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Chapter 1
2
Revisiting Multifunctional
Nanomedicines for Cancer Therapy
SwatiGupta and FarhatAfrin
Abstract
C
ancer is one of the primary causes of human deaths worldwide. Most cancer
patients receive chemotherapy and radiotherapy, but these therapeutic regimens are
usually only partially efficacious and give rise to serious side effects. Therefore, it
is necessary to develop new therapeutic strategies to optimize the pattern of cancer
treatment. The emergence of nanotechnology has had a profound impact on evolving
tumor treatment modalities, facilitated by the development of nanodrug delivery
systems that are highly tumor selective and allow for slow release of active anticancer
drugs. Vehicles such as liposomes, dendrimers and polymer nanomaterials have been
considered as promising carriers for tumor-specific drug delivery, reducing toxicity,
and improving biocompatibility. To address the challenges in cancer therapeutics such
as poor targeting of first-line chemotherapeutic drugs, easy destruction of nucleic
acid drugs, and common immune-related adverse events in immunotherapy, we discuss how nanocarriers can be synergized with these treatment modalities. The future
impact of nanomedicine-assisted cancer immunotherapies is also outlined.
Keywords: nanomedicine, cancer immunotherapy, immune checkpoint inhibitors,
nanoimmunotherapy, gene therapy
. Introduction
Cancer comprises an array of illnesses that has its roots in practically any organ or
tissue of the body. The disease surfaces when abnormal cells multiply in an uncontrolled manner, traversing their normal boundaries to infect nearby healthy cells
and/or spread to other organs. The latter process, known as metastasis, significantly
contributes to cancer-related mortality. The primary cause of greater mortality rates in the majority of nations is cancer, which is regarded as one of the most
dreaded malignant diseases. The term “cancer” refers to the unrestricted division
and proliferation of cells. The immense capacity of these cells to multiply uncontrollably, stimulate angiogenesis, and promote invasion and metastasis has earned this
condition the title of “the most feared disease” globally. The terms “neoplasm” and
“malignant tumor” has also been ascribed to cancer. Any region of the body can be
afflicted by cancer; however, the lungs, female breasts, prostate, pancreas, and liver
are particularly vulnerable to infection. After ischemic heart disease, cancer is the
second worldwide cause of death (8.97 million deaths) and is likely to become the first
in 2060 (~18.63 million deaths) [1].
Smart Drug Delivery Systems – Futuristic Window in Cancer Therapy
3
One of cancer’s distinctive characteristics is the unchecked, rapid cell proliferation
that occurs in several human organs. This growth leads to malignant tumors, which
are the main cause of mortality. The impediments of therapeutic approaches include
fatigue, numbness, changes in nails, hair loss, loss of appetite, mouth sores, nausea,
weight changes, vomiting, diarrhea, and heart damage. Cancer patients frequently
visit hospitals for chemotherapy that results in undesirable side effects. In spite of its
enormous potential, chemotherapy remains disadvantageous due to its nonspecific
delivery, resulting in off-target adverse consequences [2]. According to the World
Health Organization, approximately 50% of cancer deaths can be avoided by adopting
three different strategies, viz, consciousness, clinical diagnostic techniques, and care
[3, 4]. The treatment of cancer has relied on chemotherapy, radiation, and surgery
but these regimens are not bereft of restraints. Conventional chemotherapy, the most
popular cancer treatment, is limited in its effectiveness due to fast elimination of
most anticancer drugs. When administered more frequently and at higher doses, it
results in drug resistance and causes toxicity. Damage to healthy cells is a side effect of
chemotherapy that compromises the immune system and causes symptoms like loss
of appetite, baldness, and illness. The prime cause of such intense unfavorable fallout
and high mortality rates is the excessive dose of chemotherapeutics beyond their
remedial limit in normal healthy tissues, originating due to burst release of drugs
after administration [5]. As a result, more medication is injected than is necessary to
maintain diffusion-controlled phenomena.
Therefore, targeted drug delivery carriers for cancer therapy are currently
pertinent, as they can improve remedial efficiency, thereby minimizing adverse
side effects [6]. In order to maintain the therapeutic concentration, it is necessary
to design and develop controlled drug delivery systems (DDSs) that can release the
drug in a regulated manner for prolonged period of time. The therapeutic efficacy of anticancer drugs in various malignant tumors has increased as a result of
manifold options available for an individualized approach, tailored to the personal
patient profiles [7]. Nonetheless, the quest for new and innovative cancer therapeutics is still urgently needed across the globe. Herein, we review the challenges
in cancer therapeutics and development of nanomedicine, focusing on promising
nanocarriers, immunomodulatory nanomedicines and nanomedicine-assisted
cancer immunotherapies that may help to alleviate the shortcomings in cancer
drug delivery.
