Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489

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Colloids and Surfaces B: Biointerfaces

journal homepage: www.elsevier.com/locate/colsurfb

The application of prodrug-based nano-drug delivery strategy in

cancer combination therapy
Yanxiu Ge, Yakun Ma, Lingbing Li ∗
Department of Pharmaceutics, School of Pharmacy, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong Province 250012, China

a r t i c l e i n f o a b s t r a c t

Article history: Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing
Received 30 May 2016 of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent
Received in revised form 24 June 2016 active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-
Accepted 27 June 2016
DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review,
Available online 28 June 2016
we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations
of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the com-
Keywords:
bination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of
Combination therapy
Drug delivery
prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent
Prodrug literature are discussed to demonstrate the feasibilities of relevant technology.
Prodrug-based nano-drug delivery system © 2016 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
2. Different chemotherapy drugs combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
2.1. Prodrug + free drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
2.2. Prodrug + prodrug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3. Combination therapy of prodrug with other therapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
4. Combination therapy of prodrug with nucleic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
5. Combination chemotherapy and phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
6. Conclusion and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487

1. Introduction side effects and improved therapeutic profile has drawn more and
more attention from pharmaceutical researchers [6].
Cancer is a complex disease that represents one of the lead- Combination therapy, generally refers to either the co-
ing causes of death in developed countries [1,2]. Although a large administration of two or more therapeutic agents achieving a
number of potent chemotherapeutic anticancer agents have been synergistic antiproliferative effect or to the combination of dif-
successfully used in clinical practice, there has been no significant ferent types of therapy (e.g. chemotherapy and radiotherapy) [7].
progress in cancer treatment due to the lack of selectivity against Multi-agent therapy can generate synergistic anticancer effects by
cancer cells and associated toxic side effects [1,3,4]. Besides, the focus on different signaling pathways in tumor cells, overcome
multidrug resistance of cancer cells and limited regime of clinical mechanisms of resistance and minimize side effects [8,9]. Actu-
uses of single drug becomes the major limitations in anti-tumor ally, it is routinely used for the treatment of cancer and indeed
treatment [5]. Therefore, the combination therapy with decreased improves the therapeutic effect [10]. For instance, the combination
therapy of doxorubicin (DOX) and paclitaxel (PTX) is used as first-
line treatment for metastatic breast cancer [11–13]. The efficacy
∗ Corresponding author. of hypoxia-activated prodrug TH-302 in combination with dox-
E-mail address: cnlilingbing@yahoo.com (L. Li). orubicin for use in first-line advanced soft tissue sarcoma (STS)

