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Chapter 10
Drug Delivery to Cancer: Targeting the Tumor
Microenvironment
Sonal Saxena, Sameer Shrivastava, Pradeep Kumar, and Naveen Kumar
Abstract
Cancer remains a global health challenge, with 19.3 million new cases and 10 million cancer-related deaths
reported in 2020. Despite advancements in radiation, chemotherapy, and surgical treatments, limitations
such as poor drug specificity, toxicity, and resistance hinder their effectiveness. Emerging strategies,
including the development of smart drug delivery systems (SDDS) and tumor-homing peptides, offer a
promising alternative by enhancing drug efficacy while minimizing side effects. Tumor-homing peptides,
through selective targeting and internalization, enable precise delivery of therapeutic agents to tumor cells,
improving therapeutic outcomes. Nanotechnology has further revolutionized drug delivery systems,
providing stimuli-responsive platforms for enhanced targeting. Additionally, the tumor microenvironment
(TME) has been recognized as a crucial factor influencing cancer progression and therapy response. This
chapter highlights the role of peptides in addressing key challenges in cancer therapy, including targeting
tumor vasculature, extracellular matrix, lymphatic vessels, and cell membranes, while also presenting
innovative strategies for drug delivery and therapeutic intervention.
Key words Tumor-homing peptides, Smart drug delivery systems (SDDS), Tumor microenvironment (TME), Targeted cancer therapy, Nanotechnology in oncology, Peptide-based therapies,
Tumor-specific drug delivery
1 Background
Global cancer statistics for 2020 reveal 19.3 million new cases and
10 million cancer-related deaths [
urgent need for ongoing research and advancements in cancer
treatment. Currently, the most widely used cancer treatment modalities are radiation, chemotherapy, and surgery. However, given
the prevalence of highly aggressive tumors with a high death rate,
these approaches have clear limitations leading to unfavorable outcomes and high relapse rates. Enhancing current cancer treatments
primarily faces the difficulty of selectively delivering medications to
tumor cells with precision. Drugs used to treat cancers are frequently hampered by poor specificity and related toxicity issues.
211
16]. These figures underscore the
212 Sonal Saxena et al.
The therapeutic benefits of drugs against malignancies can be further complicated by drug resistance, insufficient concentrations at
cancer sites, and other variables. Thus, targeted drug delivery to
cancer cells remains a major limitation in enhancing current cancer
therapies.
Enhancing drug efficacy while decreasing side effects can be
achieved through the selective targeting of agents such as chemotherapeutic drugs, radiotherapeutic drugs, or oncolytic viruses to
tumors. Smart drug delivery systems have the potential to target
specificity, give controlled release, and be able to penetrate
biological barriers, all of which can lead to improved therapeutic
effects with reduced systemic adverse effects. Anticancer medications can be made more selectively lethal by encasing them in
delivery systems and delivering them to cancer cells using homing
peptide ligands or monoclonal antibodies that attach to antigens or
receptors that are either overexpressed or specifically expressed on
cancer cells. Clinical potential for monoclonal antibodies as tumortargeting therapies has been demonstrated. However, there are
important drawbacks to antibody-mediated cancer therapy, including limited tumor penetration due to their size and damage to the
liver or bone marrow due to nonspecific absorption. Peptides offer
several advantages over antibodies as targeting moieties, such as
better organ penetration and a reduced likelihood of unintended
immune reactions. Consequently, peptide-targeting agents have
been proposed to address the problems associated with antibody
cancer therapy. Phage-displayed peptide libraries have been utilized
to identify peptides that target specific organs, tumors, or proteins.
Research indicates that combining a tumor-homing peptide with a
cell-penetrating peptide can create a chimeric peptide with tumor
cell specificity capable of delivering cargo molecules into the cells.
Tumor-homing peptides are thus crucial tools for the selective
targeting, imaging, and destruction of tumor cells. In recent
years, nanotechnology has also revolutionized the field of drug
delivery systems, especially in c hemotherapy, by introducing smar t
drug delivery systems (SDDS) that utilize nanoparticles. These
systems offer significant advantages over traditional drug delivery
methods, particularly in reducing side effects. Biomedical nanotechnology has advanced dramatically over the past few decades,
transforming conventional drug delivery systems (DDS) into
sophisticated smart DDS with stimuli-responsive characteristics.
These innovative nanoplatforms leverage specific internal or external triggers to enhance drug-targeting efficacy and minimize side
effects or toxicities, which are cr ucial for improving patient
compliance.