. Challenges in cancer therapeutics
The main bottleneck for modern anticancer medications is to target and kill tumor
cells while minimizing unwanted effects. In order to decrease uptake by healthy
tissues and enhance the payload or drug in the tumor microenvironment (TME), the
idea of selective targeting has arisen [8]. Additionally, because more than 40% of
anticancer medications are hydrophobic, their ultimate bioavailability and therapeutic effectiveness may suffer. Poorly water-soluble anticancer medicines have traditionally been dissolved using solvents and emulsifiers. However, these have the potential
to cause cancer and may be harmful to the liver and neurological system. Tumors also
subvert the phenotypic plasticity of the immune compartment to advance disease
progression. Tumors may employ strategies to escape immune recognition and
repress T-lymphocyte effector functions.
Anticancer drug distribution is hampered by a variety of impediments:
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
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. Internal toxicity of the drug
Internal toxicity has the potential to limit the dosage of cancer medications
intended for systemic distribution. Systemic toxicity varies depending on the mode
of administration and the application site. Local delivery is one of the methods for
reducing systemic toxicity since it allows for high drug concentrations and ensures
that the drug remains in the local tissue. Systemically administered cancer medications have a higher likelihood of interacting with and being absorbed by the kidney,
bone marrow, and central nervous system while in circulation, leading to the death of
healthy cells.
. Barrier to tumor microenvironment
Tumors initially rely on the host tissues’ vasculature to supply them with blood. As
they grow further, they switch into an angiogenic state in order to meet their increasing metabolic needs. Poor tumor microenvironmental conditions occur because the
tumor vascular supply, which develops from the normal host vasculature via angiogenesis, is inadequate to meet the increasing metabolic demands of the growing solid
tumor mass, including oxygen and nutrients [9]. An important component of cancer
treatment is the inhibition or reduction of tumor angiogenesis.
. Systemic clearance of antitumor drugs
Since anticancer medications may be widely dispersed nonspecifically throughout
systemic organs including the heart, brain, liver, kidney, and reticuloendothelial system
(RES) organs, delivery to the tumor destination via the systemic route is challenging. The
permeability of the membrane, blood flow, and the drug’s capacity to bind to a particularly targeted tumor tissue can all have an impact on how widely the drug is distributed
throughout the body. In this scenario, anticancer drugs in blood circulation will interact
with systemic organs more often, thereby increasing the likelihood of rapid clearance
by the kidney and RES organs. Thus, the body’s normal physiology compromises the
systemic delivery of therapeutic agents via hepatic and renal clearance, uptake by cells
of the RES and degradation by enzymes in the endosome/lysosome, leading to a lower
therapeutic dose of the drug in the tumor cells [10].
. Blockade of access through the blood-brain barrier
The blood-brain barrier (BBB), a natural protective and unique semi-permeable
membrane, precludes central nervous system (CNS) from toxins and pathogens in
the blood and maintains homeostasis in the brain micromilieu [11]. The cerebrospinal
fluid molecules cannot enter the BBB because of the high cell density and strong
intracellular gap junctions of endothelial cells. Composed of around a 100 billion
2
capillaries, the 600-km long BBB spans 20 m
of the human brain. Each capillary is
approximately 7.5 μm in diameter, allowing for blood supply within 10 μm of each
brain cell [12]. The physical barrier shields the brain tumor’s microenvironment from
external drugs by impeding the flow of molecules larger than 400 daltons from the
bloodstream into the brain. Besides size, hydrophobicity also affects the BBB traversing of any drug for brain tumor delivery. Tight junctions between adjacent vascular
endothelial cells restrain paracellular movement and aid transcellular movement [13].
The continuity of the tight junctions, coupled with a lack of fenestrae and efflux
Smart Drug Delivery Systems – Futuristic Window in Cancer Therapy
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transporters, results in the BBB with distinct luminal and abluminal compartments
for strict regulation and control between the blood and the brain [14].
. Tumor hypoxia leading to poor milieu
Low oxygenation (hypoxia), a hallmark trait of TME, plays a significant role in
effecting the response of tumors to conventional radiation and chemotherapy [15].