http://dx.doi.org/10.1016/j.colsurfb.2016.06.051
0927-7765/© 2016 Elsevier B.V. All rights reserved.
 Y. Ge et al. / Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489
Table 1
Examples of recently developed P-N-DDSs for combination of prodrug plus free drug.
Name Agent 1 type (name)
Agent 2 type (name)
PluronicF127-CS-DOX + PTX Doxorubicin (DOX)
Paclitaxel (PTX)
PEGylated Taxol + DOX Doxorubicin (DOX)
Paclitaxel (PTX)
PEG-C6-AZO-CA4 + DOX Combretastatin A-4 (CA4)
Doxorubicin (DOX)
Herparin-DEX + DOX Dexamethasone(DEX)
Doxorubicin(DOX)
PLGA-PEG-CBP + PTX Carboplatin (CBP)
Paclitaxel (PTX)
5-FU-stearic acid + CDDP 5-FU
Cisplatin (CDDP)
TPGS-cisplatin + docetaxel Cisplatin
Docetaxel
PLA-Pt (IV) + docetaxel Cisplatin (Pt)
Docetaxel
Pluronic P105-DOX + PTX Doxorubicin (DOX)
Paclitaxel (PTX)
mPEG-b-PLG-g-PTX + DOX Doxorubicin (DOX)
Paclitaxel (PTX)
CS: chitosan; PEG: polyethylene glycol; C6: hexanethiol; AZO: azobenzene; PLGA: Poly (dl-lactide-co-glycolide); TPGS: d-alpha-tocopheryl polyethylene glycol 1000 succi-
nate; PLA: polyactide; mPEG-b-PLG: methoxypoly(ethylene glycol)-block-poly(l-glutamic acid).
assessed in clinical studies was favorably with outcomes achieved
compared with other first-line chemotherapies for advanced STS
[14]. Besides, the combination of gemcitabine and TH-302 signifi-
cantly improved tumor response compared with gemcitabine alone
in previously untreated, locally advanced or metastatic pancreatic
cancer [15].
Though appropriate drug combinations can produce signifi-
cant benefits in cancer treatment, current combination approach
through the cocktail administration leaves plenty of room for
improvements [16]. One major challenge is how to ensure the cor-
rect radio of the combined drugs to the target, as the optimized dose
ratio complicated by dissimilar pharmacokinetics and biodistribu-
tion is hard to be maintained due to different rates of metabolism
within the body [7]. Besides, the combination of small molecule
drugs would accompany with unfavorable toxic side effects. From
this point of view, the application of nanotechnology has opened
up unprecedented opportunities in controlled drug delivery and
novel combination strategies [16–18]. A myriad of nanoscale drug
delivery systems including micelles, liposomes, nanoparticles and
nanogels, have endowed encapsulated drugs more favorable phar-
macokinetic profiles compared to free small-molecule drugs [5,19].
They solve the shortcomings of most anticancer drugs such as low
solubility, fast blood clearance, multidrug resistance, reduce the
side effects by the selective accumulation at tumor sites over nor-
mal tissues, via both passive and active mechanisms [20–23]. They
can also improve the efficacy of multimodality treatment by their
ability to effectively delivering multiple therapeutic agents simul-
taneously and to synchronize their delivery to the target site [24].
For example, Zhen Li et al. constructed hollow silica nanoparti-
cles sealed with ZnO quantum dots to co-deliver camptothecin
(CPT) and doxorubicin (DOX· HCl) [25]. Only when the nanopar-
ticles entered into the acid intracellular compartments of cancer
cells, could the ZnO quantum dots be dissolved and trigger the
release of the drug. The pH-sensitive drug release minimized the
toxicity for normal tissues. More important, in vitro cellular assays
revealed that the two drugs combinations with different anticancer
mechanism highly improved chemotherapeutic effect [25].
However, in a single combinatorial nanoparticle, drug co-
encapsulation through non-covalent physical entrapment leads to
