Targeted Drug Therapy in Non-Small Cell Lung Cancer: Clinical Significance and Possible Solutions-Part II (Role of Nanocarriers)

Expert Opinion on Drug Delivery
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
Targeted drug therapy in non-small cell lung

cancer: Clinical significance and possible solutions-
part II (role of nanocarriers)
Khushwant S. Yadav , Archana Upadhya & Ambikanandan Misra
To cite this article: Khushwant S. Yadav , Archana Upadhya & Ambikanandan Misra
(2020): Targeted drug therapy in non-small cell lung cancer: Clinical significance and
possible solutions-part II (role of nanocarriers), Expert Opinion on Drug Delivery, DOI:
10.1080/17425247.2021.1832989
To link to this article: https://doi.org/10.1080/17425247.2021.1832989
Accepted author version posted online: 05

Oct 2020.
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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group
Journal: Expert Opinion on Drug Delivery
DOI: 10.1080/17425247.2021.1832989
Targeted drug therapy in non-small cell lung cancer:
Clinical significance and possible solutions-part II (role of
nanocarriers)
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Khushwant S. Yadav, Archana Upadhya, Ambikanandan Misra*
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Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management,
SVKM’S NMIMS, Mumbai, India
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*Correspondence
Dr. Ambikanandan Misra
Information Classification: General

Director-Pharmaceutical Research
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management,
SVKM’S NMIMS, Mumbai, India
Email: ambikanandan.misra@nmims.edu; Misraan@hotmail.com
Abstract
Introduction: Non -small cell lung cancer (NSCLC) accounts for 80-85% of the
cases of lung cancer. NSCLC is further classified into its subtypes; adenocarcinoma,
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squamous cell carcinoma and large cell carcinoma depending on histological
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features and location in the lung tissue. The conventional therapeutic effective
dosage forms used to treat NSCLC are associated with rigid administration
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schedules, adverse effects and may be associated with acquired resistance to
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therapy. Nanocarriers may provide a suitable alternative to regular formulations to
overcome inherent drawbacks and provide better treatment modalities for the
patient.
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Areas covered: The article explores the application of drug loaded nanocarriers for
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lung cancer treatment. Drug loaded nanocarriers can be modified to achieve
controlled delivery at the desired tumor infested site. Their propensity to be stable
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and protect their payload from degrading enzymes in the tumor microenvironment
and the cellular lysosomal compartment may enable administration of a reduced
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dose to acquire the desired bioavailability and efficacy. The type of nanocarriers
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employed are diverse based on polymers, liposomes, metals and a combination of

two or more different base materials (hybrids). These may be designed for systemic
delivery or local delivery to the lung compartment (via inhalation).
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Expert opinion: Nanocarriers can improve pharmacokinetics of the drug payload by

improving its delivery to the desired location and can reduce associated systemic
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toxicities. Through nanocarriers, a wide variety of therapeutics can be administered

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and targeted to the cancerous site. Some examples of the utilities of nanocarriers
are co-delivery of drugs, gene delivery and delivery of other biologics.
Nanotechnology based formulations can be exploited for passive drug delivery by a
phenomenon termed as the enhanced permeability and retention (EPR) effect which
is manifested on account of impaired lymphatic drainage of tumor tissue and its
leaky vasculature. Overall, the nanocarriers have promising potential in improving
therapeutic efficacy of drugs used in NSCLC.

Keywords: Nanocarriers; NSCLC; Gene delivery; Cell line studies; Animal studies;
Clinical trials
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Article highlights
• The article provides the rationale of using Nanocarriers for Targeting

NSCLC
• Nanotechnology based carriers have improved pulmonary delivery and

injectable delivery of drugs for NSCLC by enabling drugs to reach
intended site of action.
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• The article discusses the application of exploiting nanocarriers for co-
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delivery of drugs and gene delivery in NSCLC.
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• The recent advances in various nano-based drug delivery carrier
formulations including polymeric nanoparticles, liposomes, hybrid
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nanoparticles, metal nanoparticles etc have been discussed.
• The articles highlight the studies carried on in-vitro NSCLC cell lines,
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preclinical studies plus ongoing and completed clinical trials so as to
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provide possible solution for commercialization of nano based formulations
for NSCLC.
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1. Introduction
Conventional therapy for NSCLC (as discussed in Part 1) has limited flexibilities
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related to administration routes, therapeutic regimens, side effects and the tendency
to develop resistance. The drugs approved as treatments for NSCLC have adverse
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effects which can cause further discomfort to the patients. Some of the examples of
adverse effects include loss of appetite, mouth sores, diarrhea and headaches. A
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reduction in the therapeutic dose may cause a lessening of the manifested side-
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effects, but may cause the cancerous cells to become resistant to therapy.
Resistance to therapy may arise in all forms of therapy; chemotherapy,
immunotherapy and targeted therapy. Resistance may also be encountered on
administration of the optimum dosage regimen if the drug molecules are unable to
reach the targeted site at bio-efficacious concentrations.
Nanocarriers are defined as the nanometer sized delivery systems in the size range
of 1–1000 nm (preferably below 200 nm). Nano systems may be designed and

modified to deliver therapeutics to desired site so as to provide effective therapies
and at the same time minimize or decrease the associated adverse effects [1]. The
nanocarriers facilitate drug molecules to reach their target site by explicit orientation
and by bypassing or avoiding biological hurdles. Nano-delivery platforms wherein
drug molecules are encapsulated or adsorbed on to a suitable nanocarrier may
provide a smart alternative which may remove the drawbacks of conventional
therapy [2]. Nano-delivery in treatment of NSCLC is still under experimental
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investigation for approved therapeutics. The only drug whose nanoformulation is
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FDA approved for treatment of NSCLC is paclitaxel, as nab-paclitaxel (Abraxane®).
Abraxane has been approved since 2005 and consists of nanoparticles which are
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sized 130nm and formed of albumin conjugated paclitaxel [3]. Other
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nanoformulations of paclitaxel such as Lipusu (liposomal), Genexol-PM (polymeric
micellar) and Nanoxel (polymeric micellar) are approved in different parts of the
world besides America for treatment of NSCLC [4]. These nanoformulations are
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credited with reducing the harsh side effects of paclitaxel. Besides the above-
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mentioned formulations there are several paclitaxel nanoformulations that are under
clinical trials [4]. This part of the review describes the role of nanocarriers in
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providing a platform for development of nanotherapeutics for treatment of NSCLC.

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1.1 Benefits and deficits of nanotherapeutics

The nanocarriers may prolong half-life of drugs in circulation and increase the
bioavailability of drugs. This may be achieved by modifying the surface of the
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nanocarriers to render them invisible to the phagocytic mechanisms of the circulatory

system. These may be coated with polyethylene glycol (PEG)-for a longer
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sustenance in circulation. Further modification of drug loaded nanocarriers with

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tumor specific ligands may bring about their selective accumulation at target site as
well as decrease in the cytotoxic effect on healthy cells [5, 6]. Further, controlled
delivery of the drug payload may be possible when it is effectively entrapped or
encapsulated within the nanocarrier in a manner that facilitates its slow release over
an extended period or release at the target location. Use of biodegradable and
biocompatible materials in the preparation of drug loaded nanocarriers offers an
additional advantage since, there will be reduced accumulation of the nano-shells

within tissues and toxicity issues may be minimal on repeated administrations [7, 8].
Side effects related to higher doses of drugs may be is avoided if there is reduction
in drug dose, with enhanced therapeutic effects [9].
A multifunctional approach in the creation of these nano-delivery systems may
enhance the efficiency of the treatment [10, 11, 12]. For example, drugs may be
conjugated to the nanocarrier via acid-labile ester bonds or via disulphide bonds
which are likely to be cleaved in the acidic microenvironment of cancer cells or in the
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reducing environment within cells respectively [13, 14]. Employing such strategies
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enable the exploitation of low pH tumor microenvironments and redox environments
in cancer cell for site specific delivery of the drugs [15, 16]. Alternatively, the
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nanocarrier systems may be modulated to allow for ligands on the surface for
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targeting specific receptors that are overexpressed in NSCLC. For example, the
expression of glucose transporters (GLUT) in higher concentration in NSCLCs can
be exploited by nano drug delivery systems to have GLUT receptor-mediated
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endocytosis [17]. The local delivery to the lungs (by inhalation) would avoid
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accumulation of anticancer drug in nontarget tissues [18]. A very recent article
highlighted the role of five elements namely, use of nanotechnology, inhalation
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therapy, targeted therapy, chemotherapy and gene therapy which can substantiate
the NSCLC treatment [19]. Some of these modalities need to be used in
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combination for better therapeutic outcomes.