Hypoxia also promotes malignant progression in terms of aggressive growth, recurrence of the primary tumor and its metastatic spread. Hypoxia is not a single entity;
rather it is multifactorial and often associated with other microenvironmental parameters such as aberrant angiogenesis, impaired blood vessels, dysfunctional lymphatic
drainage, elevated interstitial fluid pressure, glycolysis, low pH and reduced bioenergetic status in the solid tumors.
. Advent of smart nanomedicines for cancer therapy
Nanomedicine is the integration of nanobiotechnology into medical practice.
Although the notion of “nano” has been around for four decades, the relationship
with drug delivery and its applications in medicine has not received much attention
until recent times.
. Development of nanotechnology
The concept of nanoparticles (NPs) was first adapted by Nobel laureate RichardP.
Feynman in his famous lecture entitled “There’s plenty of room at the bottom” on
29th December 1959 [16, 17]. The first nanosized colloidal gold particles were prepared by Michael Faraday. This discovery, dating back to more than 150years, served
as a precursor for the development and advancement of DDSs. Surface-modified liposome NPs for sustained circulation was reported for the first time in 1994 [18]. In the
years 2004 and 2006, MihailC. Roco of the U.S. National Nanotechnology Initiative
(NNI), projected the timeline encompassing four generations of nanotechnology
products and processes—passive nanostructures, active nanostructures, nanosystems, and molecular nanosystems (Figure ) [19]. Emerging technologies including
platforms for quantum information systems, artificial intelligence systems, advanced
semiconductors, wireless communication, modern bioeconomy, and advanced manufacturing have opened new horizon to address sustainable society, nanomedicine,
personalized learning, and augmented human capabilities [20]. The positive effects of
nanotechnology are evident in pharmaceuticals and healthcare [21].
. Prerequisites of nanomedicine
Nanomedicine broadly encompasses medical applications of nanomaterials. The
following are the general prerequisites for using NPs in nanomedicine, as highlighted
by HarryF. Tibbals [22].
• NPs utilized in medical applications must be biodegradable.
• The NPs should remain colloidally stable when combined with physiological
buffer solutions and in aqueous environments.
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
Figure 1.
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Timeline for the commencement of industrial prototyping and nanotechnology commercialization: new
generations of nanotechnology products and productive processes from 2000 to 2020. Adapted from Roco [19].
• The NPs should have substantial tissue-relative absorbance or fluorescence at the
necessary wavelengths.
• Toxic substances must not be used for nanomedicine synthesis.
• NPs should be easily functionalized using their surface coatings for medical
imaging or therapeutics.
. Nanomedicines for cancer therapy
To circumvent the problems associated with current cancer therapeutics, efforts
have been concentrated on creating new DDSs for cancer therapy. Over the past few
decades, there has been an unprecedented surge in the use of nanomedicines for safer
and more efficient tumor targeting, detection, and therapy. To overcome the adverse
drawbacks of current cancer therapeutic modalities, nanotechnology-based combinatorial drug delivery has emerged as a possible solution. NP-based DDSs have shown
many advantages in cancer treatment, such as improved pharmacokinetic profiles,
precise targeting of tumor cells, diminution of adverse side effects and decline in
drug resistance [23]. The National Cancer Institute (NCI) of the National Institutes
of Health (NIH), U.S. has formed an alliance with the nanotechnology domain in the
hope of realizing new breakthroughs in therapeutic and diagnostic modalities for
cancer. In alliance with NCI, an array of NPs for therapeutic and diagnostic implications have advanced to the clinical trial stage [24].
The plausible impact of nanotechnology in enhancing tumor treatment and
diagnosis is enormous. Because of its potential to revolutionize the synthesis of
clinically relevant DDSs, nanotechnology has emerged as an essential game player
in modern translational medicine, with clinical applications encompassing contrast
agents in bioimaging to carriers for gene and drug delivery into the TME [25]. The
size and properties of NPs employed in DDSs are created in accordance with the
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pathophysiology of the malignancies. Nanotherapy employs nanoscale (10–100nm)
DDS as the therapeutic strategy for intravenous delivery [26]. However, systemically
delivered anticancer drugs exhibit weak tumor selectivity and permeate and destroy
the normal as well as cancerous cells, resulting in limited therapeutic efficacy coupled
with adverse side effects. Renal clearable nanocarriers (RCNs) are newly emerged
DDSs, which enable drugs to rapidly penetrate into the tumor cores without the
need for prolonged retention in the blood stream, and thereby escape macrophage
uptake and also augment the elimination of nontargeted anticancer drugs from the
body [27]. RCNs accumulate in the TME with higher selectivity through the enhanced
permeability and retention (EPR) effect, resulting in improved therapeutic efficacy
of the anticancer drugs with concomitant reduction of side effects. This EPR-based
targeting strategy is a fundamental principle in the design of NP-based anticancer
drug delivery. By enhancing the delivery of chemotherapeutic medications to tumors
and metastatic cancers, nanomedicine normally tries to improve the direct killing of
cancer cells.