poor stability and batch-to-batch inconsistency in drug loading and
release kinetics, especially when two drugs have different solu-
483
Nanoplatform Refs.
Polymeric micelle [35]
Janus nanogels [66]
Micelle [67]
Polymeric micelle [68]
Nanoparticles [36]
Nanostructured lipid carriers (NLC) [69]
Nanoparticles [37]
Polymeric nanoparticle [18]
Mixed micelles [31]
Nanoparticles [70]
bility, charge and molecular weight [26]. It presents a challenge
for conventional nanocarriers to co-encapsulate two drugs with
different chemical and physical characters and precisely keep the
relative dosages of the two drugs, as most nanoparticle-based drug
combinations are comprised of bioactive compounds with simi-
lar water solubility [16,24,27]. For instance, polymeric micelles are
not suitable for loading well water-soluble drugs because of their
hydrophobic core, not to mention relative combination therapy
[16]. Liposomes are capable of carrying hydrophilic and hydropho-
bic drugs in its inner core and bilayer membrane, respectively.
But this formulation has disadvantages, such as a lower localized
hydrophobic drug concentration in the lipid bilayer and a higher
initial burst, as well as thermodynamic instability [28].
Prodrugs are defined as chemically modified, biologically inert
compounds that are metabolized in vivo to regenerate the parent
bioactive components [3]. The main advantages of prodrugs com-
pared to the parent free drugs are: (a) improved solubility in water
or lipid membrane [29]; (b) decreased adverse effects [30,31]; (c)
improved cell uptake [1,3]. By conjugating a polymer or a tumor-
specific ligand to chemotherapy drugs via a cleavable bond, they
can also be designed to target specific antigens or enzymes that are
over-expressed on tumor cells compared with other normal cells
[1,32]. Recently, their applications have been extended to combina-
tion therapy. Prodrug-based nano-drug delivery systems in the field
of combination chemotherapy to facilitate more efficient delivery
of anticancer drugs are still advanced and pioneering [33].
The aim of this paper is to review the use of prodrug-based
nano-drug delivery system strategy in combination therapy with
a focus on cancer treatment. We focus separately on each type of
systems, including combination therapy of prodrugs with different
chemotherapy agents, other therapeutic agents, nucleic acid and
the combination of chemotherapy with phototherapy. We also dis-
cuss some interesting examples from the recent literature on the
development of P-N-DDS strategy in combination cancer therapy.
2. Different chemotherapy drugs combinations
2.1. Prodrug + free drug
In this approach, a prodrug is administered in combination with
a low molecular weight drug. It means one free antitumor drug
484 Y. Ge et al. / Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489
Table 2
Examples of recently developed P-N-DDSs for combination of prodrug plus prodrug.
Name Agent 1 type (name)
Agent 2 type (name)
PLL-PTX + HA-GEM Paclitaxel (PTX)
Gemcitabine(GEM)
SSP-CPT + SSP-DOX Camptothecin (CPT)
Doxorubicin (DOX)
MPEG-b-P(LA-co-MCC/PTX) + Cisplatin (Pt)
MPEG-b-P(LA-co-MCC/CisPt(IV)) Paclitaxel (PTX)
P1-DRB + P2-Oxa(IV) Oxaliplatin (Oxa)
Daunorubicin (DRB)
DOX-PLA + CPT-PLA Doxorubicin (DOX)
Camptothecin (CPT)
HA-lysine (L)-BCL + Baicalein (BCL)
FA-valine (V)-PTX Paclitaxel (PTX)
ADD-DOX Adjudin (ADD)
Doxorubicin (DOX)
Ir-Cb Chemotherapy (Ir)
Chemotherapy (Cb)
PLL: poly (l-lysine); HA: hyaluronic acid; SSP: stimuli-responsive silane prodrug; PLA: poly-l-lactide; HA: hyaluronic acid; FA: folate; P1: MPEG-b-P(LA-co-MCC)-COOH; P2:
MPEG-b-P(LA-co-MCC)-OH; MPEG-b-P(LA-co-MCC): methoxyl-poly (ethylene glycol)-block-poly (lactide-co-2-methyl-2-carboxyl-propylene carbonate).
carried by a P-N-DDS formed by the amphiphilic polymer conju-
gate of another antitumor drug, or by the prodrug-encapsulated
nanosystems, in which prodrugs are encapsulated in nanocarriers.
The prodrug-based nanocarriers offer a new strategy to create ideal
combination cancer therapy systems by noncovalently encapsulat-
ing a low molecular weight drug simultaneously. They combined
the advantages of both prodrugs and co-delivery systems to facil-
itate synergistic therapeutic effects via simultaneous multi-drug
accumulation [28]. Recently developed P-N-DDSs for combination
of prodrug plus free drug are summarized in Table 1.
The P-N-DDSs can be designed to improve the selectivity and
efficacy by conjugating a polymer to the chemotherapy drug via
the bonds (e.g. ester, amide or disulfide bond) which were cleaved
under triggerable conditions such as a lowered interstitial pH,
high intracellular glutathione levels in tumors, or enzymes over-
expressed by tumors [1]. Based on this strategy, the P-N-DDSs for
combination therapy can enhance drug bioavailability for advanced
drug delivery [34]. For example, Yakun Ma et al. conjugated DOX
to Pluronic F127-chitosan (F127-CS) copolymer via acid-sensitive
amide linkage, which ensure drug release in cancer cellular acid
environment [35]. The results showed that the release of DOX and
PTX from polymeric micelles exhibited a pH-dependent manner.
And the pH-sensitive polymeric micelle system based on the con-
jugated prodrug (F127-CS-DOX) for co-delivery of DOX and PTX
exhibited a better bioavailability than the PTX plus DOX solution
in vivo pharmacokinetic study [35].
Most anticancer drugs have difficulties in formulation due
to their problems in solubility. With the help of prodrug-based
nanocarriers, the difficulty in co-encapsulating hydrophilic and
hydrophobic drugs can be overcome, as the prodrug strategy can
improve drug molecule’s compatibility with carrier platforms by
chemical modifications, and hence balance the pharmacokinet-
ics of hydrophilic and hydrophobic drugs [16,36]. For example,
hydrophilic carboplatin (CBP) in combination with hydrophobic
PTX was used for non-small cell lung cancer (NSCLC) clinically
with severe side effects [36]. Designing nanocarriers platform to
co-encapsulate the two drugs to increase therapeutic efficacy and
decrease toxic effect is urgent [36]. Wen Zhang et al. conjugated
the hydrophilic CBP to PLGA-PEG-COOH to synthesized PLGA-PEG-
CBP. Then the combination delivery of CBP and hydrophobic PTX
was achieved through encapsulating PTX into nanoparticles self-
assembled by PLGA-PEG-CBP. The synergistic anti-tumor efficacy
in NCL-H460 lung cancer cells and mice-bearing lung cancer cells
model were observed [36].
Nanoplatform Refs.
Muti-prodrug nanocarriers [28]
Nonporous silica prodrug nanoparticles [19]
Composite micelles [41]
Composite micelle [42]
Polymeric nanoparticles [40]
Nanoparticles [33]
Micelle [43]
Nanoparticles [44]
Furthermore, by exploiting selective tumor targeting through
conjugating a tumor-specific ligand to the polymer, the P-N-DDS
resulted in enhanced delivery efficiency to target cells. For exam-
ple, Yu Mi et al. have conjugated herceptin onto the D-␣-tocopherol
polyethylene glycol 1000 succinate-cisplain (TPGS-cisplatin) pro-
drug nanoparticles to co-deliver both cisplatin and docetaxel [37].
Herceptin, a humanized monoclonal antibody, can not only target
the extracellular domain of human epidermal growth factor recep-