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However, nanocarrier formulations need to be designed and formulated with caution

as there can be potential adverse effects associated with continued administration of
these drug delivery systems. The size of the nanoparticles could be a matter of
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concern since the particles may cross the blood brain barrier and cause neurological
toxicity [20, 21]. Their ability to cross cellular barriers with ease may exacerbate or
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initiate altered cellular metabolisms [22]. Accumulation of nano-shells in immune

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privileged organs such as eyes, testis may cause related toxicities [23]. The long-
term effects due to chronic exposure to nanoparticulate delivery systems include skin
discoloration, eye irritation, damage to functioning of kidney and respiratory and
gastro-intestinal dysfunctions [24]. These can be effectively dealt by using
biocompatible, biodegradable systems and modifying the size of the nanoparticles to
restrict its ease of passage into nervous, ocular, and reproductive systems.

2. Nanocarriers in targeting NSCLC
Nanocarriers allow fabrication of delivery system at the nanoscale level.
Nanocarriers can be prepared from a suitable biomaterial like polymer or a lipid.
Nanocarriers may be surface modified with tumor tissue targeting ligands, such as
folate, Arg-Gly-Asp (RGD) peptide, and hyaluronic acid [25, 26, 27, 28]. One simple
way to emphasize the application of a nano carrier is that it can preferentially change
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the pharmacokinetics of the entrapped drug [29]. Bio distribution pattern of a given
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drug is dependent on its solubility profile and its inherent hydrophilicity and
lipophilicity [30, 31].
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2.1 Polymeric nanoparticles
Among the building materials used for fabrication of nanoparticles, polymers hold a
special place due to their unique properties. The tailorable properties of polymers
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make them suitable as biomaterials for cancer therapeutics [32]. Some of the
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polymers are also termed as intelligent polymers as they respond to changes in
surrounding environment by altering their structural properties. [33]. PLGA
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(poly(lactic-co-glycolic acid) is an example of an intelligent polymer. Wang et al. [34]

formulated a dual-targeted ligand (Folic acid and hyaluronic acid) based polymeric
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nanoparticles based on PLGA and PEG (polyethylene glycol) to entrap prodrugs

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baicalein and paclitaxel. The drugs were entrapped in the inner core of PLGA. These
drugs in combination exhibited a synergistic anticancer effect on the human lung
cancer A549 cells as well as on the drug-resistant lung cancer A549/PTX cells. The
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folic acid and hyaluronic acid targeting moieties were efficient in targeting the folate
receptors and CD44/CD168 receptors overexpressed on lung cancer cells
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respectively [35].
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The use of polymers in NPs (nanoparticles) enable them to evade the mononuclear
phagocytic system (MPS). Polymeric nanoparticles can be conjugated with desired
ligands which allow for selective extravasation of conjugated nanoparticles from
vascular system into the desired tissue and its longer retention in tumor tissues due
to poor lymphatic drainage [36, 37] Polymeric nanoparticles owning to their typical
size range can effectively exploit the increased permeability through endothelial cells
due to leaky tumor vasculatures. This increased porosity enables easy uptake of

nanoparticles within a range of 100–600 nm thus leading to increased bioavailability
of drug-payload at the tumor site [38].
2.2 Liposomes
Liposomes are defined as lipid based vesicular structures which form a bilayer in
aqueous media and can entrap diverse drug molecules. To increase the drug
delivery efficiency, liposomes may be modified by polyethylene glycol (PEG) i.e they
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are PEGylated. PEGylated liposomes when injected do not allow themselves to be
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cleared rapidly by the reticuloendothelial system (RES) thereby remain in the blood
circulation for a longer duration. The PEG layer provides a protective steric barrier
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thereby preventing recognition by RES system. PEGylated liposomes were designed
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to entrap the anticancer drug vinorelbine (VRB) and apoptosis-inducing agent
quinacrine to treat NSCLC [39]. In another recent study, liposomes made up of 1, 2-
Distearoyl-sn-glycero-3-phosphoethanolamine- Poly(ethylene glycol) of molecular
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weight 2000 (DSPE-PEG2000) were explored for encapsulating anti-carbonic
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anhydrase(CA) IX, anti-CA IX and a ligand (CPP33) to enhance the targeting to
NSCLC cells by pulmonary route and to improve cell penetration of triptolide (TPL)
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[40]. A tumor targeted liposome was prepared for co-delivery of RPV‐modified

epirubicin and dioscin for inhibiting the vascular-like structures, vasculogenic mimicry
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(VM) channels in NSCLC [41]. These liposomes (made up of DSPE‐PEG2000‐RPV

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conjugate) were able to downregulate VM‐related proteins and allowed selective

accumulation of drugs in tumor site. The presence of RPV (the cell‐penetrating
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peptide) on the surface of liposomes enhanced the cellular uptake. The liposomes
were effective in disrupting the structure of tumor tissues in tumor-bearing mice,
which eventually led to tumor cell necrosis. Liposomes of doxorubicin isomer
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(epirubicin) were able to show enhanced tumor selectivity and reduction of adverse
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effects associated with free epirubicin (such as myelosuppression). This work

supported the fact that liposomes can work as effective nano-carriers due to their
ability to act as novel targeting vectors for encapsulating free anticancer drugs.
Another similar study which destroyed the VM channels effectively, selectively
targeting the NSCLC cells was by application of R8 (octa-arginine) modified
epirubicin–dihydroartemisinin liposomes at the tumor sites [42].

2.3 Hybrid nanocarriers
Hybrid nanocarriers can effectively to combine two carrier systems to deliver drugs,
genes or biomolecules. Lipid–polymer hybrid nanoparticles (LPNs) combine the
advantages of both polymeric nanoparticles and liposomes into a single delivery
platform. To treat NSCLC in which EGFR is amplified or upregulated, the epidermal
growth factor (EGF) was conjugated to lipid–polymer hybrid nanoparticles for co-
delivery of docetaxel (DTX) and resveratrol (RSV) [43]. These hybrid NPs targeted
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the EGFR receptors and were able to deliver both the drugs to the tumor cells and
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the combination was found to prevent development of resistance.
In one of the studies, the hybrid nanoparticles were prepared by using human
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immunoglobulin G (human IgG) with the block copolymer (poloxamer-188) for
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delivering siRNA to mice [44]. The study showed altered
biodistribution and pharmacokinetics properties in SCID beige mice by administering
siRNA formulated in the anti-NTSR1-mAb-functionalized hybrid nanoparticles and as
compared to naked siRNA. U
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2.4 Mesoporous silica nanoparticles
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Mesoporous silica nanoparticles (MSNs) offer distinctive features of nano drug

delivery system having large surface area and ability for surface modifications with
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tunable pore size as per the various biomedical applications. These multifunctional
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MSNs have applications in drug delivery as well as in bio-imaging. MSNs chemistries

allow for conjugation of diverse moieties such as antibodies, siRNAs or ligands like
folic acid. The multidrug resistant protein 1 (MRP1) (also called as the ABCC1) is
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known to be associated with the chemotherapy resistance. Song et al. [45] prepared
MSNs with folic acid conjugated to MRP1 and evaluated their efficacy in NSCLC.
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The study suggested enhanced apoptosis in lung cancer cells by the nanoparticles.
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When in vivo studies, were carried out, these nanoparticles were able to reduce both
tumor size and tumor volume due to higher accumulation of nanosized particles in
the tumors.
2.5 Superparamagnetic iron oxide (SPIO) nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIONs) are small synthetic γ-
Fe2O3 (maghemite), Fe3O4 (magnetite) or α-Fe2O3 (hermatite) particles with a core

