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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5398_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 219
In summary, stimuli-responsive nanoparticles represent a
highly explored and promising approach in smart drug delivery
systems, providing efficient and targeted cancer therapy while minimizing adverse effects.
5.1.1 Endogenous Stimulus-Responsive Drug Delivery Systems (DDSs)
When compared to healthy tissues, tumor tissues have unique
biological traits such as elevated redox potential, low pH, hypoxia,
and overexpression of certain enzymes. Taking advantage of these
variations, redox-, pH-, and enzyme-responsive DDSs have been
carefully created for tailored release and intelligent drug loading,
thereby improving therapeutic efficacy.
(a) pH-Responsive DDSs
The breaking of acid-labile bonds and structural or solubility
alterations of polymers with ionizable functional groups are the
basis for the construction of pH-responsive DDSs. These systems
exploit the pH gradients found at various levels within the body,
including organ, tissue, and cellular levels, to achieve targeted drug
delivery and release.
• Polymer-Based Strategy: Polymers with ionizable groups (such as
amines and
carboxylic acids)
undergo protonation or deprotonation in response to pH changes, altering their solubility or
structure to release drugs.
• Acid-Labile Bonds: Acidic settings can cause chemical
such as
hydrazone, ester, imine, oxime, and ketal to cleave,
bonds,
allowing medications specifically designed for acidic environments to be released.
The pH gradients across the body provide multiple targets for
these DDSs:
1. Organ Level: The gastrointestinal tract (GIT) features significant pH variations, from the acidic stomach to the alkaline
intestines. pH-responsive polymers can protect drugs in the
stomach and release them in the intestines, aiding in colorectal
cancer therapy.
2. Tissue Level: The extracellular pH of tumor microenvironments
is slightly acidic (pH 6.7–7.1) compared to healthy tissue
(pH 7.4). DDSs can be engineered to respond sharply to
these subtle pH differences for targeted drug release. For
example, ultra-pH-sensitive (UPS) nanotechnology uses
block copolymers with ionizable tertiary amine groups for
precise pH-triggered drug release and cancer theranostics.
3. Cellular Level: The pH within endocytic organelles (early
endosome, late endosome, lysosome) is much lower than in
the cytoplasm. pH-responsive DDSs can trigger drug release in
these acidic compartments, ensuring organelle-specific
220 Sonal Saxena et al.
activation. These systems are also designed to facilitate endosomal escape and cytosolic delivery, particularly for macromolecules such as proteins and siRNA.
(b) Redox-Responsive DDSs
The redox environment within tumor tissues differs signifi-
cantly from that of normal tissues, primarily due to elevated levels
of glutathione (GSH) and reactive oxygen species (ROS). Redoxresponsive DDSs exploit these differences to achieve targeted intracellular drug delivery:
• Disulfide Bonds: Disulfide bonds are commonly used due to their
fast cleavage by GSH, enabling the release of drugs within the
reductive environment of tumor cells.
• ROS-Responsive DDSs: These systems utilize linkages like thio-
ketal, thioether, peroxalate ester, and boronic ester that respond
to high ROS levels in tumor tissues, triggering drug release.
(c) Enzyme-Responsive DDSs
Tumors often overexpress specific enzymes, such as proteases,
phospholipases, and peptidases, which can be harnessed as triggers
for enzyme-responsive DDSs. These systems can function in
several ways:
5.1.2 Exogenous Stimulus-Responsive DDSs
• Enzyme-Triggered Drug Release: Nanocarriers can be con-
structed with enzyme-sensitive scaffolds or linkers that release
drugs upon enzymatic cleavage.
• Prodrugs and Ligand Activation: Enzyme-sensitive bonds can
activate prodrugs, ligands, or probes specifically in tumor
environments.
• Detachable PEGylation Layers: Enzyme-activated detachable
PEG layers
can enhance
blood circulation and increase cellular
internalization at target sites.
Challenges include the similarity in active sites and catalytic
mechanisms among enzymes and the variability in enzyme expression levels within different tumors and individuals.
Exogenous stimuli-responsive DDSs offer precise control over
drug release by utilizing external triggers such as light, temperature, ultrasound, magnetic fields, and electric fields. These systems
provide targeted and controlled drug delivery, maximizing therapeutic efficacy while minimizing side effects.
