Please cite this article in press as: Quader and Kataoka, Nanomaterial-Enabled Cancer Therapy, Molecular Therapy (2017),

http://dx.doi.org/10.1016/
j.ymthe.2017.04.026

Review

Nanomaterial-Enabled Cancer Therapy

Sabina Quader1 and Kazunori Kataoka1,2
1Innovation Center of Nanomedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 212-0821, Japan; 2Policy Alternatives
Research Institute, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-1709, Japan

While cancer remains the major cause of death worldwide, outcomes due to their small size (Figure 1). NM-based therapeutics
nanomaterial (NM)-based diagnosis and treatment modalities (Figure 1B) have many advantages over traditional chemotherapy,
are showing remarkable potential to better tackle clinical including improved bioavailability, dose response, and targeting effi-
oncology by effectively targeting therapeutic agents to tumors. ciency, with fewer side effects. NMs take advantage of an enhanced
NMs can selectively accumulate in solid tumors, and they can permeability and retention (EPR) effect to preferentially penetrate
improve the bioavailability and reduce the toxicity of encapsu- and accumulate in cancerous growths, which is based on the anatom-
lated cytotoxic agents. Additional noteworthy functions of ical and pathophysiological characteristics of solid tumor tissues.5 Be-
NMs in cancer treatment include the delivery of contrast agents sides EPR-mediated selective tumor accumulation, tumor-selective
to image tumor sites, delivery of genetic materials for gene delivery and pharmacokinetic profiles of chemotherapeutic and im-
therapy, and co-delivery of multiple agents to achieve combina- aging agents can be improved by carefully controlling NM size and
tion therapy or simultaneous diagnostic and therapeutic out- shape,6 surface modification with disease-targeting ligands,7 and en-
comes. Although several NM therapeutics have been success- gineered tumor microenvironment (TME)-triggered drug-release
fully translated to clinical applications, the gap between the mechanisms.8 Furthermore, multi-modal NM platforms are particu-
bench and the bedside remains ominously wide. Tumor hetero- larly exciting, such as combination therapies9 or “theranostic” combi-
geneity and the disparity between pre-clinical and clinical nations of diagnostic and therapeutic substances.10
studies have been identified as two of the major translational
challenges of NM-based cancer therapies. Herein, we review a The diverse applications and prospects of NMs in the biomedical field
handful of recent research studies on the use of NMs in cancer have initiated a myriad of research projects and publications, which
therapy and imaging, with a limited discussion on the conse- have been reviewed, discussed, and even debated in many review ar-
quences of tumor heterogeneity and pre-clinical studies on ticles.11 Recently, there has been debate in the NM field regarding the
translational research of NM-based delivery systems and prop- targeting ability and delivery efficiency of nanoparticles (NPs) in tu-
ositions in the literature to overcome these challenges. mors.11–13 In this review, we discuss NP designs and architectural
strategies for efficient tumor targeting and delivery, using examples
Cancer remains a major public health crisis in the United States and from recent research related to NMs (mostly PEGylated) for cancer
many other parts of the globe. In the United States, cancer rates are therapy and imaging. While NMs have the potential to impact cancer
on track to overtake heart disease as the leading cause of death. While therapy tremendously, there are fundamental challenges14–16 in terms
about 595,690 Americans are expected to have died of cancer in 2016, of design, delivery, and targeting ability that need to be addressed to
deaths from heart disease outnumber cancer by only 20,000.1 Globally, ensure successful translation of this technology from the laboratory to
the number of new cancer cases is expected to reach 21.7 million by clinical practice. Therefore, the challenges of translating NM cancer
2030, an almost 40% increase from the 14.1 million in 2012. Despite sig- therapies to the clinic will also be discussed within the scope of this
nificant improvements in cancer diagnosis and treatment, cancer sur- review.
vival statistics have remained grim, with a 5-year relative survival rate
of just 69% for all cancers diagnosed between 2005 and 2011, which NMs for Cancer Therapy: Anticancer Drug Delivery
is only 20% better than the 49% survival rate for cancers diagnosed be- An Overview of NM-Based Drug Delivery
tween 1975 and 1977.2 Nevertheless, in recent years, there have been Broadly, the fundamental challenge in treating cancer is to destroy tu-
remarkable developments in clinical oncology with the potential to mor cells while sparing healthy tissues and organs. Traditional treat-
radically change the overall cancer scenario; treatment approaches ment regimes often lack this specificity and are associated with
based on a patient’s genomic profile, immunotherapies, and targeted frequent and severe adverse reactions. Thus, developing chemother-
therapies are noteworthy advancements. Nanotechnology that pro- apeutics that can selectively target cancer cells is highly desirable.
duces, controls, and utilizes materials at the nanoscale (between one
and several hundred nanometers) also has potential to revolutionize
http://dx.doi.org/10.1016/j.ymthe.2017.04.026.
the conventional methods of cancer diagnosis and treatment.3,4
Correspondence: Kazunori Kataoka, PhD, Innovation Center of NanoMedicine
(iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Ka-
Nanomaterials (NMs) are being recognized as useful in oncology, wasaki-ku, Kawasaki 210-0821, Japan.
with sensitive cancer detection capabilities and effective treatment E-mail: [email protected]

Molecular Therapy Vol. 25 No 7 July 2017 ª 2017 The American Society of Gene and Cell Therapy. 1
 Please cite this article in press as: Quader and Kataoka, Nanomaterial-Enabled Cancer Therapy, Molecular Therapy (2017), http://dx.doi.org/10.1016/
j.ymthe.2017.04.026

www.moleculartherapy.org

Review

Figure 1. Nanomaterial-Based Therapeutics

(A) Application of nanomaterials in cancer therapy. (B)
Examples of nanomaterial-based therapeutics. PEG,
poly(ethylene glycol).

effect.23 In this context, tumor-targeted NM-

DDSs can prove useful due to their outstanding
ability to target a drug to the tumor site, thereby
improving tumoral drug concentrations.

