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Smart Drug Delivery Systems – Futuristic Window in Cancer Therapy
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.. Gold nanoparticles
Gold (Au) NPs are frequently used as nanosized diagnostic and therapeutic
agents. Colloid Au has shown potential in medication delivery owing to its unique
physicochemical characteristics such as strong tunable surface plasmon resonance
(SPR) which can be detected using multiple imaging modalities, capacity to bind
amine and thiol groups, enable surface modification and ability to passively accumulate on tumor cells [47]. Efforts have been made to entrap Au NPs into a lipid carrier to
enhance its antitumor potential. Au porphyrin has been documented as a very potent
antitumor drug [48]. Au NPs have been widely used as one of the leading nanomaterials for combinatorial cancer therapy [49].
.. Silica nanoparticles
Mesoporous silica nanoparticles (MSNPs) exhibit mechanical, thermal, chemical stability, high surface area and ordered porous interior to store anticancer
therapeutics with high loading capacity and tunable drug release mechanisms [50].
Furthermore, the surface of MSNPs can be easily decorated or modified by attaching ligands for specific targeting to the cancer cells exploiting their overexpressed
receptors. The controlled release of drugs at the target site without any leakage to the
healthy tissues can be achieved by employing environment responsive gatekeepers for
end-capping of MSNPs.
.. Magnetic nanoparticles
Magnetic nanoparticles (MNPs) offer high magnetic moments and surface-areato-volume ratios that make them attractive for hyperthermia-mediated therapy of
cancer as well as targeted drug delivery. MNPs are directed at the target tissue by
means of an external magnetic field. Materials most commonly used for magnetic
drug delivery contain metal or metal oxide NPs, such as superparamagnetic iron
oxide NPs (SPIONs). SPIONs are conjugated with drugs, in combination with an
external magnetic field to target the nanoparticles [51]. Due to their high osmotic
pressure and ease of separation from water by a magnetic field, magnetic NPs
functionalized with highly water-soluble and ionic strength groups have attracted
attention in recent years as promising DDSs. Recently, a study reported the use of
folic acid-conjugated poly(amidoamine) dendrimer-grafted magnetic chitosan as
a smart drug delivery platform for doxorubicin, targeting human breast cancer cell
lines [52]. This multifunctional system can address the limitations of conventional
chemotherapeutic agents by utilizing pH-triggered drug release, which enables
targeted cytotoxicity against cancer cells.
.. Carbon nanotubes
Carbon nanotubes (CNTs) are categorized into single-walled CNTs, consisting of a single piece of graphene and multiwalled CNTs comprising of a multilayer
of graphene sheet that caries peptides, proteins and genes. They can pass through
membranes, carrying therapeutic drugs, vaccines or nucleic acids deep into the
cellular targets [53]. They are safe, nontoxic vehicles and increase the solubility of the
attached drug, resulting in greater therapeutic efficacy. Multiwalled CNTs modified
by dendrimer have been used for the delivery of doxorubicin.
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
..
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Quantum dots
Quantum dots (QDs) are semiconductor NPs that have optical and electronic
(optoelectronic) capabilities depending on their size and composition. Compared
with conventional drug carriers, QD nanocarriers for drugs have become a hotspot
in the field of nanomedicine as they are small in size with large surface area [54].
These carriers have a unique mode of drug release with an initial burst followed by a
constant release over a prolonged period of time, thereby increasing the effectiveness
of drugs at a limited concentration, with negligible side effects. Since the drug-loaded
carriers have the property of adhesion and small particle size, they can improve the
absorption, bioavailability, and stability of drugs; lengthen circulation time in vivo;
enhance targeted absorption of the drug; improve biodistribution; enhance the efficacy and reduce side effects of drug; and improve the therapeutic index of the drugs.
Hybrid-based nanoparticles
.
Owing to the advantages and disadvantages of organic and inorganic NPs, com
bination of the two in a single hybrid DDS endows the multifunctional carrier with
superior biological properties that can augment therapeutic efficacy as well as lessen
drug resistance [55].
Lipid polymer hybrid nanoparticle
..