ranging from 10 nm to 100 nm in diameter [46]. They have mixed oxides of iron and
exhibit superparamagnetic properties which may be exploited for many biomedical
applications [47]. SPIONs can have an organic or inorganic coating, which may
facilitate loading of drug. An external magnet can be used for guiding SPIONs to
target tissue [48]. These nanoparticles exhibit the phenomenon of
“superparamagnetism” in response to the applied magnetic field.
Superparamagnetism is exhibited by magnetic particles that are smaller than <
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40nm. These are small single domain magnetic particles. They minimally interact
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with each other, orient themselves to the magnetic field and lose their alignment
once the magnetic field is removed [49]. For tissue targeting, external magnetic fields
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are usually used but if these are located at a large distance from the target tissue,
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localization of the magnetic particles to the tissue will be compromised. Therefore,
mostly the external magnets are positioned close to, or implanted in the target tissue
to attract the SPIONs. Magnetic nanoparticles may also be used to generate
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magnetic hyperthermia. Magnetic hyperthermia uses an external magnetic field to
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generate heat in the tissue through the accumulation of magnetic iron oxide
nanoparticles [49]. This technique may be employed for tumor ablation.
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Superparamagnetic iron oxide (SPIO) can be one of the sources of magnetic

materials which can be used for generation of heating to create magnetic
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hyperthermia which can be effectively used for tumor ablation [50]. Inhalable SPIO
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based nanoparticles have been designed with the objective to cause magnetic
hyperthermia in NSCLC [51]. But with this non-invasive approach there is a
possibility of generation of sub-lethal temperature within the tissue [52]. There are
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two major issues in such a circumstance; the development of resistance and the
toxicity caused to the healthy cells. These issues may be addressed by coating the
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magnetic nanoparticles with tumor specific targeting ligands. A study, in which

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targeting ligands conjugated to magnetic nanoparticles were used, confirmed the

hypothesis. The cancerous A549 cells were exposed to ferric chloride based SPIO
NPs which contained the EGFR-targeting peptide (YHWYGYTPQNVI). The
hydrodynamic diameter of targeted peptide SPIO NPs was 369 ± 34 nm. The EGFR-
targeted formulation of NPs was delivered into A549 cells, at a concentration that
was 4.5-fold higher than the non-targeted control [51]. When these NPs were
administered to mice through the inhalation route, effective concentrations of SPIO

nanoparticles were observed in lungs whereas minimal exposure was seen in other
organs.
2.6 Metal nanoparticles

Metal nanoparticles play a beneficial and powerful role in cancer therapy providing
better targeting, gene silencing, drug delivery and overcome problems related to
conventional chemotherapy. The distinctive features of good biocompatibility, highly
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stability and low-toxicity makes them an excellent choice for targeting NSCLC. Some
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of the properties can be summarized as their ability to conjugate with diverse
biomolecules and allow for surface modifications to enable targeting. Gold
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nanoparticles (AuNPs) as nanomaterials and nanocarriers have shown massive
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antitumor potential and can be effective against different types of cancers [53, 54].
Qian et al. [55] described a gold nanoparticle-based delivery device for targeting lung
cancer.
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One of the distinctive features of AuNPs is their ability to conjugate with the
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biomolecules. AuNPs were conjugated to cetuximab (C225), a monoclonal antibody,
to achieve a size of 14 nm. The drug loaded AuNps (C225-AuNPs) were designed to
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improve efficiency of antibody delivery and promote cytotoxicity specifically to EGFR

positive NSCLC cells [55]. The efficiency of the conjugated formulation was also
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proven in nude mice where an increased chemosensitivity was observed with C225 -
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AuNPs. It was shown that the conjugation of C225 to 14 nm gold nanoparticles

promoted cytotoxicity and antitumor capability in EGFR positive NSCLC cells than
C225 alone in vitro and in vivo.
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine

protein secreted by most cells and tissues to enable the process of apoptosis.
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However, in case of NSCLC there are possibilities of development of resistance to

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TRAIL-mediated apoptosis. AuNPs have been shown to be effective in initiating

apoptosis induced by TRAIL through mitochondrial fragmentation and dysfunction
[56]. The AuNPs showed increase in sensitivity of NSCLC cells to TRAIL-induced
apoptosis.
Afatinib is a tyrosine kinase inhibitor clinically approved for the treatment of EGFR
positive NSCLC. However, its low aqueous solubility and low bioavailability lead to
many side effects. In one of the recent studies AuNP conjugates were used to

improve the efficacy afatinib [57]. The nanoconjugate was prepared by click
chemistry using the n-alkyne-bearing Afb derivative and reacting it with azide-
functionalized lipoic acid. The drug was conjugated to AuNPs by formation of
alkylthiol–gold bond. There was 3.7 times increase in potency of Afb-AuNPs as
compared to free drug signifying the better inhibition of cell proliferation of tumor
cells.
The AuNPs synthesized by chemical reduction method were conjugated by a by
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non-covalent method to the anticancer drug docetaxel and to folic acid (FA) by
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covalent method [58]. The FA ligand is suitable for delivering the carrier conjugate to
the surface of cancer by endocytosis at pH range of 5.0–5.5. The cytotoxicity of
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these AuNPs nanoconjugates having size of 18 nm showed superior IC50 values
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compared to plain drug docetaxel against the lung cancer cell line (H520) indicating
their potential in lung cancer.
In another study, the synthesis of AuNPs was done by an eco-friendly procedure by
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using plant extracts. Herein, the extracts of Magnolia officinalis were used, which is
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known to work against NSCLC by inducing apoptosis and inhibiting cell proliferation
[61]. The NPs were of size 128 nm and showed effective cytotoxicity against A549
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cells.
Another metal selenium (Se) metal finds wide applications in drug delivery,
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especially selenium nanoparticles due to anticancer activities this trace metal has. In
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one of the studies, the surface of the selenium nanoparticles (SeNPs), the cyclic
peptide, Arg–Gly–Asp–D-Phe–Cys (RGDfC) was loaded to formulate a nanocarrier
(RGDfC-SeNPs) with superior targeting ability of doxorubicin (DOX) towards lung
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cancer [59]. The rational for the choice of this peptide (RGDfC) was that it would
precisely bind to αvβ3 integrins [60]. This multifunctional nanocarrier (RGDfC-
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Se@DOX) was effective in both inhibiting the proliferation and preventing the
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migration of the A549 cells. The nano size (18 nm) of RGDfC-Se@DOX allowed it to
show the EPR effect [33]. This was also evident in the cellular uptake shown by the
passive targeting of Se@DOX in the A549 cells and active targeting of RGDfC-
Se@DOX nanoparticles. Further studies of endocytosis mechanism confirmed that
the active process is associated with greater cellular uptake of RGDfC-Se@DOX
nanoparticles in A549 cells. The uptake was mediated by clathrin-associated
endocytosis.

3. Co-delivery of drugs using nanocarriers
Use of a single anticancer drug often leads to development of resistance by cancer
cells. Also, this resistance shown by cancer cells can also occur due to use of wider
range of anticancer drugs causing cross-resistance. There are many phenomenon
and principles which explain the mechanisms by which the resistance develops. One
of the majorly known effects is the P-glycoprotein (P-gp) over-expression on the
plasma membranes. The P-gp drug functions as the efflux pump and, and thus
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reduces the concentration of drug intracellularly. One of the objectives of co-delivery
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systems in cancer therapeutics is to exhibit a synergistic effect which overcomes the
resistance [62]. Due to the redundancy of signaling pathways, it is advantageous to
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co-deliver drugs to overcome the toxicities associated with single drug. A nanocarrier
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can be efficiently used for co-delivery of two anticancer drugs of diverse
physiochemical properties or an anticancer drug with nucleic acids [63].
Cisplatin, one of the most promising drugs used in NSCLC, damages DNA
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replication by causing DNA to cross-link thus hindering the amplification of cancer
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cells. However, the drug is associated with nephrotoxicity, bone marrow arrest and
hearing dysfunctions. Other major concern is the drug resistance which ultimately
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may lead to a relapse of the disease.