PIs have recently emerged as an important tool

for molecularly targeted therapy24 in oncology,
and they induce apoptosis and cell cycle arrest
in tumor cells. Two PIs, bortezomib (BTZ)
and carfilzomib, were approved by the Food
and Drug Administration (FDA) for clinical
use against multiple myeloma. Although pep-
From this perspective, NM-based drug delivery systems (NM-DDSs) tide aldehyde-based PIs, such as MG132, are potent inhibitors of
have already incited a paradigm shift in cancer chemotherapy by the 20S proteasome, their clinical use is greatly limited because of
reducing toxicity while maintaining therapeutic efficacy and also their poor selectivity and specificity, which is caused by the aldehyde
improving safety and biocompatibility. In contrast to healthy tissues function of MG132. Thus, a polymeric micelle-based carrier system
and organs, solid tumors generally have defective vascular architec- has been developed that covalently links MG132 to block copolymer
ture, impaired lymphatic drainage, and reduced uptake of interstitial PEG (poly(ethylene glycol))-b-poly(aspartamide) through an acid-
fluid. Utilizing this disparity, along with a longer blood circulation labile hydrazone bond (Figure 2A). This protects the aldehyde group
profile (accomplished by introducing stealth properties, such as during circulation. After endocytosis, the hydrazone bond is hydro-
PEGylation), NM-DDSs selectively accumulate in tumorous lesions, lyzed in the acidic environment of the endosomes, restoring
a phenomenon commonly referred to as EPR-based passive target- MG132’s therapeutic function.21 Polymer micelles loaded with
ing.5,17 Various types of NM-based drug carriers have been designed MG132 have demonstrated effective in vitro proteasome inhibition,
to exploit this passive targeting, a number of which have successfully which was significantly more efficient than free MG132 (Figure 2C).
progressed to the clinic.15,16 Attempts have been made to improve In vivo, the micelles enhanced antitumor activity, while avoiding the
tumor accumulation through active targeting by functionalization strong side effects of free MG132 and, more importantly, significantly
of the NM surface with ligands such as antibodies, proteins, and pep- expanding the therapeutic window (Figure 2D).
tides that interact with receptors overexpressed at the tumor site,
affording active targeting.7 Compartmentalized NM-DDSs Facilitate Combination
Therapies to Target Cancer Stem Cells
Designing NM-DDSs to Increase the Therapeutic Index of Recently, there has been significant enthusiasm to develop cancer
Molecularly Targeted Agents stem cell (CSC)-targeted drug delivery strategies.25,26 This is due to
Aside from targeting and delivery objectives, researchers are currently the realization that multiple tumor types, including leukemia and
focusing on additional benefits of NMs in cancer therapy, such as us- solid tumors, are sustained by a subpopulation of stem-like cells,
ing NMs to overcome multi-drug resistance (MDR) in cancer,18 commonly referred to as CSCs, which are associated with drug resis-
inhibit metastasis,19 or increase the therapeutic index of molecularly tance, metastasis, and recurrence. Because CSCs are the “drivers” of
targeted agents.20,21 Molecularly targeted therapeutics (e.g., tyrosine tumor progression, therapeutically targeting CSCs is expected to
kinase inhibitors, proteasome inhibitors [PIs], histone deacetylase in- inhibit tumor progression. However, tumor cell plasticity (the ability
hibitors, and angiogenesis inhibitors) have been increasingly recog- to dynamically shift between non-CSC and CSC states) limits CSC-
nized as an efficient alternative to classical cytotoxic chemotherapeu- targeted therapy.27 Thus, the effective combination of CSC inhibitors
tics, due to their ability to specifically interfere in the growth, with cytotoxic therapies that kill both CSCs and non-CSCs would be
progression, and spread of cancers.22 However, their unfavorable bio- the most effective way of accomplishing a successful clinical response.
distribution upon systemic delivery hampers their use as “precision An NM-DDS with a compartmentalized structure would prove useful
medicines.” These molecularly targeted agents are either rapidly for accommodating these two drugs, facilitating their co-delivery to
cleared from the circulatory system or deactivated before reaching the target site, and ensuring optimal therapeutic outcomes from syn-
the tumor site. In certain cases, the targeted drugs are rapidly deacti- ergistic combinations of drugs.28–30 Accordingly, a pH-sensitive poly-
vated inside the cancer cells and fail to display a robust therapeutic meric micelle has been developed to incorporate the CSC inhibitor

2 Molecular Therapy Vol. 25 No 7 July 2017

 Please cite this article in press as: Quader and Kataoka, Nanomaterial-Enabled Cancer Therapy, Molecular Therapy (2017), http://dx.doi.org/10.1016/
j.ymthe.2017.04.026

www.moleculartherapy.org

Review

Figure 2. Proteasome Inhibitor MG132-Loaded Polymeric Micelles

(A) The micelles were self-assembled in water after conjugating MG132 to the hydrazide moieties of poly(ethylene glycol)-b-poly(hidrazinyl-aspartamide) copolymer. (B)
In vitro CLSM study of the dissociation of BODIPY TR-labeled MG132/m (red) in late-endosomal compartments, which were marked with GFP (green); the enlarged section is
shown in the inset. (C) Direct comparison of time-dependent in vitro proteasome activity of MG132 and MG132/m against a breast cancer cell line MDA-MB-231 at a
concentration equal to that corresponding to their IC50 values at 72 hr. Proteasome activity of untreated cells was taken as 100% (Student’s t test, *p < 0.05). (D) Antitumor
activity of free MG132 and MG132-conjugated micelles against a HeLa-Luc tumor model (*p < 0.01, **p < 0.0001, Student’s t test). CLSM, confocal laser scanning mi-
croscopy; IC50, inhibitory concentration of 50%; PEG, poly(ethylene glycol). Reproduced with permission.21 Copyright ª 2014 Elsevier B.V.