tor 2 (HER2) but also be used as a biological therapeutic agent for
HER2-overexpressing breast cancer [37–39]. The in vitro cytotoxic-
ity showed the nanoparticles achieved the highest efficacy for HER2
positive cancer cells and much better therapeutic efficacy than each
of the two original drugs alone [37].
2.2. Prodrug + prodrug
In this approach, two prodrugs each carrying a single therapeu-
tic agent are administered in combination. It means the co-delivery
of two polymer-drug conjugates or drug-drug conjugate in one P-
N-DDS. Recently developed P-N-DDSs for combination of prodrug
plus prodrug are summarized in Table 2.
Although nanoparticle-based combination therapies unify the
pharmacokinetics and biodistribution of different drug molecules
and thus enable the dosage optimization in vivo, it presents a chal-
lenge for controlling the ratios of different types of drugs in one
nanoparticle [40]. Steric hindrance between the polymer back-
bones and different drug molecules, variability in drug-to-polymer
and drug-to-drug interactions, and batch-to-batch inconsistency
in conjugation chemistry are the influencing factors [40]. One
approach to address these issues is the combination of two
polymer-drug conjugates, each carrying a single therapeutic agent,
and the final loading yield of the therapeutic agents follows the
same molar ratio as the drug-polymer conjugates used during the
nanoparticle preparation [16,40]. For example, Haihua Xiao and
colleagues synthesized a cisplatin (IV) conjugate and a paclitaxel
conjugates starting with the same biodegradable and amphiphilic
block copolymer. Composite micelles with desirable drug contents
and ratio can be obtained by simply mixing the two conjugates at
desirable molar ratios of Pt/PTX and co-assembling them. More-
over, the synergistic effects have been demonstrated in vitro and
the combination therapy in micellar dosage-form led to safer
and better antitumor efficacy in vivo than the small molecules
based combination [41]. Applying the same principle, the same
group also evaluated the therapeutic effect of the composite
 Y. Ge et al. / Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489
Fig. 1. Schematic illustration of multi-prodrug nanocarriers consisting of PLL-PTX and HA-GEM.
micelles co-assembled by polymer-daunorubicin (DRB) conjugate
and polymer-Oxaliplatin (IV) conjugate, which has the similar car-
rier polymer as in the Polymer-DRB conjugate. The relative drug
doses in the micelles can be modulated easily by simply adjusting
the mixed ratios of polymer-DRB conjugate and polymer-Oxa (IV)
conjugate. Treatment with the combination significantly reduced
systematic toxicity and improved synergistic effect compared with
combination of small molecules of the two anticancer drugs both
in vitro and in vivo [42].
The low delivery efficiency to target cells can be changed
as a result of exploiting selective tumor targeting. For example,
Ilkoo Noh and colleagues developed multi-prodrug nanocarriers
consisting of poly (l-lysine)-carboxylate paclitaxel (PLL-PTX) and
hyaluronic acid-conjugated gemcitabine (HA-GEM) (Fig. 1). HA has
a strong affinity for cell surface receptors of cluster determinant
44 (CD44), which is only over-expressed in malignancy. In vitro
and in vivo studies showed that this combination enhanced cellular
uptake of PTX and GEM into CD44-expressing human biliary cancer
cells compared to free drugs. And this system exhibited synergistic
cancer therapeutic efficacy with different treatment pathways of
the dual drugs [28].