Cisplatin with gemcitabine is a standard therapy as the first-line treatment of
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advanced NSCLC [64]. However, to overcome neurotoxicity, renal toxicity and

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resistance caused by the combination, a nano formulation was suggested. Chitosan

and Platinum (Pt) (IV) (CH-Pt) with hyaluronic acid -Gemcitabine (HA-GEM)
prodrugs were synthesized by layer-by-layer technique [36]. Here, the positive
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charges on the core of CH-Pt and negative charges on the shell of HA-GEM were
utilized for the process to complete. The cytotoxicity of the formulated NPs showed
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promising results compared to the free drug solutions against non-small lung cancer
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cells (NCl-H460 cells). When these drugs were administered in solution, they were
found to accumulate in organs in a non-specific manner (for eg. heart and kidney). In
contrast, the drug-loaded NPs were mainly distributed to the lungs. The layer-by-
layer technique was also useful in changing the positive zeta potential to a negative
one. Zeta potential of the nanoparticles is responsible not only for the cytotoxicity but
also the cellular uptake of the particles within the cancer cells [65, 66, 67, 68]. The

cytotoxicity of the cationic NPs is mainly due to positive charge which renders the
vacuolization of cytoplasm, cause cell shrinking and cell mitoses is reduced [69].
Another study showing impactful role of co-delivery of cisplatin nano formulation, to
treat NSCLC by Xiong et al. [70]. In this study, cisplatin was co-encapsulated with an
antidiabetic drug (metformin) to address the toxicity issues of cisplatin. In the first
step polyglutamic acid (PGA) was used to conjugate with cisplatin to give an anionic
formulation which eventually was complexed with the cationic polymeric metformin
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electrostatically. The co-encapsulated nano-formulation when tested in in NSCLC
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H460 tumor-bearing mice showed suppression of tumor growth with no
nephrotoxicity [70]. The synergistic activity observed on administration of the self-
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assembled core-membrane NPs could be attributed to the way both drugs act on the
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AMPK (AMP-activated protein kinase) pathway and reduce activation of mTOR [70].
Iron–platinum nanoparticles (FePt NPs) are known for the optical and magnetic
properties. In addition, their synthesis permits controllable morphology eventually
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making them useful in many biomedical therapeutics. FePt-Cys NPs exerted a
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synergistic effect with cisplatin causing suppression of proliferation and induction of
apoptosis in NSCLC cells [71].
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A cluster nanoparticle formulation was proposed for co-delivery of platinum (Pt) and
gemcitabine (GEM) using ultra-small platinum nanoparticles (USPtNs) for
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preferential killing of NSCLC cells [72]. To obtain multi-drug release for NSCLC
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targeted therapy, this stimuli-responsive material used the disulfide-bond for grafting
the drugs to copolymers (PEG-b-P(LL-g-GEM). The formulation preferentially
released Pt ions in the acidic lysosomes (to avoid degradation) and GEM in
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cytoplasmic reduction environment.

In a yet another study synergism of cisplatin was shown with 2-(4-aminophenyl)
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benzothiazole molecule for a precise site-specific antitumor effect [73].

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In a recent study, lipid-coated calcium-phosphate (LCP) NPs were explored for co-
delivery two anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX) as
therapeutics in human lung cancer [74]. The LCP delivery system made it possible to
combine two drugs of different solubilities. The hydrophilic drug (DOX) was
entrapped in the hollow core formed from the calcium phosphate and the
hydrophobic drug (PTX) was entrapped in the lipid bilayer coated on the surface of
hollow calcium phosphate. The formulated nanoparticles were of size 335 nm with a

highly negative zeta potential of -41.1 mV. A mass ratio of 12:1 for DOX and PTX
showed an optimized synergistic effect against A549 cells.
The lipid-based delivery systems using mixture of solid lipid and liquid lipid to
eventually form an amorphous solid matrix is known as nanostructured lipid carriers
(NLCs) and have shown promise to be used for efficient delivery of
chemotherapeutics [75]. The liquid portion of the lipid is responsible to induce
formation of amorphous lattice. A synergistic effect has been reported by the co-
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delivery of paclitaxel and doxorubicin via NLCs in the treatment of NSCLC [76].
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4. Physicochemical characteristics of nanocarriers suitable for lung delivery
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The pulmonary route of drug delivery possesses many favorable characteristics such
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as large alveolar surface area and thin epithelial barriers permitting efficient
absorption, extensive vascularization and low metabolic activity [77, 78]. Drugs
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delivered by the inhalation route travel throughout the upper respiratory tract, the
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tracheobronchial region before they reach the distal alveolar regions of the
respiratory system [79, 80]. The physicochemical properties of the nanoparticles
such as size, shape, surface charge and surface property determine its fate in the
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respiratory tract; whether it is cleared, degraded or translocated into the circulatory

or lymphatic circulation. The size of the nanoparticle determines its propensity to
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deposit in a particular region of the respiratory system. The sizes of particles used
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for inhalation therapy are expressed as mean median aerodynamic diameter

(MMAD). The principal mechanisms that govern the deposition of a nanoparticle in
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the lung are impaction, sedimentation and diffusion [81, 82]. All of these depend on
the MMAD of the nanoparticle. The other factors that govern the mechanism of
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uptake are dependent on the condition and working of the respiratory system and
may vary from patient to patient. These include breathing rate, lung volume,
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respiratory volume, heath of the individual, respiratory volume, and the tendency to
breathe through nose or mouth. The particle sizes determine the mechanism of
deposition and the site of deposition in the respiratory tract. Particles ranging from 1
to 5 μm in aerodynamic diameter reach the lower regions of the respiratory tract and
are inhalable [83]. Particle sizes >10μm, land in the oropharyngeal region, by inertial
impaction. Inertial impaction refers to deposition by collision with the regions
independent of the airflow trajectory. Impaction also determines the deposition of

particles from sizes 5μm-10μm in large conducting airways and in the oropharyngeal
region. The range of particle sizes 1μm -5μm, get targeted to small airways or alveoli
by gravitational sedimentation, this process also holds true for particles <0.3μm
which land in smaller airways and alveoli. Gravitational sedimentation refers to
settling of particles in the lung compartments under the influence of gravity.
Diffusion is the prominent mechanism for deposition of 0.1-1μm particles in the lower
airways and alveoli, and for <0.01 μm particles, in the peripheral airways and alveoli.
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Diffusion refers to the collision of particles with the structures of the respiratory tract
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by Brownian motion [84]. The size of the particle also plays a role in its clearance
from the lung compartment. Clearance from the lung occurs by two main systems,
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one is through the mucociliary escalator in the conducting airways while the other is
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via alveolar macrophages that are situated in deep lungs, near the alveoli [85]. The
ability of the nanoparticle to cross the viscous mucus layer and reach the underlying
epithelia depends on the size and surface properties. Sizes larger than 1000 nm
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were sterically hindered by the mucus while sizes in the range of 60-300nm were
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retained to some extent [86]. Hydrophobic particles get cleared from the lungs faster
and are easily opsonized [87]. Thus, coating the nanoparticle with low molecular
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weight PEG (~2.5 KDa) renders it more hydrophilic and increases retention time in
the lung. With respect to surface charge, a high positive charge or a neutral surface
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charge enables mucoadhesion and greater penetration through the mucus. With
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regards to alveolar uptake, microspheric particles that were in the size of 1μm were
more likely to be phagocytosed than smaller (0.2-0.5μm) particles or larger particles
(6-10μm) [88]. The surface charge on the microspheres is also a criterion for uptake,
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the macrophages are studded with sialic acid residues that give it an overall negative
charge, thus positively charged nanoparticles adhere and are taken up to a greater
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extent by these immune cells.