staurosporine (STS) alongside the widely used anticancer drug epiru- improved survival time in experimental animals (Figure 3C). The
bicin (Epi) to treat an aggressive phenotype of malignant mesotheli- STS/Epi/m system is also expected to have good potential for clinical
oma with an enriched CSC population (an aldehyde dehydrogenase translation, because the Epi/m system is already in the clinical
[ALDH]-high subpopulation in mesothelioma cell line MSTO- pipeline.31,34
211H, which shows CSC features).28 STS was incorporated in a pre-
viously developed epirubicin-micelle (Epi/m) system,31 where Epi is NMs in Gene Therapy, with a Specific Focus on Combination
conjugated to a PEG-PAsp-hydrazide block copolymer through a Therapy
pH-sensitive hydrazone bond.32 The compartmentalized architecture Outline of Gene Therapy Using NMs
of the micelles is utilized to preserve the drug combination until it rea- Gene therapy, which exploits genomic materials as therapeutic
ches the intracellular space of cancer cells and CSCs, where the release entities, is already proven to have great potential for treating many se-
of both drugs is triggered by low endosomal pH to accomplish coor- vere diseases, including malignancy. Cancer is a genetic disease that is
dinated therapeutic effects. Although STS is one of the most potent primarily caused by mutations of certain genes instigating unregu-
protein kinase inhibitors, its clinical translation is severely hampered lated cell proliferation; thus, taking a genetic treatment approach as
due to its toxicity, lack of specificity, and poor pharmacology.33 Incor- an alternative or in addition to traditional cytotoxic therapy is an
poration of STS into a micelle not only improves its safety and po- ingenious tactic. For the last few decades, there has been over-
tency but also reverses Epi resistance by inhibiting the ATP-binding whelming enthusiasm in the scientific community with regard to
cassette (ABC) transporter (Figure 3A). The STS/Epi/m system was applying gene therapy in cancer treatment.35 Nonetheless, in vivo de-
shown to cause cell cycle arrest and effectively eliminate the CSC pop- livery of genetic therapeutics into target cells poses a significant chal-
ulation, with a convincing tumor suppression effect (Figure 3B) and lenge, mainly due to their instability in biological fluids and inefficient

Molecular Therapy Vol. 25 No 7 July 2017 3

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Review

Figure 3. Co-delivery of Staurosporine and

Epirubicin Using pH-Sensitive Polymeric Micelles
(A) Combined and synchronized therapeutic effects of
staurosporine and epirubicin at the intracellular level to
reverse the drug-resistance profile of Epi through inhibition
of the ABC transporter. In vitro confocal laser scanning
microscopy of MSTO-211H and MSTO-211H Epi-R cells
incubated with Epi, Epi plus STS, Epi plus verapamil
(a known ABC transporter inhibitor), Epi/m, and STS/
Epi/m. (Top) Intracellular fluorescence of Epi (red). (Bot-
tom) Intracellular fluorescence of EFLUXX-ID MDR (green).
(B) STS/Epi/m eradicates orthotopic mesothelioma
tumors. (C) Survival curves of mice. *p < 0.05 and **p <
0.001 by log-rank test. ABC, ATP-binding cassette; Epi,
epirubicin; Epi/m, epirubicin-micelle; MDR, multi-drug
resistance; STS, staurosporine; VPM, verapamil. Repro-
duced from an open-access publication.28

complex core surrounded by a PEG layer is a

convincing approach for developing an effective
non-viral gene carrier system.47 It is worth
noting here that the shape (folded rod or
collapsed sphere) and size of the PMs can be
precisely controlled by modulating the length
of the polycationic segment of the block copol-
cellular uptake. Several systems, broadly categorized as viral and non- ymer and ultimately affects their biological activity.44–46 Intriguingly,
viral vectors, have been developed to enable the cellular delivery of rod-shaped polyplexes, formed by a quantized folding mechanism,
genetic materials.36 Favorably, a number of viral gene carriers have exhibited higher gene expression than polyplexes containing
reached clinical practice due to their high transfection efficiency. collapsed globular pDNA formed by random separation of the
However, severe toxicity and immunogenicity inhibits their use. DNA double helix, indicating that controlled packaging of pDNA
In this regard, non-viral vectors are generally considered safer into an appropriate structure is critical for achieving effective gene
alternatives.37 expression.47 Optimized PEG shielding of PMs is equally important
to achieve superior biological activity after systemic administration.
Design Aspects of Polyplex Micelles for Effective Gene Delivery PEG crowdedness directly correlates with the pDNA packaging struc-
Systems ture within PMs, which ultimately affects their size/shape and blood
Among the non-viral vectors, cationic polymer-based NMs are the retention profile.45,46,48 Recently, the role of PEG in rod-shaped PMs
most widely investigated and offer several benefits, such as non- was investigated further using a detachable PEG strategy, which
immunogenicity, low cost, relative safety, and, more importantly, revealed that the rod shapes transform to compact globular shapes
the capability of carrying larger amounts of genetic material than after the removal of PEG from PMs prepared with acid-cleavable
viruses. However, due to the presence of numerous positive charges block copolymer PEG-[acetal]-PLys.49 Interestingly, although the
on the surface of cationic nanocarriers, aggregation and non-specific detachment of PEG segments from the polyplex (through exposure
interaction remain two major issues in their systemic application.38,39 to acidic milieu) occurred gradually, the rod-to-globule transforma-
PEGylation of these carriers is considered a prerequisite for reducing tion was rather abrupt. Analysis of PEG density revealed that the
non-specific interactions with biomacromolecules, such as serum abrupt transition occurred when the remaining tethered PEG of the
proteins, and avoiding an undesirable immune response.40,41 Poly- rod shapes had diminished to a critical crowdedness, allowing neigh-
plex micelles (PMs), formulated by the self-assembly of oppositely boring PEG groups to segregate. The abrupt transition behavior could
charged PEG-polycation block copolymers and anionic plasmid be explained by the rigidity of bundled double-stranded DNA, which
DNA (pDNA), have gained significant interest due to the highly regu- helps maintain the rod shape.
lated folding of pDNA through polyion complexation. The outer hy-
drophilic PEG layer of the core-shell architecture provides a stealth PM Systems Address the Challenges Associated with Efficient
effect, minimizing non-specific interactions and prolonging circula- mRNA Delivery
tion time in vivo.42,43 More importantly, the adaptable size44 and While the aforementioned studies reaffirm that PM systems can pro-
shape45,46 of these polyplexes, along with their excellent gene expres- duce effective pDNA delivery systems, nuclear localization remains a
sion efficiency, confirms that the packaging of pDNA into a polyion challenge. In this regard, therapeutic gene delivery using mRNA has