. Nanomedicines to circumvent the hurdles in cancer therapy
Penetration of a tumor’s core still represents a formidable barrier for existing
DDSs. Nanocarriers may be functionalized with traditional chemotherapeutic
agents or nucleic acids, and hence can be a game changer for drug delivery or gene
therapy, respectively by enhancing bioavailability and reducing immune systembased side effects, and delivering the cargo accurately [28, 29]. Based on the EPR
effect, NPs favorably collect within tumors due to their leaky vessels and limited
lymphatic drainage (Figure ). In addition, NPs can also enter solid tumors by
active trans-endothelial processes, particularly notable for human tumors showing
rather weak EPR.
Figure 2.
EPR effect in tumors. Unlike normal healthy tissues, in tumor tissues, endothelial cells are poorly aligned with
wide fenestrations effecting escalated vascular permeability; lymphatic drainage is impaired and there is absence
of a smooth muscle layer, resulting in EPR effect. This results in accumulation of macromolecules (10–200nm or
40–800 kD) more in tumor tissues than in normal tissues.
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
Some of the challenges defeated by nanomedicine in generating a new wave of
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nanoscale drug delivery are:
.
Curtailing systemic toxicity
A NP carrier system favors controlled drug targeting and release, in turn, mini
mizing systemic uptake and is thus crucial for reducing systemic toxicity; thereby,
making cancer therapy more efficacious [30]. NPs have been actively explored as
carriers to encapsulate and deliver hydrophilic drugs. Placing drug molecules inside
or on the surface of a NP carrier allows for controlled release, which offers multiple
benefits compared to the conventional dosing forms based on free drugs. Sustained
release aims to deliver a drug at a predetermined rate over an extended period of
time.
Attenuation of tumor angiogenesis
.
NPs play a role in blockage or attenuation of tumor angiogenesis [31].
Extravasation allows NPs to effectively pass the vascular-endothelial barrier via the
leaky blood capillaries of the tumor vasculature (inter-endothelial gaps as large as
500nm), but they still need to navigate the challenging tumor milieu. NPs accumulate at the tumor site as a result of inadequate lymphatic drainage via passive targeting
and exert their anticancer effect.
Tumor tissue retention and inhibition of aggregation
.
The ideal size of NPs for cancer treatment has been reported to be in the range of
70–200nm effecting deep tumor tissue penetration, efficient cancer cell internalization coupled with gradual tumor clearance [32]. Smaller NPs get eliminated while
the bigger ones are taken up by the RES in the spleen and Kupffer cells of the liver.
Nanocarriers of 50nm have been found to exhibit the maximum tumor tissue retention, integrated over time, thus resulting in the highest efficacy against both primary
and metastatic tumors in vivo [32].
The NP size that obviates aggregation is more likely to prevent thromboembolism,
which makes it advantageous for systemic distribution of the NPs when considering
the capacity to pass through capillaries [33]. The degree of NP agglomeration at interstitial sites is impacted by surface properties of NPs [34]. For instance, hydrophilic
NPs are more likely to interact poorly at the interstitial sites with ground materials.
. Access through the blood-brain barrier
Permeation through the BBB is challenging for any drug, even in the nanosize
range. Both size and hydrophobicity represent crucial determinants in the design of
nanodrugs for brain tumor delivery [35]. Small, lipophilic molecules diffuse passively
into the brain, whereas larger hydrophilic molecules such as peptides or proteins
require transport mechanisms [36].
. Targeting tumor hypoxia
Hypoxia-induced chemo-resistance of tumor cells still represents a formidable
barrier, as it is difficult for existing DDSs to penetrate the tumor hypoxia core. NPs
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can modulate hypoxia that is indispensable to tumor angiogenesis, metastasis, and
multidrug resistance. Hypoxia-triggered nanovehicles achieve controlled drug release
at the target sites and enhance the anticancer activity [37].