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5. Gene delivery using nanocarriers

The in vivo gene delivery for lung cancer is proposed to be one of the most
sought-out systems for enhanced therapeutics in biotechnology. However, the
hydrophilic nature and negative charges of the nucleic acids (DNA and RNA)
make them less bioavailable to a cell due to the presence of a negatively charged
lipid bi-layered cytoplasmic membrane. Thus, vectors and the nano carriers are

employed to deliver these molecules to cells. Nanoparticles have been effectively
used to target cancer lung cancer cells and enable the delivery of most of the gene
molecules like the DNA, siRNA, plasmid DNA (pDNA), mRNA and miRNA [89].
MicroRNAs (miRNAs) are short sequences of non-coding RNA molecules found in
plants and animals for the regulation of gene expression. In nucleic acid therapy,
miRNAs are one of the evolving candidates in treating many genetic disorders. In the
miRNA-based therapeutics, the miRNA-29b has shown a promising role in NSCLC.
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However, miRNA-29b been shown to stimulate immune response, suffers from low
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cellular uptake and is rapidly cleared from blood. The use of nanoparticles may
overcome the associated drawbacks associated with miRNA-29b. Nucleic acid-
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based therapeutics was designed with the hybrid nanoparticle delivery system by
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using poloxamer-188 coating to prevent uptake by macrophages and human IgG to
prevent any immune response upon entry to body [90]. Use of MUC1- aptamer was
the additional important feature of this delivery system which enabled miRNA-29b to
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be actively targeted to MUC1-expressing cancer cells in NSCLC. The
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pharmacokinetic parameters studied in SCID mice confirmed non-accumulation of
drug in healthy cells and the downregulation of the protein coding gene DNA
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Methyltransferase 3 Beta (DNMT3B) was responsible for inducing apoptosis in tumor

tissues. In a yet another study, MUC1- aptamer was used for co-delivery of miRNA-
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29b and genistein via hybrid nanoparticles in NSCLC and showed higher
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antiproliferative effect compared to individual loaded nanoparticles [91]. The nano

formulation Genistein-miRNA-29b-loaded hybrid nanoparticles (GMLHN) efficiently
downregulated target oncoproteins and favorably internalized into the A549 cells.
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Almost a decade back the use of inhalation has been exploited in gene therapy for
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promising outcomes in lung cancer [92]. Mesoporous silica nanospheres were used
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to deliver bortezomib and the tumor suppressor gene p53 as an effective therapeutic
against p53 -mutant NSCLC [93].
A pioneering multi-tier treatment approach for inhibition of TKs in NSCLC cells by
gene therapy by use of multiple siRNAs in combination with chemotherapy was
tested and reported to be efficacious [94]. This formulation was a multifunctional
approach which was tumor-targeted and led to considerable enhancement in
efficiency and reduction of side effects of chemotherapy by exploiting the inhalation

route for delivering drugs locally to the lungs. Studies conducted on human A549
NSCLC cells showed efficient cellular internalization of NLC, where paclitaxel and
siRNA were released effectively in cancer cells. The in vivo studies on orthotopic
mouse model of human lung cancer showed higher accumulation of tumor-targeted
nanoparticles after inhalation as compared to the particles administered by I.V.
6. Small molecule–drug conjugates (SMDCs) conjugated to folic acid
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The construction of small molecule drug conjugates (SMDCs) has three
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components, a targeting ligand, a linker and finally a drug or therapeutic moiety.
These linkers are responsible for releasing the drug from complex in the specific
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cancer cell [95]. Folic acid (FA) is a ligand that is useful for targeting cell membrane
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and promoting nanoparticle endocytosis through the folate receptor. It is a stable,
inexpensive, and generally poorly immunogenic chemical with a high affinity for the
folate receptor. The folate receptor is overexpressed on many human epithelial
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cancer cell surfaces, such as cancers of the colon, ovary, kidney, and lung,
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conjugation of drugs and macromolecules with FA ligands could increase their
cellular uptake.
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When the SMDCs are conjugated with folic acid (FA-SMDCs) they would have a
higher affinity for FRs on cancer cells [96] (Fig. 1). Interestingly, their size would still
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be smaller than monoclonal antibodies which would enhance the blood clearance
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and enhanced tumor accumulation. One of the most famous case with FA–SMDC is
vintafolide, (formerly EC145) [97]. This water-soluble conjugate is able to selectively
deliver drugs to tumors that overexpress FRα. Vintafolide has shown potential as
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single therapeutic as well as in combination with doxorubicin in two phase II trials for
NSCLC.
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6. Understanding local and systemic delivery of nano-formulations

6.1 Local delivery by inhalation of nano formulations for NSCLC
Lungs can be effectively used as a promising alternative to invasive delivery route for
treatment of lung cancer by imparting localized therapy [98]. It is postulated that
targeting the lung offers better bioavailability of drug than oral or intravenous
injection and it also bypasses the first pass metabolism [99].

The benefits of the inhalation of nanoparticle-based drugs in lung cancer treatment
includes reduction in drug dose, faster onset of action, avoidance of drug
metabolizing enzymes (like the gastrointestinal tract) and enhanced bioavailability of
the drug at a much lower dose [100]. Another landmark feature associated with
pulmonary drug delivery is the superior accumulation of drug within the cancer cell
which would be minimizing the systemic adverse effects. Hence, the pulmonary
route in comparison to the systemic chemotherapy, is able to show maximum anti-
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tumor efficacy by locally delivering the drug and minimizing the systemic toxicity. The
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nano delivery systems can be surface modified by different ligands such as folate,
LHRH (Luteinizing hormone releasing hormone), Tf (transferrin) or iRGD to actively
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target the NSCLC via receptor-mediated endocytosis [101].
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Nebulizers permit delivery of liquid-based aerosol systems in a solution or
suspension form as finely atomized droplets. The process of nebulization permits
delivery of higher amount of aerosolized drug in the form of droplets with the
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generation of high fine particle fraction (FPF) enabling better lung deposition of
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drugs. This eventually ensures smaller doses of chemotherapeutics to be
administered to cancer patients without reduction of benefits [100]. There are
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reported studies where inhalation chemotherapy has shown to be promising for gene
therapy via nanocomplexes. The cationic polymer polyethyleneimine (PEI) was used
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to prepare nanocomplex to efficiently deliver DNA to tumor cells and the nebulization
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was the mode of delivery [102, 103]. Such delivery system was able to protect the
DNA by the DNAse. In one of the recent studies, nebulization was used for delivering
siRNA-loaded nanoparticles using Omron NE-C801 to efficiently deliver into the lung
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[104].
Liposomes of paclitaxel were prepared using dilauroylphosphatidylcholine (DLPC) to
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fit into a jet nebulizer having GSD of 1.9 and MMAD of 2.2 microns in size [105]. The
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in vivo studies in murine renal carcinoma model showed promising pharmacokinetics

with nebulization of liposomal formulation showing 20-fold higher AUC as compared
to the IV administration. The nebulized liposomal formulation showed reduction in
tumor size with increase in survival time. Nebulizer administration of doxorubicin was
done in BALB/c mice by formulating doxorubicin in bEGF/gelatin nanoparticle [106].
A reduction in tumor volume by 90% with suppression of metastasis was observed.
In yet another study, paclitaxel loaded SLN was administered to B6D2F1 mice by

nebulization and a reduction in tumor growth by 75% was reported compared to IV
administration. Plus, there was complete suppression of metastasis [107].
Doxorubicin was administered as dry powder insufflator in C57BL/6 mice in the form
of PLGA porous nanoparticles with higher deposition of drug in the lung and a 50%
reduction in metastasis of lung tumors was reported [108]. In another study,
doxorubicin was administered as dry powder insufflator to BALB/c mice by as
polybutyl cyanoacrylate nanoparticles. The group of mice that were administered the
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drug-loaded nanoparticles had longer survival times compared to the group of mice
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which were given free drug [109]. There was also a reduction in metastasis and the
cardiotoxicity usually associated with the free doxorubicin was less.
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Application of inhaled cationic nanoparticles loaded with sorafenib in PLGA NPS
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show promising localized treatment against NSCLC. The in-vitro and ex-vivo studies
showed improved therapeutic activity due to localized deep lung accumulation of
sorafenib [110].
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Some of the recent drugs to show enhanced antitumor effects in lung cancer models
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by use of inhalable nanoparticles include rapamycin [111], erlotinib [112], taxanes
[113]. Application of nano-emulsion for delivering hydrophobic drug quercetin,
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potentially induced cytotoxicity towards A549 lung cancer cells without affecting the
normal cells [114].
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Table 2 gives a summarized information on different types of nano based delivery

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systems used by inhalation.