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 213
2 Importance of the Tumor Microenvironment (TME) in Cancer Progression and Therapy
The tumor microenvironment (TME) plays a pivotal role in cancer
biology, influencing tumor progression, therapeutic response, and
clinical outcomes. Composed of a diverse array of cell types and
extracellular components, the TME creates a dynamic niche that
supports tumor growth, invasion, and metastasis. Understanding
its complexity has led to the development of targeted therapies
aimed at disrupting these supportive interactions.
2.1 Components of the TME
2.2 Therapeutic Targeting of the TME
The TME comprises of the following components:
• Immune Cells: Including T cells, B cells, tumor-associated
macrophages (TAMs), dendritic cells (DCs), natural killer
(NK) cells, myeloid-derived suppressor
cells (MDSCs), and
neutrophils.
• Stromal
Cells: Such as cancer-associated fibroblasts (CAFs), peri-
cytes, and mesenchymal stromal cells.
• Extracellular Matrix (ECM): Provides structural support and
signaling cues, composed of proteins like collagens,
cans, and
glycoproteins.
proteogly-
• Vascular Networks: Blood and lymphatic vessels crucial for nutri-
ent supply, oxygenation, and immune cell trafficking within
tumors.
1. Immune Cells in the TME
• TAMs: TAMs can promote tumor progression through
immunosuppressive cytokine secretion. Therapeutic strategies aim to polarize TAMs toward an anti-tumor phenotype
or deplete them.
• T Cells: Efforts focus on enhancing cytotoxic T cell
responses (CD8+ T cells) against tumor cells through
immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1).
• DCs: Dendritic cells are critical for antigen presentation and
initiating adaptive immune responses against tumors. Strategies involve enhancing DC function to stimulate antitumor immunity.
2. Tumor Vasculature
• Targeting angiogenesis
(formation of new blood vessels) is
crucial to cut off nutrient supply to tumors. Anti-angiogenic
therapies (e.g., VEGF inhibitors) disrupt tumor vasculature
to starve tumors of oxygen and nutrients.
214 Sonal Saxena et al.
3. Extracellular Matrix (ECM)
• The ECM provides a physical scaffold and regulates signaling pathways that promote tumor growth and invasion.
Therapeutic strategies involve ECM-targeting agents to
inhibit tumor progression and metastasis.
4. Cancer-Associated Fibroblasts (CAFs)
• CAFs contribute to tumor growth and resistance to therapies. Targeting CAFs aims to disr upt their pro-tumorigenic
signaling and reduce ECM remodeling.
2.3 Impact of Standard Therapies on the TME
• Chemotherapy: Can induce DNA damage in stromal cells, acti-
vate survival pathways, and promote immunosuppressive cell
types like TAMs.
• Radiotherapy: Alters the TME by af fecting tumor vasculature,
inducing hypoxia, and promoting fibrotic responses from CAFs.
3 Tumor-Homing Peptides
Tumor-homing peptides are peptides that selectively bind to specific receptors or overexpressed markers on tumor cells. They play a
crucial role in targeted therapy and imaging by delivering drugs or
imaging agents directly to tumor cells. These peptides can be
categorized based on their ability to target and interact with
tumor cells:
1. Peptides Targeting Specific Sites on Tumor Cells
2. Peptides Capable of Targeting and Internalization
3. Peptides Capable of Targeting, Internalization, and Cell
• These peptides selectively bind to molecules or receptors on
the surface of tumor cells. They are designed to recognize
and home to a particular location on the cell surface but do
not enter into the cells themselves. This category of peptides
is useful for targeting therapies where surface binding is
sufficient to deliver therapeutic agents or imaging agents.
• Peptides in this category not only target specific receptors
on tumor cells but also possess the ability to internalize into
the cells after binding. Internalization allows these peptides
to deliver payloads such as drugs directly into the tumor
cells. This characteristic is particularly valuable for targeted
drug delivery and imaging purposes.
Destruction
•
These peptides exhibit
all the properties of the second category but go further by inducing cell death or apoptosis
within the targeted tumor cells. They may carry cytotoxic
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 215
payloads or possess inherent cytotoxic properties themselves. This capability makes them potent candidates for
therapeutic peptides aimed at eliminating cancer cells
selectively.