. Nanomedicine as an evolving oncology landscape
Cancer nanomedicine has enabled the improvement of existing cancer therapies
by capitalizing on the specialized attributes of nanoparticles (NPs), including their
structural features and prolonged circulation in the blood [38]. FDA-approved
nanotechnology-based products are on the rise and include synthetic polymers;
liposomes and nanoliposomes; micellar NPs; protein NPs; nanocrystals and many
others often in combination with drugs or biologics [23]. Three groups of NPs have
been engineered for gene delivery applications such as hybrid NPs, organic NPs and
inorganic NPs (Figure ).
. Organic nanoparticles
Organic NPs have been extensively studied for decades and may be liposome
based, polymer based, or dendrimers.
.. Liposome-based organic nanoparticles
Typically, liposomes have a spherical morphology and are made up of one or two
lipid bilayers. Liposomes are primarily utilized to deliver both lipophilic and hydrophilic medications, with the inner aqueous core stabilizing the hydrophilic molecule
while the lipid bilayer integrates the former. The effectiveness of liposomes as drug
vehicles is related to their pharmacokinetics and depends on the physicochemical
conditions, e.g., size, surface charge, membrane lipid packing, steric stabilization,
Figure 3.
Types of NPs applied to drug delivery systems in cancer therapeutics.
Revisiting Multifunctional Nanomedicines for Cancer Therapy
DOI: http://ITexLi.115175
dose, and administration route [39]. The US Food and Drug Administration (FDA) in
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1995 approved polyethylene glycol (PEG)ylated liposomes with doxorubicin (DOX),
i.e., Doxil®. PEG incorporation on the liposomal surface enhanced the half-life
circulation, thus taking advantage of the EPR effect [40]. BesidesPEG, various
hydrophilic polymers such as poly-N-vinyl pyrrolidone (PVP), polyvinyl alcohol
(PVA), polyoxazoline (Pox), hyperbranched polyglycerol, or zwitterionic polymers,
have also been employed [41]. Nano-DDSs such as liposomes also offer an option for
drug combination, thereby ameliorating the therapeutic efficacy while reversing drug
resistance [42]. An array of liposome-based drugs is currently under clinical translation for cancer therapy.
Lipid or polymeric nanoparticles
..
Lipid nanocarriers are a burgeoning field for the transport and delivery of a
diverse array of therapeutic agents, from biotechnological products to small drug
molecules, and significantly improve the therapeutic effectiveness of drugs [43].
Polymeric NPs are small polymeric colloidal particles with a therapeutic drug either
dispersed in the polymer matrix (nanosphere) or encapsulated in polymer (nanocapsule) [44]. The advantages of polymeric NPs as drug carriers include their potential
for controlled release, their ability to protect drugs and other biologics, couple with
improved bioavailability and therapeutic index.
Dendrimers
..
These synthetic macromolecules resemble trees with multiple branches and sub-
branches radiating out from a central core. They are highly branched polymers with
easily modifiable surfaces that makes them promising structures for functionalization (for improved delivery and targeting) and conjugation with drugs and nucleic
acids. Dendrimers help to enhance the solubility and bioavailability of hydrophobic
drugs [45]. The drugs may be encapsulated in the intramolecular cavity of the dendrimers or surface conjugated to their functional groups. Nucleic acids usually form
complexes with positively charged surface of cationic dendrimers. The shape, size,
charge, and solubility of these nanocarriers can be controlled by different synthesis
processes.
. Inorganic nanoparticles
Inorganic NPs include metal and metal oxide NPs such as silver (Ag), iron oxide
(Fe3O4), titanium oxide (TiO2), copper oxide (CuO), and zinc oxide (ZnO). Gold
NPs, carbon nanotubes, quantum dots, magnetic NPs, and silica NPs are some of the
inorganic NPs that have been examined. The advantages of inorganic NPs include
a larger surface area-to-volume ratio, ease of preparation, enhanced therapeutic
efficacy, reduced drug resistance and other side effects, a wide range of surface
conjugation chemistry, albeit at the trade-off of their lower biocompatibility and
biodegradability [46]. The major drawback of inorganic NPs is their toxicity. The
increased reactive oxygen species (ROS) can be harmful to the normal cells, which
can trigger other protective mechanisms like enzymatic and nonenzymatic antioxidant defense mechanism. Further, failure in restoring these protective mechanisms
may lead to the damage of proteins, lipids and DNA, resulting in tissue damage,
inflammation, and loss of normal cell function.
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