4 Molecular Therapy Vol. 25 No 7 July 2017

 Please cite this article in press as: Quader and Kataoka, Nanomaterial-Enabled Cancer Therapy, Molecular Therapy (2017), http://dx.doi.org/10.1016/
j.ymthe.2017.04.026

www.moleculartherapy.org

Review

recently emerged with remarkable potential as an efficient substitute dichloroacetate65) has been attempted via NM-DDSs. Loss of p53
for pDNA in gene therapy due to several unique advantages. mRNA suppressor function, through mutations or inactivation of the p53
does not require nuclear uptake for transfection activity, allowing effi- pathway, is a frequent event in tumorigenisis.66 The tumor suppressor
cient protein expression (even in non-dividing cells), and has a trivial p53 gene is mutated in approximately 50% of cases of non-small-cell
chance of insertional mutagenesis.50 However, due to instability, sus- lung cancer (NSCLC), and these mutations are generally associated
ceptibility to degradation, and immune-stimulatory effects, mRNA with worse prognosis and greater resistance to chemotherapy and ra-
delivery for therapeutic application is somewhat cumbersome. diation.67 Appropriately, Li et al.64 utilized combination therapy with
Opportunistically, carriers established for DNA and small interfering the p53 gene and BTZ using hollow mesoporous silica nanospheres
RNA (siRNA) offer useful platforms for the development of mRNA (HMSNs) for p53 mutant NSCLC treatment. From their previous
delivery techniques.51–53 Recently, PM systems have been successfully work, they found that the tumor-suppressing effect of free BTZ or
utilized for in vivo delivery of mRNA in brain diseases,54 apoptosis- BTZ loaded in HMSNs was compromised in p53-null/mutant
associated diseases,55 and also cancers.56 The core-shell structure of NSCLC.68 Co-delivery of BTZ and p53 in HMSNs displayed better
PMs, comprising a hydrophilic PEG shell surrounding the mRNA- therapeutic efficacy than single treatment with HMSNs-BTZ. They
polyamine complexed core, prevents nuclease-mediated degradation hypothesized that restoration and re-activation of the p53 signaling
of mRNA, recognition by the immune system, and aggregation in pathway is the basic molecular mechanism for the positive therapeu-
physiological environments. Fine-tuning of the polyamine structures tic outcome of their HMSN-based drug-gene co-delivery system.
maximizes the in vitro translational efficiency of mRNA loaded in
PMs.57,58 For in vivo delivery, stability of PMs was attained by conju- Pigment epithelium-derived factor (PEDF) has also been the focus of
gating a cholesterol moiety at the u terminus of the block copolymer a number of research projects, due to its antitumor, antimetastatic,
to induce the required hydrophobicity.56 Subsequently, this strategy and antiangiogenic properties.69 Recently, Xu et al.70 utilized the anti-
has been successfully utilized to deliver mRNA encoding an antian- angiogenic property of PEDF to synergize with the therapeutic effi-
giogenic protein (sFlt-1) to a subcutaneously implanted pancreatic tu- cacy of the widely used anticancer drug paclitaxel (PTX) to suppress
mor in mice to produce a remarkable anticancer effect. Thus, PMs tumor growth in a C26 subcutaneous tumor model, using a PEG-pol-
deliver a promising approach for therapeutic delivery of mRNA as y(lactic-co-glycolic acid) (PLGA) NP-based co-delivery system. They
an efficient gene therapy module. confirmed that the PEDF/PTX combination resulted in enhanced
PEDF expression, G2/M phase arrest (a characteristic cellular mech-
NM-Based Platforms Assist Drug-Gene Combination Therapy anism of Taxol to promote apoptosis), reduced angiogenesis, and
In addition to using genetic materials in a single therapy mode for greater apoptosis.
cancer, research efforts have recently focused on their use in combi-
nation therapy.59,60 NMs again offer a practical resolution to accom- Multi-compartmental NM-DDSs to Achieve Photothermal
modate multiple therapeutic modalities within their compartmental- Therapy/Photochemical Internalization-Mediated Gene
ized structures. Cancer is a multi-faceted disease, and a multi-modal Therapy
therapeutic approach is expected to deliver better treatment outcomes A number of research groups have also combined photothermal ther-
by combining or synergizing the therapeutic advantages of the multi- apy (PTT) with gene therapy.71 PTT has significant benefits in cancer
ple treatment modes or by overcoming the therapeutic limitations of a treatment, due to its minimally invasive approach and precise spatio-
monomodal therapy. MDR is one such limitation associated with temporal control. The development of plasmonic NMs, such as gold
conventional anticancer drugs. MDR generally develops due to the and silver NPs, was a significant advancement for PTT, leading to
elevated levels of drug-efflux pump proteins on the cell membrane good clinical translation potential. Considerable attention has been
that reduce the intracellular drug concentration, causing inefficient given to combining chemotherapeutic agents with plasmonic NMs
treatment outcomes. NM-DDSs have greatly reduced the problems for synergistic cancer therapy with PTT.
of drug efflux,61 but other resistance mechanisms (e.g., the activation
of antiapoptotic pathways) might not be so easily overcome by simply Similarly, photochemical internalization (PCI)-mediated gene trans-
using more efficient delivery systems. siRNA-based therapy has duction has also attracted much attention, due to the enhanced cyto-
demonstrated significant promise to suppress antiapoptotic proteins plasmic delivery of macromolecules through photochemical disrup-
and thus overcome chemoresistance. Accordingly, numerous tion of the endosomal/lysosomal membrane.72 However, to realize
research projects have been cleverly designed to co-deliver siRNA the optimal therapeutic potential of this PCI-gene combination in vivo,
and anticancer drugs, using NM-based platforms to sensitize cells simultaneous systemic delivery of the genetic material and the photo-
to chemotherapy. Creixell and Peppas62 shed light on this subject sensitizer (PS) to the target cell is crucial. A multi-compartmentalized
in a review covering drug-resistance mechanisms, drug-sensitizing nanocarrier, which can incorporate both the gene and the PS inside the
strategies, and the use of nanocarriers to co-deliver siRNA and same nanoassembly to ensure co-delivery but at the same time keep the
small-molecule drugs to overcome MDR. two therapeutic entities separately compartmentalized to prevent gene
inactivation by the PS through the formation of reactive oxygen species
Besides siRNA, co-delivery of the tumor-suppressing p53 gene along (ROS), can potentially serve this purpose. A three-layered PM system
with a variety of small-molecule drugs (e.g., doxorubicin,63 BTZ,64 or (Figure 4) made of PEG-poly{N-[N-(2-aminoethyl)-2-aminoethyl]