Another type of the P-N-DDSs in the field of combination
chemotherapy is the self-assembling conjugates composed of two
different antitumor drugs, each of which is conjugated with differ-
ent polymers separately to achieve dual targets [33]. The polymer
prodrugs in this kind of P-N-DDS have a dual-targeting effect, which
means better synergistic effect compared with a single target [33].
For example, Wei Wang et al. developed self-assembled nanopar-
ticles (NPs) for the co-delivery of hyaluronic acid-lysine-baicalein
(HA-l-BCL) and folate-valine-paclitaxel (FA-V-PTX). The PTX-BCL
NPs which have dual-targeted ligands of HA and FA displayed
remarkably better antitumor activity and lower systemic toxic-
ity than their free drug counterparts in mice bearing an A549/PTX
drug-resistant lung cancer xenograft [33].
Another strategy to maintain the radio between two drugs with
drastically different properties is to covalently conjugate dual drugs
using a hydrolysable bond and then encapsulate the drug-drug con-
jugates into nanoparticles for co-delivery [40]. For example, Xu
Li and colleagues has conjugated Adjudin (ADD) to DOX via an
acid-sensitive hydrazone bond, and then encapsulated by DSPE-
485
PEG2000 into micelles. ADD could trigger mitochondrial dysfunction
in cancer cells and restore the chemosensitization of DOX-related
multidrug resistance (MDR) cancer cells. The rapidly release of
free DOX and ADD within the acidic endolysosomes of MCF-7/ADR
cancer cells, enhanced the anti-MDR capability of ADD-DOX (M)
micelles [43].
Though nanocarriers have lots of advantages in enhancing ther-
apeutic efficacy, in these delivery systems, carriers almost have no
therapeutic efficacy by themselves or even cause side-effects to
tissues and organs in the course of degradation, metabolism, and
excretion [44]. To avoid the problems from carriers, Ping Huang
et al. designed a drug self-delivery system. Instead of modifying
the hydrophilic compound with a hydrophobic polymer deriva-
tive, the amphiphilic drug-drug conjugate (ADDC) composing of
the hydrophilic anticancer drug irinotecan (Ir) and the hydrophobic
anticancer drug chlorambucil (Cb) via a hydrolysable ester link-
age can self-assembles into nanoparticles in water with an average
hydrodynamic diameter of 88.3 nm. By passive accumulation via
enhanced permeability and retention (EPR) effect, the accumula-
tion of Ir-Cb conjugate in the tumor tissue increased. After the
hydrolysis of the ester bond in the tumor cells, both free Ir and
Cb can be released to kill the cancer cells with synergetic cytotox-
icity, leading to an excellent anticancer activity in vitro and in vivo
[44]. Though the ratio between two drugs with different properties
can be maintained, the linker of drug-drug conjugates also limited
clinical applicability by constraining the molar ratio [40].
3. Combination therapy of prodrug with other therapeutic
agents
The P-N-DDSs for co-delivery of anticancer drugs and other
therapeutic agents can also be used for enhancing chemothera-
peutic effects furtherly, such as the combination of chemotherapy
drugs and anticancer synergists [45]. For example, P-N-DDS for
treating MDR cancer was emerged by the combination of DOX
with disulfiram (DSF), a P-gp inhibitor as well as an apoptosis
inducer. DSF was encapsulated into the micelles formed by the self-
assembly of SMA-ADH-DOX (SAD) conjugate, which was obtained
by conjugating DOX to poly(styrene-co-maleic anhydride) (SMA)
derivative with adipic dihydrazide (ADH) through an acid-cleavable
486 Y. Ge et al. / Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489