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6.2 Systemic delivery by injectable nano formulations for NSCLC

The basis of development of lipid-coated calcium-phosphate (LCP) nanoparticle
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was to have a versatile delivery platform capable of encapsulating phosphorylated

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drugs or prodrugs [115]. The delivery system is composed of a solid core with a
lipid membrane coating. This combination permits the NP to cross delivery barriers
in vivo. Research in this area has shown that the LCP nanoparticles can efficiently
encapsulated diverse biotherapeutics ranging from the chemotherapeutics to
proteins and peptides including genes [116].
The conventional nanoparticles are liable to be degraded after endocytosis due to
presence of lysosomes. At this stage the delivery system must be ready for

endosomal escape to prevent being subjected to lysosomes. To solve this issue,
an LCP based nanoparticle delivery system was designed to entrap gemcitabine
triphosphate and allow it to efficiently to target the NSCLC [117]. The calcium
phosphate in the formulation was used to precipitate and entrap the anticancer
drug. On to the surface of the core was a lipid bilayer membrane along with
polyethylene glycol. This designing of delivery system increased EPR effect and a
significant amount of drug (gemcitabine) reached the tumor site. Further, the
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delivery system released entrapped gemcitabine to the cytoplasm and
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subsequently was directed to the nucleus. The same research group, used LCP to
deliver small interfering RNA (siRNA) into the cytoplasm of NSCLC cells [118].
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Patients initially treated with EGFR tyrosine kinase inhibitors (TKIs) such as
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Erlotinib (ELTN) later on develop resistance to EGFR-TKIs. Such situation is a
major hindrance in treatment of the advanced-stage NSCLC. To resolve this
problem, erlotinib (ELTN) and fedratinib (FDTN) were co-delivered by formulating
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in a polymeric nanoparticle system prepared form poly (ethylene glycol) (PEG) and
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poly (lactic acid) (PLA) to treat ELTN-Resistant NSCLC [119]. The nanoparticle
formulation (ELTN+FDTN@PEG-PLA) via subcutaneous injection showed
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enhanced efficacy on the ELTN-resistant lung cancer cells (H1650) xenograft

tumor models. This efficacy of co-delivery of drugs through NPs was due to down-
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regulation of JAK2/STAT3 signaling pathway.

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7. Nanocarriers showing promise in NSCLC cell line studies, preclinical and in

Clinical Trials
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7.1 In vitro cell line studies

The use of cancer cell cultures can be used at early stages of product development
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before going for the animal studies. These cell line studies can be used to study the
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qualitative and quantitative cellular uptake and cytotoxicity of the delivery systems
[120]. These in vitro studies can be thought as the preliminary predictive tool to study
the fate and pharmacological activity of the therapeutic agent before going for a full
in vivo study. It is however important that these studies have significant correlation to
the in vivo human studies. The NSCLC A549 is one of the most commonly used
cancer cells in studies for studying the lung cancer. These in vitro cell models can be
effectively used in cancer research to easily mimic the architecture of human

cancers. As per the heterogeneous tumor tissues, different cell lines are available.
Table 1 shows in vitro cell lines studies on NSCLC to show efficacy of nanocarriers
against pure drug.
A three-dimensional (3D) architecture comprising the human adenocarcinoma

(A549) cells were developed as an in vitro model to effectively examine the inhaled
formulation against NSCLC [127]. The model reiterated lung epithelium along with
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the tumor tissue. This was an air-liquid interface-based model which was human-
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relevant and efficacious for screening inhaled anti-cancer drugs.
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7.2 Pre-clinical studies
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The preclinical outcomes with studies on animal models form the basis for clinical
trials of drugs and nano formulations for cancer. The animal models are used to
develop valid scientific data on cancer nanomedicine with either tumor suppression
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or complete disappearance of tumor in animals. The dosing schedules can also be
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optimized with similar tumor xenograft protocols. Animal models in cancer research
are helpful in identifying carcinogens and understanding the molecular mechanisms
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of tumor growth [128]. The immunocompromised mice or the genetically engineered

mice can be further used for understanding different cancers with physiological
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relevance [129]. Table 2 gives summarized information on nano formulations

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showing promise in pre-clinical studies by use of single drugs as well as use of a

combination of drugs (co-delivered) in cancer.
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7.3 Clinical Trials on nanocarriers for NSCLC

Although there are some nanocarriers approved (fifteen as on now) by US Food and
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Drug Administration (FDA) for passive targeting of cancer [141]. The only approved
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US Food and Drug Administration (FDA) nanotechnology-based product for clinical

use in NSCLC is the albumin-bound paclitaxel nano formulation Abraxane®
(Celgene). The nano formulation improves solubility of paclitaxel and also enhances
delivery to tumor [142].
The nano formulation of nanoparticle albumin-bound (nab) paclitaxel (nab-
paclitaxel), has undergone many clinical trials with promising clinical efficacy in
treating advanced NSCLC. Two major outcomes are achieved by this nano

formulation is reducing toxicities associated with solvent based paclitaxel and other
is the enhanced targeted delivery in tumor cells [143].
In a phase II trial comprising of 63 patients, carboplatin with nanoparticle albumin-
bound (nab)-paclitaxel was evaluated for NSCLC patients who were otherwise
ineligible for bevacizumab [144]. The study reported improvements in most of the
data reported with a response rate (RR) of 38%, median progression-free survival
was reported to be 5 months and median overall survival (OS) was 9.7 months.
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These improved figures led to a conclusion that the therapy with carboplatin and
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nab-paclitaxel every 21 days not only showed improved efficacy but also enhanced
tolerable toxicity in NSCLC patients.
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A phase III clinical trial was carried out to determine the optimal dose of every-3-
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week and weekly administration of nab-paclitaxel with carboplatin for patients with
advanced NSCLC as first-line therapy [145]. The median PFS was reported to be
within 4.8 and 6.9 months, the (OS) ranged from 8.3 to 15.0 months (all cohorts).
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Response rate (RR) was 47% the weekly administration versus 30% in q3w cohorts.
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The study concluded that the combination therapy of nab-Paclitaxel with carboplatin
was more effective in advanced NSCLC.
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BIND-014 is a targeted polymeric nanoparticle produced by Bind Therapeutics Inc. A

phase II clinical trial was conducted for the docetaxel nanoparticles meant for
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injection in a suspension form for the 2nd line therapy for squamous cell NSCLC
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[146]. The primary outcome measures were reported in terms of disease control rate
and the reduction in time frame using response evaluation criteria in solid tumors
(RECIST) measurements. A phase II clinical trial was reported for nanoparticle
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formulation of albumin-bound paclitaxel showing better efficacy in advanced NSCLC

[147]. The nano formulation was reported to have better tumor response rate and
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was reported to be safer as compared to the conventional solvent-based paclitaxel.