(a) Te
mperature-Responsive D
Temperature-responsive
DSs
DDSs release drugs in response to
temperature changes, particularly in the range of 40 °C or higher.
Common materials include poly(N-isopropyl acrylamide)
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 221
(PNIPAM) and poly(2-oxazoline)s (POxs), which undergo phase
changes at specific temperatures to release their cargo.
(b) Light-Responsive DDSs
Light-responsive DDSs, particularly those activated by nearinfrared (NIR) light, allow remote control over drug release
through photoisomerization, photocleavage, and photothermal/
photodynamic effects. These systems can achieve deep tissue penetration and precise control over irradiation power and exposure
time. Examples include selenium-containing polymeric nanoparticles and bifunctional light-responsive platinum nanocomplexes that
synergistically combine photothermal and chemotherapy.
(c) Ultrasound-Responsive DDSs
Ultrasound-responsive DDSs leverage high-frequency ultrasound waves to trigger drug release,
enhance tumor
permeability,
and improve drug accumulation at tumor sites. They also utilize
physical effects such as cavitation and local hyperthermia to achieve
targeted delivery.
(d) Electric Field-Responsive DDSs
Electric field-responsive DDSs use conductive polymers and
materials to control drug release through electrochemical processes. Electroporation can also enhance drug permeability through
cell membranes, facilitating the delivery of macromolecules like
proteins and genes.
5.2 ReceptorLigand-Based Smart
DDS
(e) Magnetic Field-Responsive DDSs
Magnetic field-responsive DDSs incorporate magnetic materials like superparamagnetic iron oxide nanoparticles (SPIONs) to
achieve targeted drug delivery under an external magnetic field.
These systems can also generate local hyperthermia for on-demand
drug release.
(f) Other Exogenous Stimuli-Responsive DDSs
Other stimuli-responsive DDSs include systems triggered by
high-energy radiation (e.g., X-rays) and other physical or chemical
stimuli. These systems offer opportunities for overcoming
biological barriers, reversing multidrug resistance, and integrating
novel therapeutic modalities such as photodynamic and photothermal therapy.
Targeted delivery is a crucial aspect of modern smart drug delivery
systems (DDSs). Tumor-targeting drug delivery can be achieved
through two main strategies: passive targeting and active targeting.
While passive targeting has been the focus of many studies, its
efficiency, particularly the enhanced permeability and retention
222 Sonal Saxena et al.
(EPR) effect, has come under scrutiny. Li et al. [8] demonstrated
that receptor-mediated targeting (active targeting) contributed
more to the accumulation of nanoparticles (NPs) in tumors over
time compared to the EPR effect. They highlighted that NP transportation through gaps between endothelial cells in tumor blood
vessels was a significant factor in the EPR effect. However,
Sindhwani et al. recently found that these gaps covered only
0.048% of the blood vessel surface area, suggesting that passive
targeting al
in tumors. This
one cannot account for the observed NP accumulation
has shifted the focus toward a combination of
passive and active targeting in cancer nanomedicine research. Active
targeting, however, faces challenges such as unwanted interactions
with non-target sites. This can result in on-target off-tumor effects
through both nonspecific and selective interactions with target and
non-target locations expressing pertinent receptors at varying
degrees. Nume
problems. To
Wang et al. [
nanoparticles that
rous tactics have been put out to address these
improve tumor penetration and cellular absorption,
18], for instance, created tumor acidity-responsive
expose the targeted ligand in the acidic tumor
microenvironment while shielding it from systemic circulation.
5.2.1 The Effect of
Spatial
Distribution of
Ligands on Drug Delivery
Traditionally, ligands are attached to drug-delivery vehicles like
liposomes, nanoparticles, or micelles in required quantities, and
increasing ligand density can enhance targeting effectiveness to a
certain extent. However, ligands are typically randomly distributed
on the vehicle surface due to their symmetrical structure, which
limits receptor recognition and ligand utilization. High ligand
density can also lead to protein corona formation with plasmabinding proteins during blood circulation, causing off-target
effects, rapid clearance, and increased immunogenicity. For
instance, folic acid-modified liposomes can adsorb large amounts
of natural IgM post-injection, resulting in unexpected off-target
effects.