The most commonly used matrices in these nanocarriers are polymers and lip
ids. Among the polymeric nanosystems, polymeric NPs, polymeric micelles, and
polymer-drug conjugates have been distinguished, while the lipid-based nanosystems
include liposomes, solid lipid NPs, and nanostructured lipid vectors [56]. Lipid-based
nanocarriers offer several advantages such as low production cost, high trapping
efficiency of the therapeutic agent; however, they tend to display reduced stability, a
fast load release, and high polydispersity.
Organic-inorganic hybrid nanoparticles
..
One popular approach to creating NPs is to combine organic and inorganic hybrid
NPs to integrate their merits and minimize their intrinsic drawbacks. A liposomesilica hybrid (LSH) NP comprising of a silica core encapsulated by a lipid bilayer has
been reported to be effectual in delivering drugs to kill prostate and breast cancer
cells [57]. The LSH NP has also been shown to offer a platform for the synergistic drug
delivery, such as gemcitabine and paclitaxel to pancreatic cancer in a mouse model of
the disease [23].
.. Cell membrane-coated nanoparticles
This strategy for NP design involves hybridization of natural biomaterials with
organic or inorganic NPs. Cell membrane-covered drug-delivery nanoplatforms have
been garnering attention because of their enhanced biointerfacing capabilities that
originate from the source cells. In this top-down strategy, NPs are covered by various
membrane coatings, including membranes from specialized cells or hybrid membranes from different types of cell membranes. NPs coupled with a hybrid membrane
derived from macrophage and cancer cells could treat breast cancer-derived lung
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metastases and accumulated at sites of inflammation, targeting specific metastasis,
with homogenous tumor targeting abilities and exhibited excellent chemotherapeutic
potential with inhibitory effects on cell viability, motility, and invasion and no overt
cardiotoxicity [58]. This hybrid cell membrane-disguised nanoplatform is a promising strategy for specific targeted therapy of tumor metastasis.
. Mechanism of targeting with nanodrugs
A crucial aspect of nanocarriers for drug delivery is their ability to target cancer
cells specifically to boost therapeutic effectiveness while shielding normal cells from
damage. Owing to their specific cell uptake and trafficking mechanisms, NPs permit
the delivery of sensitive therapeutics in sufficient concentration to their target site
in active form, and prevent accumulation in undesired organs. Hence, proper NP
formulation and optimization is pertinent to enable cellular/nuclear targeting. Active
and passive targeting are the two basic categories into which the NP targeting systems
can be categorized (Figure ).
. Active targeting
Active targeting precisely targets the cancer cells through direct interaction
between ligands decorated on the surface of NPs with their receptors that are overexpressed on cancer cells. Internalized NPs successfully release therapeutic medications by receptor-mediated endocytosis. This strategy promotes the affinities of the
nanocarriers for the surface of cancer cell and thus enhances the drug penetration.
Since proteins and small interfering RNAs (siRNAs) are macromolecular drugs, active
targeting is particularly suited for their delivery. The frequently studied receptors
Figure 4.
Targeting of NPs to cancer cells to enhance therapeutic efficacy and minimize systemic toxicity. Active targeting is
affected through interaction between ligands on NPs and overexpressed receptors on cancer cells. Passive targeting of
NPs is enabled by EPR effect, which exploits escalated vascular permeability and impaired lymphatic drainage of
cancer cells and NPs enter the tumor vasculature through leaking blood capillaries. Adapted from Yao et al. [23].
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
include the transferrin receptor, folate receptor, glycoproteins (such as lectins), epi-
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dermal growth factor receptor (EGFR) and Human epidermal growth factor receptor
2 (HER2). These ligands precisely bind to receptors on target cells [59].
.
Passive targeting
Under certain conditions such as inflammation and hypoxia, characteristic of
tumors, the endothelium of blood vessels becomes more permeable than in the
healthy state. NPs extravasate from blood arteries that nourish the tumor and concentrate in tumor tissue as a result of rapid and efficient angiogenesis. The rapidly
growing tumors capitalize on hypoxia to recruit new blood vessels or engulf the
existing ones. The newly formed leaky vessels allow selective enhanced permeation of macromolecules larger than 40 kD and nanocarriers to the tumor stroma.