3.1 Different Strategies for Targeting Peptides to Tumor Microenvironment
Cancer is characterized by genetic and epigenetic changes that
enable cells to proliferate uncontrollably, evade apoptosis, sustain
angiogenesis, and invade surrounding tissues. Targeted peptides
have emerged as promising tools to disrupt these tumor-specific
processes through various strategies:
1. Targeting Unique Receptors on Tumor Cells: Tumor cells often
overexpress specific receptors that distinguish them from normal cells, offering potential targets for selective peptide-based
therapies. Examples include HER2 in breast cancer, GnRH in
ovarian carcinomas, CXCR4 in multiple malignancies, and
somatostatin receptors in neuroendocrine tumors. Peptide
ligands for these receptors can serve as carriers for cytotoxic
drugs or radiopharmaceuticals. Notably, octreotide, targeting
somatostatin receptor subtype 2, is used clinically for radiopeptide therapy. CXCR4 DV3 ligand, linked to anticancer
peptides, enhances tumor cell killing in CXCR4-expressing
cancers, demonstrating targeted therapeutic efficacy. Similarly,
FROP-1 targets various tumor cells, showing stable accumulation in vivo, particularly in thyroid and mammary carcinomas.
Peptides like SP94 and SP94-conjugated liposomal doxorubicin target PSMA and enhance therapeutic efficacy against hepatocellular carcinoma.
2. Targeting Cell Death Regulators
Cancer cells often evade apoptosis by upregulating antiapoptotic proteins like Bcl-2. Peptides derived from proapoptotic proteins, such as Bad and BH3 domain peptides, have
shown promise in inducing apoptosis in various cancer cell
lines. Strategies targeting p53, through peptides like 37AA,
restore apoptotic pathways, offering potential therapeutic
avenues.
3. Ta
rgeting Tu
Tumor
mor Blood Vessels/Antiangiogenesis Strategies
angiogenesis, crucial for tumor growth, involves
specific markers on tumor vasculature like αvβ3 integrin. Peptides such as RGD motif bind selectively to these integrins,
inhibiting angiogenesis and offering avenues for targeted drug
delivery and imaging. Other peptides like NGR motif target
vasculature in multiple tumors without binding to
corresponding normal tissues. SP5-52 peptide, another
angiogenesis-targeting peptide, linked to liposomal doxorubicin, enhances therapeutic efficacy against lung and oral cancers,
demonstrating potential clinical applications.
216 Sonal Saxena et al.
4. Targeting Tumor Lymphatic Vessels
Lymphatic vessels play a role in tumor metastasis, making
them potential targets for therapy. Peptides like LyP-1 bind
specifically to tumor lymphatics, offering avenues for developing agents that can destroy tumor lymphatics and inhibit
metastasis. LyP-1 also exhibits cytotoxic effects on tumor
cells, fur ther enhancing its therapeutic potential.
5. Targeting Extracellular Matrix and Cell-Matrix Interactions
The extracellular matrix (ECM) and its interactions with
cells are critical for tumor invasion and metastasis. Peptides like
RGD motif, targeting integrins involved in ECM interactions,
induce apoptosis and inhibit tumor growth and angiogenesis.
Peptides derived from proteins like laminin (YIGSR) also show
promise in decreasing tumor metastasis and growth.
6. Targeting Cell Membranes: Peptides with Necrotic Activity
Necrosis-inducing peptides selectively target cancer cell
membranes due to their negative charge and induce necrotic
cell death. Examples include peptides from frog skin glands
(melittin and defensins) and mammalian cecropins, which
exhibit broad cytotoxic activity against various cancers, including resistant phenotypes.
3.2 Applications and Development
3.3 Examples and Discoveries
These strategies highlight the diverse roles of peptides in targeting specific aspects of tumor biology, from receptors and cell
death pathways to angiogenesis and metastasis. Peptide-based
therapies hold significant promise in advancing cancer treatment
by offering targeted approaches with reduced off-target effects
compared to traditional therapies.
• Targeted Therapies: Tumor homing peptides are crucial for tar-
geted therapies where drugs are specifically delivered to tumor
cells, minimizing damage to healthy tissues.
• Imaging Agents: Peptides that can internalize
into tumor
cells
are also used as imaging agents, allowing for the visualization
and monitoring of tumors in diagnostic procedures.
• Advantages Over Traditional Therapies:
of
fer advantages such as higher specificity, reduced side effects,
Peptide-based therapies
and potentially overcoming resistance mechanisms observed
with conventional chemotherapy.
• Biopanning with Phage Display Libraries: This technique has led
to the discovery of numerous tumor-homing peptides that recognize specific markers on various types of cancer cells.