Molecular Therapy Vol. 25 No 7 July 2017 5

 Please cite this article in press as: Quader and Kataoka, Nanomaterial-Enabled Cancer Therapy, Molecular Therapy (2017), http://dx.doi.org/10.1016/
j.ymthe.2017.04.026

www.moleculartherapy.org

Review

polymer76,77 made of PEG and a cationic (oligoethanoamino) amide

coupled to cMET-binding peptide (cMBP2). This polyplex system is
targeted against cMET-overexpressing prostate cancer cells and hep-
atocarcinoma cells. Researchers also confirmed the reporter function
of cMET-targeted polyplexes in vivo by utilizing 123I gamma camera
imaging. Convincingly, three rounds of polyplex and radioiodide
(131I) application significantly reduced tumor growth and prolonged
survival in mice. Considering that the NIS gene has already been used
clinically as a diagnostic and therapeutic modality, an efficient
actively targeted systemic delivery method using a polymer with a
defined structure would increase its therapeutic potential in clinical
oncology.

RNA Nanotechnology as a Nature-Derived Cutting-Edge NM-

DDS Trend
While the use of synthetic polymer-based NMs to deliver nucleic
acid-based therapeutics is fairly common, the use of nucleic acids
as a naturally derived delivery system has recently emerged as a cut-
ting-edge trend.78 RNAs have unique functional, structural, and
chemical properties for the construction of nanodevices. For example,
it is easy to prepare multiple copies of RNA through in vitro transcrip-
tion, and RNA often crosses the nuclear membrane to affect biological
pathways or regulate gene expression.79 RNA is a safe material due to
Figure 4. Schematic Representation of the Rod-Shaped DPc-Loaded its natural biological origin. RNA also offers versatile chemical modi-
Ternary Polymer-pDNA Complex Micelle (DPc-TPM) Delivery at the fication and self-assembly opportunities and has been used to create a
Systemic and Intracellular Levels variety of NPs.78–80 These NPs have been successfully utilized for sys-
DPc-TPM circulates in the blood, avoiding non-specific interactions with biological
temic delivery of siRNA to tumors, including triple-negative breast
components, and reaches the target (a solid tumor tissues), where DPc-TPM is
endocytosed and trapped in endosomes/lysosomes. In response to the low pH in
cancer81 and glioblastoma,82 to accomplish sequence-specific gene
the environment of endosomes/lysosomes, DPc is released from the DPc-TPMs silencing. A combination therapy against multi-drug resistant cancer
owing to the protonation of the peripheral carboxyl groups and interacts with the was also adopted by Jang et al.83 utilizing RNA-NPs, which co-deliver
endosomal/lysosomal membrane through hydrophobic interactions. Upon photo- two types of therapeutic siRNAs against MDR1 and BCL2, with a
irradiation, DPc generates ROS that destabilize the endosomal/lysosomal mem- potent synergistic effect. While RNA nanotechnology has exciting po-
brane, facilitating endosomal/lysosomal escape. ROS, reactive oxygen species.
tential as an innovative nanodelivery platform, it remains to be seen
Reproduced from an open-access publication.73
whether this experimental technology can translate into a practical
therapeutic option in oncology.
aspartamide}-poly(L-lysine) (PEG-PAsp(DET)-PLys) has been devel-
oped to facilitate this.73 The outer hydrophilic PEG layer protects the NMs for Cancer Diagnosis, with a Specific Focus on MI Signal
core, which holds stably packaged pDNA at the inner core and PS- Amplification Utilizing the TME
incorporated dendrimers (DPcs) as a middle layer. This rod-shaped Amalgamation of MI with Nanotechnology
DPc-loaded ternary polymer-pDNA complex micelle (DPc-TPM) Contemporary developments in molecular imaging (MI) techniques,
demonstrated 100-fold photo-enhanced gene expression in cultured along with NM-based delivery systems, have significant potential for
cells and exhibited light-induced in vivo gene transfer in solid tumors early cancer diagnosis, which is crucial for ensuring effective treat-
following systemic administration. ment outcomes and better patient survival. MI allows non-invasive
and real-time imaging of biological processes at the cellular, subcellu-
Designing Sequence-Defined Polymers as a NM Platform to lar, or even molecular level in living subjects, with widespread appli-
Appreciate Theranostic Opportunities cations for efficient disease screening and treatment outcome moni-
While the use of multi-component systems for achieving combined toring. From an oncological and imaging point of view, an ideal MI
effects is widely employed, the use of a single component with multi- probe would possess high specificity toward cancerous cells over
ple functions is quite unique. The sodium iodide symporter (NIS) has healthy tissue to avoid non-specific accumulation and would have a
the unique property of offering both therapeutic and diagnostic (i.e., high signal-to-background ratio for highly sensitive detection by
theranostic) function. NIS, a well-defined theranostic gene, can target techniques such as MRI, positron emission tomography (PET),
different cancer types, allowing non-invasive imaging of functional single-photon emission tomography (SPECT), optical imaging, and
NIS expression and therapeutic radioiodide application.74 Urnauer ultrasound imaging. Amalgamation of MI techniques and nanotech-
et al.75 have encapsulated the NIS gene in a sequence-defined nology can considerably expand the specificity and sensitivity of

