Maltzahn, T. J. Harris, T. Duza, K. S. Vecchio, 14, 2411.
E. Ruoslahti, S. N. Bhatia, Adv. Mater. 2007, 19, 3932. [106] a) C. J. Carling, F. Nourmohammadian, J. C. Boyer, N. R. Branda,
[96] A. Riedinger, P. Guardia, A. Curcio, M. A. Garcia, R. Cingolani, Angew. Chem. Int. Ed. 2010, 49, 3782; b) N. M. Idris,
L. Manna, T. Pellegrino, Nano Lett. 2013, 13, 2399. M. K. Gnanasammandhan, J. Zhang, P. C. Ho, R. Mahendran,
[97] K. Katagiri, Y. Imai, K. Koumoto, T. Kaiden, K. Kono, S. Aoshima, Y. Zhang, Nat. Med. 2012, 18, 1580; c) H. Wang, C. Dong,
Small 2011, 7, 1683. P. Zhao, S. Wang, Z. Liu, J. Chang, Int. J. Pharm. 2014, 466, 307.
[98] Y. Jin, X. Gao, J. Am. Chem. Soc. 2009, 131, 17774. [107] S. Link, C. Burda, B. Nikoobakht, M. A. El-Sayed, J. Phys. Chem.
[99] B. Yan, J.-C. Boyer, N. R. Branda, Y. Zhao, J. Am. Chem. Soc. B 2000, 104, 6152.
2011, 133, 19714.
[100] a) J.-H. Lee, K.-J. Chen, S.-H. Noh, M. A. Garcia, H. Wang, Received: April 2, 2016
W.-Y. Lin, H. Jeong, B. J. Kong, D. B. Stout, J. Cheon, H.-R. Tseng, Revised: May 27, 2016
Angew. Chem. Int. Ed. 2013, 52, 4384; b) S. Wang, K.-J. Chen, Published online:
DOI: 10.1002/smll.201601129

Recent Advances of Using Hybrid Nanocarriers

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Recent Advances of Using Hybrid Nanocarriers

Uploaded by

Copyright:

Available Formats

www.MaterialsViews.

Recent Advances of Using Hybrid Nanocarriers in

From the Contents

of application. In this section, some strategies to stimulate

4. Structures of Hybrid Nanovehicles

Le Guevel and co-workers demonstrated the fabrica-

usually used to encapsulate drugs which are hydrophilic in

of covalent bonds’ and hydrogen bonds’.

temperature so as to allow for more precise control on the

5.5. Rupture of Nanostructures

In the applications whereby controlled and sustained release

controlled DDS with significant cancer-

6. Concerns and Limitations

You might also like