• Clinical Applications: Peptides
like LyP-1, targeting tumor lymphatics, and RGD motif peptides, targeting angiogenic blood
vessels, have shown promising results in preclinical and clinical
studies.
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 217
4 Tumor Microenvironment Responsive Drug Delivery Systems (DDSS)
Tumor microenvironment-responsive drug delivery systems
(DDSs) are considered “smart” formulations capable of releasing
drugs on-demand in response to stimuli from the tumor cellular
environment, making them highly sought-after in nanomedicine.
These systems achieve responsiveness by dynamically altering their
physicochemical properties, such as size, surface charge, or exposure of ligands [
aiming techniques, such as passive and active targeting. The
increased permeability and retention (EPR) effect, which is necessary for tumor accumulation when using passive targeting, requires
nanocarriers more than 100 nm in size. However, for optimal
tumor penetration, nanocarriers around 30 nm are preferred, creating a size disparity. Active targeting employs ligands that bind to
overexpressed receptors on cancer cells [
interact non-specifically with plasma proteins or normal cells during
circulation. In contrast, stimuli-responsive drug delivery systems
modify nanocarriers by incorporating responsive moieties, enabling
size adjustments, alteration of surface charge, or reversible exposure of targeting ligands. This approach ensures that nanocarriers
possess the necessary characteristics for effective penetration of
drugs in the tissues, as well as drug accumulation at targeted sites,
cellular absorption, and regulated release. These intelligent DDSs
promise targeted delivery of medicinal drugs with increased therapeutic efficacy and decreased side effects. By combining functional
groups that react to different tumor-associated signals, the design
strategy underlying these DDSs takes use of the unique physicochemical distinctions between cancer and normal cells.
12]. There are many obstacles facing traditional
1], but these ligands may
5 Nanoparticle-Based Smart Drug Delivery Systems
Smart drug delivery systems aim to achieve efficient and targeted
cancer therapy by utilizing nanoparticles, which provide an excellent platform for this purpose. Combining nanotechnology with
smart drug delivery systems has shown great promise in reducing
the side effects of chemotherapy compared to traditional drug
delivery methods. Here’s how these advanced systems work and
why they are more effective:
1. Targeted Delivery
• Precision:
cancer cells, reducing damage to healthy cells.
• Ligand Attachment:
allows nanoparticles to bind to specific receptors on cancer
cells.
Nanoparticles
Surface modification with ligands
can be engineered to target specific
218 Sonal Saxena et al.
2. Controlled Release
• Temporal Control: Nanoparticles can be designed to release
drugs at controlled rates, ensuring a sustained therapeutic
effect.
• Stimuli-Responsive Release: Some nanoparticles release their
payload in response to specific stimuli (e.g., pH changes,
temperature, or light) found in the tumor
microenvironment.
3. Improved Solubility and Stability
• Enhanced Solubility: Nanoparticles can improve the solubil-
ity of hydrophobic drugs, increasing their bioavailability.
• Stability: Encapsulation in nanoparticles can protect dr
from degradation
before they reach the target site.
4. Reduced Dosage and Frequency
• Efficiency: By ensuring more of the drug reaches the cancer
cells, the overall dosage can be reduced.
• Extended Circulation Time: Nanoparticles can circulate in
the bloodstream for longer periods, reducing the frequency
of administration.
5. Minimized Side Effects
• Reduced Off-Target Effects: Targeted
delivery minimizes
exposure of healthy tissues to toxic chemotherapy agents.
• Lower Systemic Toxicity: Controlled release and precise tar-
geting lead to lower systemic toxicity and fewer side effects
like nausea, hair loss, and immunosuppression.
ugs
the
5.1 NanoparticleBased StimulusResponsive Drug
Delivery Systems
(DDSs)
For developing stimulus-responsive drug delivery systems (DDSs),
the nanoparticles can be engineered to respond to a variety of
exogenous (like temperature, light, ultrasound, electric field, and
magnetic field) or endogenous (like pH, enzymes, or redox gradients) stimuli in a way that they selectively release their therapeutic
payload at tumor locations.
Stimuli-responsive nanoparticles offer several advantages:
1. On-Demand Drug Release: They
can release
drugs in a controlled manner, ensuring that the therapeutic agents are delivered precisely when and where they are needed.
2. Enhanced Therapeutic
Effects
: By targeting drug release to
tumor sites, these nanoparticles can achieve more effective
treatment outcomes.
3. Prevention of
Drug Leakage: The design of these systems helps
prevent premature drug release in the bloodstream, reducing
off-target side effects.