6 Molecular Therapy Vol. 25 No 7 July 2017

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Review

Figure 5. Mn2+-Loaded PEGylated CaP Nanoparticle as an MRI Probe with Signal Amplification Ability
(A) Schematic illustration of the structure of PEGMnCaP. The PEGMnCaP consists of a CaP-based core, covered with a PEG layer. Within the core, poly(glutamic acid) blocks
(yellow) of the block copolymers control the growth of the core by inhibiting the mineralization of large CaP blocks, such as hydroxyapatite crystals (orange). The Mn2+ ions are
trapped in the CaP core. (B) In vivo MR images of subcutaneous C26 tumor-bearing mice pre- (left) and post- (right) intravenous (i.v.) injection of PEGMnCaP, measured with
7T MRI. (C) MR images of subcutaneous C26 tumor-bearing mice 4 hr after the i.v. injection of PEGMnCaP measured by 1T MRI. The contrast in the tumor (yellow dashed
square) was selectively enhanced, and the hypoxic regions (white dashed area) exhibited a higher contrast enhancement compared with the surrounding tumor tissues.
Scale bar, 1 cm. (D) MR images of liver metastasis measured by 1T MRI. The contrast in the metastatic tumor regions (yellow arrows) was enhanced specifically by
PEGMnCaP. The contrast in the gallbladder (white arrows) gradually increased because of the clearance of PEGMnCaP. CaP, calcium phosphate; MR, magnetic resonance;
PEG, poly(ethylene glycol); PEGMnCaP, Mn2+ ion-loaded PEGylated CaP nanoparticle. Reproduced with permission.92 Copyright ª 2016, Rights Managed by Nature
Publishing Group.

diagnostic imaging by enhancing the contrast between malignant and However, fluorescence-based imaging techniques suffer from an
benign tissues.84 The contrast-enhancing capabilities of MI probes intrinsic limitation of tissue penetration depth, preventing the imag-
loaded in NMs can generally be attributed to atomic constraints ing of any tissue more than a few centimeters below the surface. This
that occur at the nanoscale, with the cumulative effect of packing limitation can be overcome by applying TME-sensing NMs to MRI
tens of thousands of contrast agents into nanometer-sized particles.85 probes. One of the latest reports in this area discusses the entrapment
Contrast can be further amplified by installing targeting moieties of Mn2+ ions within pH-sensitive calcium phosphate (CaP) NPs
against specific cancer biomarkers. A wide range of cancer bio- covered with a PEG shell.92 The design depends on the pH-triggered
markers have been utilized in NP-based MI platforms to achieve release of Mn2+ ions from the CaP matrix, as well as complexation of
higher specificity, such as Her2/neu,86 epidermal growth factor recep- Mn2+ ions with proteins to form slowly rotating Mn-protein systems
tors (EGFRs),87 and folate receptors.88 However, there are often geno- that promote a sharp contrast enhancement. Thus, the Mn2+ ion-
typic and phenotypic differences between tumors, even tumors of the loaded PEGylated CaP NP (PEGMnCaP; Figure 5A) rapidly enhances
same histopathological subtype. In addition, individual tumors the tumor-to-normal (T/N) contrast ratio for MRI (Figure 5B). Fasci-
usually contain a heterogeneous population of cells. These inter- natingly, hypoxic regions displayed even higher contrast enhance-
and intra-tumor differences make it impossible to develop a universal ment, and the lower local pH environment of the hypoxic regions
tumor detection system by targeting a specific cancer biomarker.89 facilitated the triggered release of Mn2+ to achieve higher contrast
Inversely, almost all tumors share some features of the TME,90 such enhancement than the surrounding non-hypoxic tumor region (Fig-
as low pH,91,92 altered redox potential,93 hypoxia,92 and angiogen- ure 5C). Additionally, the sharp contrast-enhancement ability of
esis.91 These properties can be used to efficiently amplify MI signals. PEGMnCaP allowed the detection of millimeter-scale colon cancer
metastases in the liver (Figure 5D). It is well known that tumor hyp-
Utilizing the Acidic TME to Amplify the Signal of MI Nanoprobes oxia contributes to chemo- and radiation therapy resistance and also
Wan et al.91 elegantly utilized the low-pH conditions of the TME, facilitates metastasis progression. Again, metastasis (the final stage of
along with the angiogenic tumor vasculature, for fluorescence imag- neoplastic progression) remains the primary cause of cancer death.
ing. They developed a library of “pH transistor” nanoprobes with Thus, the capability of PEGMnCaP NPs to image hypoxic regions
broad pH tunability and fluorescence emission and confirmed the and metastases, two very common but crucial events of malignancy,
generality of these techniques by imaging a variety of cancer models, confirms their versatility for cancer imaging. More importantly, their
including transgenic, orthotopic, and subcutaneous models. non-toxic and biocompatible nature would be beneficial for successful