Furthermore, poor lymphatic drainage in tumor contributes to retention of drugencapsulated nanosized drug carriers, enhancing the pharmacokinetics (prolonged
systemic circulation) of the drug, providing tumor selectivity and minimizing
adverse effects. Nanocarriers then distribute their therapeutic contents to tumor cells
and this biodistribution of NPs promotes the EPR effect. Drugs after being successfully delivered to the target site, unveil their therapeutic magic. This type of tumor
targeting termed “passive” relies on carrier characteristics (size, circulation time) and
tumor biology (vascularity, leakiness) but does not possess a ligand for specific tissue
or organ binding unlike active targeting [59].
The tumor microenvironment plays a significant role in the passive distribution
of nanomedicines in addition to the EPR effect. Glycolytic cancer cell metabolism
and hypoxia yield an acidic tumor microenvironment. Subsequently, the low pH
environment triggers some pH-sensitive NPs to release chemotherapeutic drugs in the
vicinity of the cancer cell [60]. However, there are some limitations with respect to
passive targeting, such as nonspecific drug distribution, nonuniversal existence of the
EPR effect and varying vascular permeability across various tumors.
.Smart nanoparticles for cancer gene therapeutics
The massive data available from human genome sequencing has accelerated the
identification of target genes, making gene and nucleic acid therapeutics the next
generation of medicine. In the past decades, gene therapy has undergone a notable
progress, and is now poised to become a first-line therapy for cancer. By cellular
administration of therapeutic nucleic acid, gene therapy modifies gene expression
with the goal of treating a disease.
Cancer gene therapeutics
.
Opposed to conventional treatment paradigms, with the advancements in cancer
genomics, gene therapy has the potential to treat cancer by directly targeting or
focusing on the culprit genes. Gene therapy leverages a multitude of advantages for
anticancer therapeutics such as high potency and specificity, low off-target toxicity
and delivery of multiplex genes that can concurrently target cancer tumorigenesis,
recurrence and drug resistance. Strategies for cancer gene therapy comprise of: (i)
suicidal gene therapy, wherein an enzyme expressing transgene is introduced into
the cell, thereby converting inactive prodrug into metabolites cytotoxic to the host
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cells [61]; (ii) gene silencing, whereby gene expression is suppressed by RNA interference (RNAi) techniques such as siRNA, small hairpin RNA (shRNA), antisense
oligonucleotides, micro RNA (miRNA) [62]; and (iii) DNA/messenger RNA (mRNA)
vaccination, wherein specific tumor antigen-encoding plasmid DNA/mRNA is
introduced into the cell to induce an immune response [63, 64].
. Cancer genes and nanotechnology: a promising alliance for next generation
cancer therapeutics
Novel delivery methods are required in furtherance of this rapidly evolving field
of cancer genomics to be translated into clinically viable gene therapy for patients.
Among the numerous gene delivery strategies, NP-based anticancer gene therapy has
attracted significant attention due to low toxicity profiles, well-controlled and high
gene delivery efficiency, and multifunctionalities [65]. Magnetic NPs have unleashed
the potential to achieve selective and efficient delivery of therapeutic genes and transform the challenge of gene therapy into a new frontier for cancer treatment [66, 67].
mRNA vaccine nanoformulations have been used to maximize cellular immunity for
cancer treatment [68]. Nano-RNAi-based biodrugs have been engineered to inhibit
the target genes in cancer patients [69]. Iron oxide and gold NP carriers for RNAi
therapy have also been explored for targeted delivery and RNA payload release,
coupled with auxiliary properties supporting imaging functionality for theranostic
application. Moreover, the RNAi gene delivery may be paired with combination
therapies such as chemotherapy, photothermal therapy, immunotherapy, and
radiotherapy [70].
. Harnessing the combined potential of cancer nanomedicine
and immunotherapy: a new paradigm in immunotherapeutic
nanomedicines
The immune system is a vital determinant of cancer, suppressing or promoting its
development and progression and thus shapes the cancer trajectory. It may polarize
to an immune-stimulatory state, enabling T cell immune-surveillance or orchestrate
a tolerogenic immunosuppressive niche, interfering with the cytotoxic potential of
tumor antigen-specific T cells [71]. Thus, novel therapeutic strategies are needed that
aim to restore the TME to an immune-reactive state.