Table 3
Examples of recently developed P-N-DDSs for combination of prodrug with nucleic acid.

Name Agent 1 type (name) Nanoplatform Refs.

Agent 2 type (name)

DSS-BEN + DNA N1 ,N11 -bisethylnorspermine (BEMSpm) Polyplexes [71]

TNF␣ plasmid DNA
CPTssR5H5 + siRNA Camptothecin(CPT) Vesicles [47]
MAP3K7 siRNA
CPT-PCB + siPlk1 Camptothecin(CPT) Liposomes [49]
siPlk1 siRNA
TPGS-siRNA + docetaxel Docetaxel Micelle [58]
siPlk1 siRNA
PC-DOX + wtP53 plasmid Doxorubicin (DOX) Nanocomplex [53]
wt P53 plasmid

R5H5: oligo-peptide RRRRRHHHHHC; PCB: poly(carboxybetaine); TPGS: ␣-tocopheryl polyethylene glycol 1000 succinate; PC: ␤-cyclodextrin-polyethylenimine.

hydrazone bond. Encapsulated DSF was released faster than DOX prepared by grafting Dox to PC through peptide bonds linkages.
to inactivate P-gp and subsequently inhibits the pumping out of PC-Dox functions dually acted as a gene delivery vector as well
the chemotherapeutic drug. The smart co-delivery system showed as an anticancer prodrug. The prodrug-based drug delivery system
increased tumor accumulation of DOX and excellent antitumor (DDS) formed by PC-Dox could co-deliver Dox and wt p53 plasmid.
effect in MDR tumor [26]. The tumor suppressor gene p53 can not only induces apoptosis of
cells under DNA damage but also enhances the chemosensitivity of
tumor cells to chemotherapeutic drugs through the inhibition P-gp
4. Combination therapy of prodrug with nucleic acid
expression. The PC-Dox/p53 nanocomplexes efficiently deliver pro-
drug and gene to the same cancer cells simultaneously and increase
Due to severe side effects and gradually developed resistance of
the anticancer activity with synergistic therapeutic effects in vitro
those traditional anticancer drugs, nucleic acid therapeutics such
and in vivo [53]. The non-viral gene carriers offer great advan-
as small interfering RNA (siRNA), antisense oligonucleotides (AON),
tages, such as easy chemical modification and functionalization,
small hairpin RNA (shRNA), and plasmid DNA (pDNA) have been
easy preparation, high stability and good safety [46,54].
developed based on the increasing knowledge on molecular biol-
P-N-DDSs can also achieve in controlling the rate and sequence
ogy and biochemistry and shown promise in cancer treatment [46].
of release of the individual agents [46,49]. For instance, Yan Li
The efficacy of siRNA for the treatment of cancer in human has
et al. constructed CPT prodrug based cationic liposomes for the co-
been proven in a phase I clinical trial [47,48]. The combination
delivery siPlk1. The two drugs could be simultaneously delivered to
of chemotherapy drugs and nucleic acid-based therapy targeting
tumor cells and the siRNA targeting Plk1 was released earlier and
multiple disease pathways can cooperatively enhance anticancer
faster than CPT to enhance the sensitivity of CPT to cancer cells by
effect through synergistic or combined effect [45,47,49]. Therefore,
down-regulating the Plk1 expression, while CPT was released in a
considerable efforts have been made to develop safe and effec-
sustained and pH and esterase-dependent manner. As a result, this
tive vehicles to spatiotemporally co-localize anticancer drugs and
co-delivery system exhibited a synergistic effect in vitro and in vivo
nucleic acids in cancer cells [50,51]. Recently developed P-N-DDSs
[49].
for combination of prodrug with nucleic acid are summarized in
As widely investigated in co-encapsulation of nucleic acid
Table 3.
and hydrophobic chemotherapeutic drug are self-assembled block
A large amount of cationic lipid- and polymer-based nanocarri-
copolymers consisting of a hydrophobic block and a cationic block
ers have been used to deliver both nucleic acids and chemotherapy
incorporating the hydrophobic drug and nucleic acid, respectively
drugs [46]. However, the complexes formed by nucleic acids with
[46,55,56]. As the nucleic acids were absorbed on the cationic sur-
cationic polymers or lipids do not allow for easy co-encapsulation
face by electrostatic interaction, the release of them may not be well
of small molecule drugs [46]. One approach to the issue is the
controlled. They could dissociate from the surface and conjugate to
utilization of P-N-DDS, directly conjugating the drug to the poly-
other molecules such as cholesterol or peptide, upon changing in
meric vector via a biodegradable linker [52]. For example, cationic
pH or salt concentration, thus the stability can be improved, and
␤-cyclodextrin-polyethylenimine-Dox (PC-Dox) conjugates were

Fig. 2. Schematic illustration of TCAD@Ce6 and their application in vitro.