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Table 1. Examples of NM-DDSs Already in Clinical Use and in the Clinical Pipeline

NM Platform Encapsulated Drug Trade Name Application Current Status

HIV-related Kaposi sarcoma, ovarian cancer,
PEGylated liposome doxorubicin Doxil FDA approved in 1995
and multiple myeloma
Liposome daunorubicin DaunoXome HIV-related Kaposi sarcoma FDA approved in 1996
Liposome cytarabine DepoCyt lymphomatous meningitis FDA approved in 1999
Liposome doxorubicin Myocet metastatic breast cancer FDA approved in 2000
Albumin nanoparticles paclitaxel Abraxane breast, lung, and pancreatic cancer FDA approved in 2005
Liposome vincristine Marqibo scute lymphoblastic leukemia FDA approved in 2012
PEGylated liposome irinotecan Onivyde/ MM-398 pancreatic cancer FDA approved in 2015
PEGylated liposome cisplatin Lipoplatin NSCLC phase III
Polymeric micelle paclitaxel NK-105 metastatic breast cancer phase III
Polymeric micelle cisplatin NC-6004 pancreatic cancer phase III
FDA, Food and Drug Administration; NM, nanomaterial; NM-DDS, nanomaterial-based drug delivery system; NSCLC, non-small cell lung cancer.

clinical translation. Furthermore, this PEGMnCaP-based MRI system are hypovascular and show poor permeability. However, poor
could also be utilized to determine NP permeability in solid tumors; vascular permeability can be overcome by carefully controlling NP
that is, the extent of the EPR effect could be effectively determined, size. For instance, sub-100-nm micellar nanostructures easily
which is a critical factor for NM-DDSs. The importance of precisely permeate hypervascular tumors; however, only sub-50-nm micelles
defining the extent of the EPR effect is further discussed in the can extravasate and penetrate into hypovascular tumors.96 Neverthe-
following section. less, there are several methods to augment the EPR effect and enhance
NP permeability in hypovascular tumors, such as the use of trans-
NM Application in Cancer Therapy: Challenges in Clinical forming growth factor (TGF)-b inhibitors, tumor necrosis factor
Translation (TNF)-a, or collagenase.95,97
Addressing the Issue of Tumor Heterogeneity/EPR
Heterogeneity through Appropriate Design of NPs and Transient Many research groups have also taken advantage of tumor vascu-
Modulation of Tumor Vasculature lature maturation or extracellular matrix remodeling to increase
NMs have been successfully applied to cancer therapy, with several intratumoral distribution.98,99 The pore cut-off size of the tumor
anticancer drug-loaded NM-DDSs already in clinical use and several vasculature also critically affects transvascular transport of macro-
others in the pipeline (Table 1). Notably, the majority of the NM- molecules. Additionally, tumor location greatly impacts the EPR
DDSs in clinical use or in development are primarily designed to effect; for example, intracranial tumors are known to have a
exploit the EPR effect. Doxil (doxorubicin-loaded PEGylated lipo- weak EPR effect with a much smaller pore cut-off size (7–
somes) is the first FDA-approved NM-DDS for clinical use in sar- 100 nm).100 The challenge of crossing the blood-brain barrier
coma, ovarian cancer, and other cancers, and it exclusively relies on (BBB) or blood-brain-tumor barrier (BBTB) gives large NPs signif-
selective accumulation in solid tumors through the EPR effect. The icantly inferior transvascular transport in brain tumors.101 How-
recently approved NM-DDS Onivyde MM-398 (irinotecan in ever, a smart NM-DDS capable of targeting receptors overex-
PEGylated liposomes) also utilizes passive targeting for anticancer pressed in the BBTB vasculature can induce active transcellular
therapy. While the EPR effect remains an indispensable theory in transport. Thus, platinum anticancer drug-incorporating poly-
NM-based cancer therapy, tumor heterogeneity (both intra- and meric micelles modified with cyclic Arg-Gly-Asp (cRGD) peptide
inter-tumor) is emerging as an alarming factor in oncological achieved efficient drug delivery to glioblastoma tumors via an
research. The link between tumor heterogeneity and the EPR effect active transcellular pathway, with significant antitumor effects in
(EPR heterogeneity) is being increasingly recognized as a challenge an orthotopic mouse model of U87MG human glioblastoma.102
for the clinical translation of NM-DDSs.94 Particularly, several het- cRGD is well known to bind preferentially to the avb3 and avb5 in-
erogeneous structural features (e.g., tumor vascularity, pore size, loca- tegrins, the expression of which is much higher in glioblastoma
tion, presence or absence of functional lymphatic system, and the cells than in normal brain tissue. Active targeting could therefore
nature of the surrounding stroma) directly influence the EPR effect be an effective method to deliver NPs to tumors that do not have
and ultimately affect the therapeutic performance of NM-DDSs.95 a functional EPR effect. Significant differences in the EPR effect
also exist between a primary tumor and its metastases. The absence
Tumor vascular density that affects NP permeability varies with tu- of neovasculature in preangiogenic micrometastases is expected to
mor type. Colon adenocarcinoma and renal cell carcinoma are hyper- reduce EPR-mediated transport of NM-DDSs. However, the in-
vascular and highly permeable, while prostate and pancreatic cancers flammatory microenvironment of preangiogenic micrometastases

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Figure 6. Schematic Demonstrating the