. Immune evasion as a hallmark of cancer
Cancer cells are known to elude the host’s immune system’s defensive machinery
and avert immunological killing. The concept of cancer immunoediting underpins
this hallmark and comprises three key phases, namely: elimination, equilibrium and
escape [72]. Immunosurveillance is shaped by the interplay between innate and adaptive arms of immunity, working in tandem to eliminate dysregulated cancer cells.
. Cancer immunotherapy targeting immune cells versus tumor cells
To counter the immunosuppressive TME, cancer immunotherapy seeks to either
activate immune cells (within peripheral lymphoid organs or the TME) or remove
immunodeficient cells in the TME, ultimately resulting in the killing of tumor
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
cells [73]. Currently, FDA approved antiangiogenic drugs have shown modest levels
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of clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance,
and poor targeting of TME. To defeat these constraints, targeting angiogenesis
synergistically with immunosuppressive TME could offer potential therapeutic
opportunities [31]. Cancer immunotherapy can be augmented with toll-like receptor
agonist (TLRa) as adjuvants which elicit potent immune activation. Despite their
potential, their clinical translation is limited due to lack of pharmacokinetic control,
causing systemic toxicity from unregulated systemic cytokine storm [74].
.
Immune checkpoint blockade therapy
Immune checkpoints are the gate-keepers of immune response that maintain
self-tolerance. Stimulatory immune checkpoint molecules promote T-cell activation
and potentiate immunological response; concomitantly, immune checkpoint inhibitors (ICIs) suppress the body’s immune response and prevent onset of autoimmunity.
Immune checkpoint blockade therapy (ICBT) strengthens immune response to fight
against tumors by modulating immunological checkpoint signaling pathways, aids
antiangiogenesis by lowering vascular endothelial growth factor expression and
alleviating hypoxia [75]. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
and programmed cell death-1 (PD-1) on the surface of activated T cells, as well its
ligand on tumor cells, programmed cell death-ligand1 (PD-LI), are the principal
targets of clinically accessible ICIs. Other immune checkpoint molecules include
lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin and immunoreceptor
tyrosine-based inhibitory motif (ITIM) structural domain proteins, T cell immunoglobulin mucin-3 (TIM-3), variable domain of immunoglobulin suppressor of T
cell activation (VISTA), to name a few. Until recently, as many as 70 ICIs are in phase
III and IV clinical trials; while seven ICIs have been FDA-approved [76]. The first
immune checkpoint targeting agent, ipilimumab, a monoclonal antibody (mAb)
targeting CTLA-4, was approved by FDA in 2011 which opened the domain of ICBT.
Subsequently, mAbs blocking other checkpoints such as PD-1 or PD-L1 have received
FDA approvals to treat a number of tumor types.
Despite the unprecedented durable clinical responses observed in subsets of
patients, most patients do not respond, and few develop resistance to therapy after
initial response. Furthermore, ICBTs can result in life-threatening toxicities, known
as immune-related adverse events (irAE).
. Cancer nanoimmunotherapy as a renaissance of cancer nanomedicine
Immunotherapeutic approaches have been revisited with the advent of nano-
technology that can target the peripheral immune system as well as the key cellular
components of TME and tumor cells more precisely. Thus, nanoplatforms have been
engineered to improve the delivery efficiency of cancer nanomedicines that can
target immune cells such as dendritic cells (DCs) for peripheral immune activation
or inhibit immunosuppressive cells within the TME. These nanoimmunomedicines
have brought a paradigm shift in cancer therapy by embracing cancer nanomedicine
and immunotherapy, resulting in synergistic effects such as the immune system
activation to remove immunosuppression as well as induction of immunological
memory [77].
Several cancer nanomedicines have been shown to boost anticancer immu-
nity by working in concert with clinically proven immune therapeutics [78].
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Nanoimmunomedicines can also repurpose cancer nanomedicine to reduce the toxicity of various immunotherapies (Figure ). Integration of antiangiogenic therapy
with immunotherapy in a single nanoplatform has been reported as a promising
nanotechnological advancement oriented to modulate the immunosuppressive TME
without eliciting systemic toxicity [31]. NPs have been found to constitute a modular
platform to deliver TLRa that potently synergized with PD-L1 checkpoint blockade to
slow tumor growth while potentially diminishing the encapsulated dosage to achieve
therapeutic efficacy, resulting in increased potency, reduced systemic cytokine
release and decreased toxicity [74].