 Y. Ge et al. / Colloids and Surfaces B: Biointerfaces 146 (2016) 482–489
the biodistribution is changed [57]. In response to this issue, Jing
Zhao et al. have conjugated siPlk1 to TPGS via disulfide bond to
form TPGS-siPlk1, which could prevent premature release of siRNA
and facilitates triggering of its release in cell cytoplasm due to ele-
vated glutathione concentration. The micelles consisted of TPGS
and TPGS-siRNA conjugates for co-delivery docetaxel and siPlk1,
further enhances the efficacy to the HER2 positive breast cancer
through herceptin conjugation. The synergistic effects and the tar-
geting effects are assessed in vitro by IC50 [58].
5. Combination chemotherapy and phototherapy
Photodynamic therapy (PDT) refers to the cancer treatment
through the selective uptake of a light-sensitive agent, a photosen-
sitizer (PS), which can produce highly reactive oxygen species (ROS)
followed by exposure to a specific wavelength that irreversibly
induce cell apoptosis or necrosis in the targeted tissue [59–61]. As
the activating light is non-ionizing and the PS itself is minimally
toxic in the absence of light, only those cells that are simultane-
ously exposed to the PS, light and oxygen are exposed to cytotoxic
effect [62–64]. Thus PDT displayed the possibility of dual-selectivity
for cancer treatment by the preferential accumulation of PS in the
tumor through developing technologies and light irradiation selec-
tively on the tumor [62]. Based on the attractive tumor therapy
properties of PDT, the combination therapy of phototherapy and
chemotherapy may have synergistic therapeutic effects [59].
For example, a P-N-DDS based on chemo-photodynamic combi-
nation was prepared by co-delivering the photosensitizer chlorine
e6 (Ce6) and DOX in TCAD@Ce6 nanoparticles. TCAD was obtained
by conjugating TPGS to acid-sensitive cis-aconitic anhydride-
modified doxorubicin (CAD), and Ce6 was loaded into the prodrug
nanoparticle. The system could be easily hydrolyzed in the acid
microenvironment of tumors (Fig. 2). Compared with the free form
of DOX and Ce6, TCAD@Ce6 nanoparticles exhibited higher uptake
of DOX and Ce6 in vitro experiments, and induced higher inhibi-
tion of A549 tumor cells under near-infrared laser irradiation both
in vitro and in vivo [59].
Instead of polymer conjugates, chemotherapy drugs conju-
gates with PS can also be utilized for the combination therapy of
chemotherapy and phototherapy. For example, fullerenes, which
also have photoexcitation properties, covalently incorporated DOX
via a cleavable bond. The formed water-dispersible fullerene
aggregates with targeting ligands onto fullerenes could not only
exhibit a photodynamic effect but also enhanced cytotoxicity
towards folate receptor-positive cancer cells. The combined effect
of chemotherapy and PDT increases the therapeutic efficacy of the
DOX-fullerene aggregate prodrug. The P-N-DDS successfully com-
bined pH-responsible chemotherapeutic, active targeting, and PDT
properties into one system [65].
6. Conclusion and future perspective
Due to the molecular complexity of many diseases, the mul-
tidrug resistance of cancer cells and associated toxicity of clinical
uses of single drug, successful cancer therapies need to be based on
combination approaches, especially there is a significant process
in our understanding of various molecular basis and signal trans-
duction pathways in cancer. Because of the advances in polymer
chemistry, nanopreparations have evolved for combination ther-
apy, such as the incorporation of different chemotherapy drugs
and the combination of chemotherapy and phototherapy. Besides,
availability of advanced genomic technologies spurred co-delivery
of chemotherapy drugs and nucleic acid. However, it is more chal-
lenging to develop combination therapies than mono-therapies.
The combination within a nanopreparation requires sophisticated
487
optimization strategies to arrive at the identification of appropri-
ate drug combinations, correct choice of dosages, the optimal ratio
of the co-loaded therapeutics to achieve synergy, accurate drug
release and the critical features like relative safety and stability.
Prodrug-based nano-drug delivery systems synchronized the
advantages of prodrugs and nanotechnology, and thus able to
achieve enhanced antitumor efficiency. What’s more, numerous
nanoparticles based on self-assembling polymer-drug conjugates
are under clinical trials. This shows the great potential of these P-
N-DDSs in the clinical application in the future but at the same time
poses new challenges, such as the industrial production of chemi-
cal synthesis, the correction of in vitro studies with behavior in vivo
and the kinetics of drug release [45].
The successful development of P-N-DDSs has inspired the inter-
est of scientists to utilize them for combination therapy, which
combined the advantages of P-N-DDSs and combination therapy.
This kind of nanoprepatrations can seamlessly integrate not just
multiple therapeutic payloads with improved stability and drug
loading, but also co-delivery of hydrophobic drugs and hydrophilic
drug. Besides, it has been served as the effective delivery platforms
for drug-nucleic acid combination. Sophisticated nanoparticles,
which have active molecular targeting and respond to multi-
ple stimuli, could achieve more efficient therapy. Although, such
nanopreparations aroused great interest of scientists, they are
largely limited to research laboratories for now. While few anti-
cancer prodrugs have actually reached the market, numerous
prodrugs of cytotoxic anticancer agents are currently under clinical
trials.
This review article provides an overview of recent advances of
prodrug-based nano-drug delivery systems in the field of combi-
nation therapy against cancer. The benefits of combination therapy
for improved cancer therapies are clearly established. The future of
these systems is optimism and the need for designing multifunc-
tional P-N-DDSs for combination therapy will keep growing in the
future.
Declaration of interest
The authors gratefully acknowledge financial support from Nat-
ural Science Foundation of Shandong Province (ZR2015HM070).
The authors have no relevant affiliations or financial involvement
with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the
manuscript.
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