Consequences of Dynamic Vents for NM-DDSs
A static pore allows for extravasation of only small nano-
particles. Alternatively, dynamic vents allow extravasation
of both large and small nanoparticles. Small particles can
penetrate and diffuse deeply into the tumor region;
however, large nanoparticles are trapped as clusters in the
interstitial space. EPR, enhanced permeability and
retention; NM-DDS, nanomaterial-based drug delivery
system.

must have a long blood circulation profile after

systemic delivery to selectively accumulate in
the tumor region while avoiding non-specific
distribution in other major organs. The size,
shape, and surface charge of NM-DDSs dictate
their distribution among the major organs,
including the lungs, liver, spleen, and kidneys.
This topic was comprehensively reviewed and
discussed by Blanco et al.105 In addition, recent
research also confirmed the importance of pre-
cise architectural control of the nanoassemblies
to maintain structural integrity during circula-
can induce vascular permeability and facilitate accumulation of tion, which eventually leads to selective tumor accumulation while
systemically injected nanocarriers.103 reducing non-specific accumulation in the excretory organs.106 An
NM-DDS also needs to successfully extravasate from blood vessels
Enhanced Permeability through Spontaneous Vascular Bursts into the tumor mass and then offload the cargo efficiently to demon-
Spontaneous vascular bursts also prompt enhanced permeability of strate therapeutic efficacy. This means that a facilitated transport
tumor blood vessels and improve NP delivery in a poorly vascular- system coupled with an effective drug-release mechanism would
ized tumor. Using intravital confocal laser scanning microscopy maximize NM-DDS efficacy. However, for successful extravasation,
and dye-labeled polymeric micelles, the occurrence of dynamic the size of the NM-DDS is crucial and only small-sized particles
and transient enhanced permeability of tumor blood vessels, char- (sub-100 nm) can effectively extravasate.107 In this context, a facili-
acterized by “vascular bursts,” was recently confirmed (Figure 6).104 tated transport mechanism would work only with NM-DDSs that
These vascular bursts are innately followed by a brief vigorous out- have an optimal size range. Engineered release mechanisms sensitive
ward flow of fluid (named “eruptions”) into the tumor interstitial to TME-associated stimuli (e.g., pH, redox potential, or enzyme activ-
space. This transient porosity in tumor blood vessels has been ity) can further enhance the therapeutic capacity of nanomedicine.108
referred as a “dynamic vent,” through which both large (70 nm) After release from the carrier, bioactive payloads need to escape from
and small NPs (30 nm) can extravasate, while only the small par- the harsh environment of the endosomal/lysosomal compartments;
ticles can pass through the static pores. As the vents close, 70-nm thus, an effective endosomal escape mechanism is crucial, especially
particles are trapped in the interstitial space, forming clusters. In for protein- and nucleic acid-based therapeutics, as they cannot
contrast, 30-nm particles diffuse and penetrate deeply in the tu- diffuse through the vesicle membrane. Various strategies are being
mor, demonstrating higher therapeutic benefits in a hypovascular employed to address this issue, such as pH-buffering effects, mem-
tumor model.96 Nonetheless, by incorporating a dynamic disas- brane fusion, pore formation, and photochemical disruption of the
sembling or release mechanism in larger-size NPs, the dynamic membrane of endosomal compartments.109 Thus, from the above
vents and associated eruptions can be effectively capitalized to examples and discussion, it would be reasonable to state that there
expand the capacity of the EPR effect to counteract tumor are substantial opportunities to modulate the delivery and targeting
heterogeneity. ability of NM-DDSs to achieve successful clinical translation.

Optimal Features of NM-DDSs to Enhance Tumor Targeting and Additionally, genetic screening is taking over traditional histology-
Delivery Potential based cancer classification, and patient selection has been progres-
Characteristics of NM-DDSs (e.g., size, surface property, blood circu- sively recognized as one of the crucial factors in designing oncological
lation profile, and drug release) also affect the delivery, disposition, clinical trials. In this context, an effective tumor-imaging tech-
and distribution of the therapeutic load in tumors. An NM-DDS nique110,111 is indispensable to image cancer biomarkers and properly

Molecular Therapy Vol. 25 No 7 July 2017 9

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characterize the extent of the EPR effect to enable patient preselection ing the extent of the EPR effect and tumor biomarkers is crucial. Aug-
for an optimized response to NM-DDSs. menting the EPR effect or utilizing a facilitated transport mechanism
that enables precise delivery of NM-DDS to tumors and, finally, the
Disparity between Pre-clinical and Clinical Studies integration of cancer biology with materials engineering and chemis-
While we discussed the delivery and targeting ability of NM-DDSs to try to accomplish the optimal design of NM-DDS, allowing adequate
ensure successful bench-to-bedside translation, the poor representa- distribution of therapeutic payloads in the diseased area, is essential to
tion of human cancers in pre-clinical animal models is another crucial truly revolutionize cancer therapy through NMs.
aspect limiting the clinical translation of anticancer therapeutics
including NM-DDSs.15,112,113 Mouse cancer models (transplantation ACKNOWLEDGMENTS
of murine or human cancers into mice) are most commonly used in We thank Dr. Samuel T. Crowley for reviewing and editing this manu-
pre-clinical studies, and these models can provide invaluable pharma- script. This project was supported by the Japan Science and Technol-
cological and toxicological information. However, decisive physiolog- ogy Agency (JST) Center of Innovation (COI) Program. This work was
ical, immunological, genetic, molecular, and cellular disparities be- also partially supported by the Japan Agency for Medical Research and
tween humans and mice limit the translational potential of animal Development (AMED) Project for Cancer Research and Therapeutic
studies in human trials. Also, conventional xenograft tumor models Evolution (P-CREATE) (project no. 16 cm0106202h0001) and
inadequately represent cancer heterogeneity and complex tumor- Grants-in-Aid for Challenging Exploratory Research (no. 16K12904
host immune responses that have critical consequences on tumor to S.Q.).
development as well as the therapeutic response to anticancer treat-
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