. Nanotechnology to enhance immune checkpoint blockade therapy
As checkpoint inhibitors targeting the principal inhibitory axes alone do not elicit
adequate response in patients bearing poorly immunogenic tumors, a combination
of ICIs with nanotechnology-driven immunostimulatory treatment, such as nanochemo/photo/thermo therapy has been implemented as a viable strategy to break
immune tolerance locally and enhance systemic antitumor immunity. To improve the
long-lasting response rate of ICBT, nanotechnology was employed for the delivery
of single immune checkpoint inhibitor that unfortunately led to resistance and a
restricted period of response. However, ICBT (targeting different inhibitory pathways
or both inhibitory as well as costimulatory pathways) in concert with nanotechnology
delivery systems has generated promising results [79].
The creation of novel NPs, such as lipid nanoparticles, nanoscale metal-organic
frameworks, polymeric NPs/micelles/nanogels, inorganic NPs, and nanocarriers
derived from cell membranes, has provided efficient solutions for the targeted
delivery of the cargoes, stimulation of antitumor immune responses, sensitization
of tumors to immunotherapy, and/or reduction of side effects. Nanomedicines can
even achieve sequential release of various treatments to generate a cascade immune
response, induce immunogenic cell death (ICD) of cancer cells to improve cancer
immunotherapy, and modify the tumor immune-microenvironment.
Figure 5.
Nanomedicine-based immunotherapy: a promising solution for cancer therapeutics.
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
Particularly in pre-clinical settings, the synergism of nanomedicine with immuno
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therapy has yielded impressive results. Nevertheless, molecularly targeted small molecule anticancer treatments, as well as nanotherapeutics and immune therapeutics,
only perform well in specific patient subpopulations. As a result, methods for patient
stratification in clinical trials need to be developed that may be crucial for ensuring
rapid and effective clinical translation of nanoimmunotherapy.
.
Conclusion
For the treatment of cancer, nanotechnology has been developed as effective
DDS. The development of nanocarriers for controlled drug delivery and targeted
therapy has increased the efficacy of cancer medicines, lowering off-target adverse
effects. Few of these active anticancer medicines are FDA approved while others
have progressed onto clinical trials. Cancer treatment effectiveness is also enhanced
by employing strategies such as immunotherapy that prime our bodies to attack
cancer. Additionally, nanocarrier delivery technologies offer enhanced platforms
for combination therapy, which aids in overcoming drug resistance due to efflux
transporter overexpression, faulty apoptotic pathway, and hypoxic TME. With
rational therapeutic combinations, next-generation multifunctional cancer nanomedicine and NP-mediated integrated gene therapy and/or ICI immunotherapy
are needed to support “multitargeted therapy” by obstructing adaptive chemoresistance, immune escape and amplifying the impact of therapeutic combinations.
Nanoimmunomedicines may be clinically translated and may lead to a paradigm shift
in cancer treatment.
-
. Future perspectives and challenges ahead
NP carriers penetrate tumors and exert efficient antitumor effect. An ideal
carrier would be “theranostic nanocarrier” that can carry the antitumor medicine
while also being coated with particles for tumor surveillance and imaging to integrate the therapeutic and diagnostic procedures in the same NP carrier provided
the medication has strong imaging potential. A few of these are undergoing clinical
trials. Nanotechnology is anticipated to form alliance with pharmacogenomics and
revolutionize pharmacotyping and “personalized medicine” to predict anticancer
pharmacotherapeutic outcomes. It is further necessary to create novel platforms that
combine cancer biology and “antimetastatic nanotechnology” while considering the
biological mechanisms of different stages of cancer metastasis. A merger of these
disciplines may hasten cancer diagnosis at a very early stage, excluding the need for
costly late-stage emergency therapies for metastatic cancer. To realize the clinical
potential, a focused therapeutic intervention specific to TME is preferred. Through
minimally invasive surgery, “implantable devices” can be directly put into tumors,
releasing the nanomedicines/chemotherapeutics and increasing the in vivo efficacy of
chemotherapy, making it more cost-effective.
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Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
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