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Another phase 2 study was done on paclitaxel albumin-stabilized Nanoparticles in

treating patients with previously treated advanced NSCLC. To evaluate the overall
response rate of weekly nab-paclitaxel safety profile in patients with EGFR
mutations.
A phase II trial to examine paclitaxel albumin-stabilized nanoparticle formulation in
combination with sunitinib to work for first-line therapy in stage IV NSCLC [148]. To
examine the safety and efficacy of paclitaxel liposome along with cisplatin was tested

in a phase 2 clinical trial and compared with gemcitabine and cisplatin as first-line
therapy in NSCLC [149]. A Phase II study studied the efficacy and toxicity of
pegylated liposomal doxorubicin and Carboplatin in patients with previously
untreated NSCLC [150].
Most of studies discussed in clinical trials would come in the category of
investigational nanotherapeutics. Some of these studies are still not completed,
indicating more profound work and research is needed in the area of nano
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formulations in cancer so as to come with possible solutions.
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8. Expert opinion
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It is well understood that there are many drawbacks in the clinical application of
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conventional therapy associated with NSCLC. These drawbacks include the low
aqueous solubility of anticancer drugs, development of drug resistance in the long
run. Also, there are severe toxicity induced by use of these anticancer drugs such
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as, peripheral neuropathy, neutropenia, hypersensitivity reaction, occurrence of
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mucositis and stomatitis. Most of these drawbacks can be overcome by use of
targeted nano drug delivery systems. For better clinical outcomes in NSCLC, it is
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more important to understand the complicated molecular mechanisms involved in the

disease and then develop newer therapeutics which would enhance the quality of life
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of patients.
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Formulation development of nanocarriers for drugs used in NSCLC is a promising

approach for these already efficient drugs to show more effectiveness. Nano drug
delivery systems have dimensions in the nano range which enable them to easily
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diffuse through tight junctions and cell membranes. Delivery of nano formulations by
inhalation route can be used to enhance the accumulation of drug at local site
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thereby protecting secondary organs from systematic exposure.

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Drugs encapsulated or entrapped in such nano delivery system accumulated at the

tumor site in a higher concentration due to targeting or preferential localization
strategies. For example, the cationic charged nanoparticles are able to permeate
cancer cells more efficiently. Some of the remarkable features in the nanosized
particles which needs to be mentioned include their drug binding or loading ability,
easy engineered surface characteristics, tailorable features for attachment of ligands
enabling nanoparticles reach specific sites in the deep lung tissue.

The clinical translation of the promising nano formulations in NSCLC have to
undergo toxicity profiling so as to allow the FDA concerns to be cleared and achieve
efficacious formulations. There are lot of challenges in the clinical translation of the
targeted delivery i.e. biological challenges, lack of data on IVIVC, large scale
manufacturing, safety and biocompatibility and insufficient regulatory guidelines to
name some. Hence, research on targeted delivery using nanocarriers opens the
door for the future clinical translation of the product.
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Funding
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This paper was not funded.
Declaration of Interest
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The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject
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matter or materials discussed in the manuscript. This includes employment,

consultancies, honoraria, stock ownership or options, expert testimony, grants or
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patents received or pending, or royalties.

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Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to

disclose.
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AC

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FIGUR
RES
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SC
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Fig. 1: Use of SM
MDC in targ
geting canc
cer cells in
n NSCLC [rre-drawn frrom Vlaho
ov et
al., 201
12 Ref. [96
6]
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Informattion Classifica
ation: Genera
al
TABLES
Table 1: In vitro cell lines studies on NSCLC to show efficacy of nanocarriers

against pure drug
SN Drug / IC50 Cell Outcome Reference

Nanocarrie line/Incub
T
r ation time
IP
1 Doxorubici 0.06200 A549 TF-LP decreased 33.8
n 48 h and 64.8% in the [121]
R
DOX IC50 values compared
SC
PLGA-NP- 0.00938 with L-P and PLGA-NPs
DOX respectively.
LP-DOX,
DOX-loaded
0.00650
U
AN
lipid-coated
PGLA-NPs
M
TF-LP-DOX 0.00330
2 Erlotinib 2500 nM A549 lung A 25-fold decrease in
D
solution cancer IC50 with the erlotinib [122]

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Erlotinib 100 nM cells after loaded CSLPHNPs

loaded 72 h compared to erlotinib
EP
Core–shell incubation solution.

type lipid–
polymer
C
hybrid
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nanoparticle
s
(CSLPHNPs
)
3 Methotrexa 4.78 μg/ A549 lung Methotrexate (MTX) with
te (MTX) mL cancer Pemetrexed (PMX) [123]
Free MTX cells delivered by chitosan

MTX- 1.56 nanoparticles (CNPs)
PCNPs μg/mL showed synergistic
MTX-PMX- 0.76 anticancer efficacy due to
PCNPs μg/mL use of stealth
nanocarriers.
4 Pure 37 mM A549 lung Cisplatin-encapsulated [124]
Cisplatin (24 h), cancer cell Fe3O4
T
26 mM line magnetic nanoparticles
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(48 h), 24, 48 and modified with PLGA-
23 mM 72 h PEG6000 triblock
R
(72 h) copolymer have potent
SC
Cisplatin 30 mM time-dependent anti-
loaded (24 h), growth effects in an
Fe3O4-
PLGA-
20 mM
(48 h), U A549 lung cancer cell line
AN
PEG6000 12 mM
NP (72 h)
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5 Afatinib 0.05 μM PC9 cells Afb-AuNPs showed a 2.5- [57]

(Afb), fold increase in potency
D
Free Afb-A
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Afb-AuNPs 0.02 μM
Free Afb-A 6.08 μM A549 cells In A549 cells the Afb-
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Afb-AuNPs 1.65 μM AuNPs, showed a 3.7-

fold potency increase
6 Free 2.02 A549 cells The cytotoxic effect of [41]
C
Epirubicin μmol/L free epirubicin was further

AC
Epirubicin 2.32 enhanced by the addition

liposomes μmol/L of different concentrations
Epirubicin 1.96 of dioscin.
and dioscin μmol/L
co‐delivery
liposomes

RPV‐ 1.06
modified μmol/L
epirubicin
and dioscin
co‐delivery
liposomes
7 Pirfenidone 0.43 A549 cell Inhalable Pirfenidone [125]
T
(PFD) plain mg/mL line (PFD) Liposomes were
IP
PFD found to be more
PFD– 0.37 cytotoxicity in NSCLC cell
R
Liposomes mg/mL lines at minimal
SC
PFD–D-Lip 0.2 concentrations
(DOTAP mg/mL
8
based)
ERL Plain 45.29 μM A549 cellU There was the significant [126]
AN
Drug line reduction of IC50 values
ERL-PCL- 30.11 μM Day 1 in A549 cells in 3 days
M
MP-14 indicating a sustained

ERL Plain 41.8μM A549 cell cytotoxic effect showed
D
Drug line by the PCL based

TE
ERL-PCL- 15.7 μM Day 3 microparticle.

MP-14
EP
C
AC

Table 2: Nanocarriers showing promise in Pre-clinical studies
A. Single Drug
Nanocarrier Active Animal Outcome of the Referenc

component/ Model/ work e
s/ Route of
T
Moiety admin
IP
mPEG–SS–PBAE– Platinum BALB/c nude Improved anti-
PLGA (PSPP) complexes mice (female, metastasis [130]
R
nanoparticles of Curcumin 6–8 weeks, activity of Pt–
SC
encapsulate the 20 ± 2 g) CUR@PSPPN in
platinum complexes A549 xenograft
of curcumin (Pt–
CUR@PSPPN) U
Intravenous
Injection
tumor-bearing
nude mice.
AN
Application of
M
dual
responsiveness
D
of pH and redox
TE
to effectively
target NSCLC.
EP
Chitosan (CS)- Cy5.5 Female ICR CS05-PLGA NPs [89]

modified poly(d,l- Fluorescent mice (∼20 g selectively
lactic-co-glycolic) acid Dye body weight. accumulated in
C
(PLGA) nanoparticles the lung

AC
Intravenous capillaries.
Injection CS05-PLGA NPs
formed transient
aggregates in the
blood stream
after intravenous
administration .

Transferrin targeted Doxorubicin 4–6 week-old The enhance in
lipid-coated PLGA BALB/c male tumor [121]
NPs. athymic nude internalization
mice. was due to TF-LP
EGF-PEG-DSPE ligand-receptor
CDDP-loaded Intravenous interactions by
hybrophobic administrati the outer layer of
T
polymeric core, a on EGF-PEG-DSPE
IP
DOX-loaded ligand.
phospholipid layer.
R
Mannose as the Gemcitabine Eight weeks Higher uptake of [131]
SC
targeting ligand in old albino SLN due to
SLN rats of receptor
U
Sprague-
Dawley strain
mediated
endocytosis.
AN
(250 ± 20 g) Targeting of
of either sex. gemcitabine/MSL
M
Ns
Intravenous in lungs evident
D
administrati by biodistribution
TE
on studies in a rat
model.
EP
Catanionic lipid Curcumin Male BALB/c High anti-tumor

nanosystems nude mice effect of curcumin [39]
loaded
C
CLNs in C57BL/6
AC
J mice compared
with control as
confirmed with
lower
tumor volume
and limited tumor
growth

Liposome Docetaxel Sprague Micropinocytosis
Folic acid- Dawley (SD) was the [133]
conjugated liposomes rats endocytosis
for dry powder (weighing pathway.
inhalation co-spray- 180 g– Tracheal
drying 220 g) administration
showed 45-fold
T
Intratracheal higher
IP
administratio concentration
n using a of docetaxel in
R
syringe lung of rats as
SC
For compared with IV
Pulmonary administration.
delivery
Dry Powder 5- U
Male Improved
AN
Inhalation (DPI) azacytidine Sprague pharmacokinetics [134]
Inhaled dry powder Dawley rats, and efficacy for
M
6-8-weeks- lung cancer

old therapy through
D
genome
TE
Inhalation reprogramming.
Inhaled dry
EP
powder 5AZA
showed superior
pharmacokinetic
C
properties in
AC
lung, compared
to injected
formulation.
Polymersomal Docetaxel BALB/c nude Glutathione-

Nanotherapeutic mice (female, triggered DTX [135]
formulation 16-20 g) to release behavior

build α3β1 integrin-
subcutaneou targeting
s A549 polymersomal
xenografts docetaxel
Formulation of
Injection cyclic
cNGQGEQc
T
peptide-directed
IP
polymersomal
docetaxel
R
SC
U
B. Use of Dual Drug/ Co-delivery in nanocarriers
AN
Nanocarrier Active Animal Outcome of the Reference
M
component/s/ Model/ work

Moiety Route of
D
admin
TE
Nanocomposite Pemetrexed Male BALB/c Inhalable LF/CS-

Nanoparticulate (PEM) and mice (3-4 coated PEM-RES- [136]
EP
liquid crystals Resveratrol weeks old, LCNP

formulated as (RES) 15-20 gm). nanocomposites
inhalable dry showed superior
C
powder By antitumor activity.

AC
nanocomposites. inhalation for synergistic co-

chondroitin encapsulation of the
sulfate (CS) and cytotoxic
lactoferrin (LF) chemotherapeutic
were selected as drug, pemetrexed,
oppositely and the phytoherbal
charged natural drug, resveratrol

biodegradable (PEM-RES-LCNPs).
polymers
PEGylated Vinorelbine Male BALB/c PEGylated VRB plus
cationic and nude mice quinacrine cationic [137]
liposomes quinacrine liposomes
Administered targeted cancer cells
to mice via and treated NSCLC
T
tail vein via
IP
Injected eliminating all
cancer cells and by
R
activatating caspase
SC
9 and caspase 3, to
activate
U Bax and P53, and to

suppress Bcl-2 and
AN
Mcl-1.
EGFR targeted Dual loading Male In vivo studies
M
Lipid Polymeric of Cisplatin C57BL/6 revealed that [138]

Nanoparticles and mice (6 EGF C/D LPNs
D
Doxorubicin weeks of exhibited improved

TE
age, 20-25 anticancer activity

g) along
EP
Intravenous
Injection
C
AC
Liposome Co-delivery of Female Synergistic

7-O-geranyl- BALB/c nude treatment of NSCLC [139]
quercetin and mice of age by siRNAs
IGF-1R siRNA 4–6 weeks combined with
chemotherapeutic
Injection drugs is a promising
strategy.

Spray dried lipid Co-delivery of Wistar rats The higher
nanoparticles paclitaxel and of either sex concentration of the [140]
doxorubicin (180- drug(s) in lungs is
200 gm) attributed to multiple
reasons including
Inhalation the aerodynamic
diameters of spray
T
dried
IP
nanoaggregates,
which allow site
R
specific localization
SC
of the inhalable
carriers.
a possible strategy
U to reverse the
AN
growing concern of
drug resistance
M
Self-assembled Co-delivery of Female nude Nanoparticles

core-membrane polymeric mice of 6– exhibited [66]
D
nanoparticles metformin and 8 weeks old significantly

TE
cisplatin increased tumor

Injection accumulation H460
EP
bearing mice as
compared to free
drug.
C
polymet-CDDP NPs
AC
can activate the

AMP-activated
protein kinase α
(AMPKα) pathway
co-encapsulation of
CDDP and
metformin will avoid

the prominent
toxicity of CDDP
T
IP
R
SC
U
AN
M
D
TE
EP
C
AC

Targeted Drug Therapy in Non-Small Cell Lung Cancer: Clinical Significance and Possible Solutions-Part II (Role of Nanocarriers)

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Expert Opinion on Drug Delivery

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20

Targeted drug therapy in non-small cell lung

Khushwant S. Yadav , Archana Upadhya & Ambikanandan Misra

To link to this article: https://doi.org/10.1080/17425247.2021.1832989

Accepted author version posted online: 05

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Journal: Expert Opinion on Drug Delivery

Information Classification: General

employed are diverse based on polymers, liposomes, metals and a combination of

Expert opinion: Nanocarriers can improve pharmacokinetics of the drug payload by

toxicities. Through nanocarriers, a wide variety of therapeutics can be administered

Information Classification: General

Information Classification: General

• The article provides the rationale of using Nanocarriers for Targeting

• Nanotechnology based carriers have improved pulmonary delivery and

Information Classification: General

providing a platform for development of nanotherapeutics for treatment of NSCLC.

1.1 Benefits and deficits of nanotherapeutics

nanocarriers to render them invisible to the phagocytic mechanisms of the circulatory

sustenance in circulation. Further modification of drug loaded nanocarriers with

Information Classification: General

combination for better therapeutic outcomes.

However, nanocarrier formulations need to be designed and formulated with caution

initiate altered cellular metabolisms [22]. Accumulation of nano-shells in immune

Information Classification: General

(poly(lactic-co-glycolic acid) is an example of an intelligent polymer. Wang et al. [34]

nanoparticles based on PLGA and PEG (polyethylene glycol) to entrap prodrugs

Information Classification: General

[40]. A tumor targeted liposome was prepared for co-delivery of RPV‐modified

(VM) channels in NSCLC [41]. These liposomes (made up of DSPE‐PEG2000‐RPV

conjugate) were able to downregulate VM‐related proteins and allowed selective

effects associated with free epirubicin (such as myelosuppression). This work

Information Classification: General

Mesoporous silica nanoparticles (MSNs) offer distinctive features of nano drug

MSNs have applications in drug delivery as well as in bio-imaging. MSNs chemistries

2.5 Superparamagnetic iron oxide (SPIO) nanoparticles

Information Classification: General

Superparamagnetic iron oxide (SPIO) can be one of the sources of magnetic

magnetic nanoparticles with tumor specific targeting ligands. A study, in which

targeting ligands conjugated to magnetic nanoparticles were used, confirmed the

Information Classification: General

2.6 Metal nanoparticles

improve efficiency of antibody delivery and promote cytotoxicity specifically to EGFR

AuNPs. It was shown that the conjugation of C225 to 14 nm gold nanoparticles

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine

However, in case of NSCLC there are possibilities of development of resistance to

TRAIL-mediated apoptosis. AuNPs have been shown to be effective in initiating

Information Classification: General

Information Classification: General

may lead to a relapse of the disease.

advanced NSCLC [64]. However, to overcome neurotoxicity, renal toxicity and

resistance caused by the combination, a nano formulation was suggested. Chitosan

Information Classification: General

cytoplasmic reduction environment.

benzothiazole molecule for a precise site-specific antitumor effect [73].

Information Classification: General

respiratory tract; whether it is cleared, degraded or translocated into the circulatory

for inhalation therapy are expressed as mean median aerodynamic diameter

Information Classification: General