By adjusting
the multivalent ligands’ presentation mode to
produce an uneven ligand distribution, these problems can be
mitigated. This strategy improves specificity, targeting efficiency,
and ligand utilization. Lipid-based vesicles containing HER-2-targeting short peptides (KCCYSL) were created by [
13].
These vesicles, often referred to as sticky vesicles, partition ligands inside the
lipid phase-separated domain in the acidic tumor interstitium
(pH 6.0–7.0) and distribute them uniformly throughout their
surface during circulation (pH 7.4). As a result, there is an increase
in local ligand density and target tissue recognition and a decrease
in interactions with normal cells that have low receptor expression.
This leads to low reactivity in the circulation and high reactivity
even in cells with few target receptors. Similar to this, Poon et al.
used hydrophilic/hydrophobic interaction to create selfassembling linear dendritic polymers (LDPs). Their experiments
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 223
showed that increasing ligand density did not linearly increase
targeting effectiveness but reached saturation dynamics. Beyond a
certain point, excess ligands in a small binding area caused steric
binding interference, lowering binding energy. According to their
research, concentrating on the precise modification of ligand cluster presentation on molecularly targeted NPs may have a major
effect on cell targeting and result in the creation of more efficient
targe
ted delivery systems.
5.2.2 Dynamic Strategies for Tumor Targeting
Dynamic tumor targeting strategies involve adaptable drug delivery
systems capable of adjusting their properties to optimize drug
release in response to specific conditions within the tumor microenvironment. Traditional approaches often fall short due to inadequate circulation time, limited tumor specificity, and poor
penetration into tumor tissues. To address these challenges, nanoparticles (NPs) are engineered with tailored physicochemical properties that ensure prolonged circulation in the bloodstream and
enable rapid drug release upon encountering tumor-specific signals,
such as acidic pH or overexpressed enzymes [
3].
(a) Size Shrinkage Targeting
Effective drug delivery relies on nanoparticles that can first
accumulate around leaky blood vessels via the enhanced permeability and retention (EPR) effect and then penetrate deep into tumor
tissues for optimal therapeutic efficacy [
13, 15]. Research indicates
that NPs around 100 nm in diameter achieve optimal circulation
and tumor accumulation, while smaller NPs (<30 nm) demonstrate superior penetration into tumor interstitial spaces [
2, 4, 11,
17]. Size shrinkage targeting addresses this by integrating smaller
NPs within larger carriers that initially maintain a size conducive to
circulation and accumulation but shrink upon exposure to specific
tumor signals. For instance, strategies involving MMP-2 cleavable
peptides have shown promising results, enabling NPs to transition
from larger to smaller sizes in response to MMP-2 activity, and
facilitating deeper tumor penetration [
6, 7].
(b) Surf
Surface
ace Charg
charge plays a crucial role in determining NP interac-
e Switchable Targeting
tions with biological systems. NPs with neutral or negative charges
exhibit prolonged circulation by avoiding interactions with blood
proteins and immune cells. However, once at the tumor site,
pH-responsive NPs can undergo a charge conversion (from negative to positive) in the slightly acidic tumor microenvironment
(pH ~6.8). This conversion enhances NP binding to negatively
charged cell membranes, promoting cellular uptake and internalization. Key pH-responsive moieties, such as CDM and DMMA,
enable this charge switch, enhancing the therapeutic efficacy of NPs
by improving their tumor-specific interactions [
5, 9, 14].
224 Sonal Saxena et al.
(c) Surface Ligand Activatable Targeting
Active targeting employs specific ligands on NP surfaces to
bind receptors or antigens overexpressed by cancer cells, enhancing
selective uptake and internalization into tumor cells. However,
conventional ligand-targeting strategies often suf fer from
non-specific interactions with healthy tissues during circulation.
To mitigate this, smart ligand-targeting strategies shield these
ligands during circulation and activate them upon reaching the
tumor site. For example, stimuli-responsive modifications of cellpenetrating peptides (CPPs) allow for controlled activation of
ligand exposure in response to tumor-specific cues, improving the
targeting precision and therapeutic efficacy of NPs [
6 Challenges and Opportunities for Targeted Delivery to Cancer Cells
• Complexity of the TME: The TME’s heterogeneity and dynamic
nature pose challenges for targeted therapies, requiring comprehensive approaches that consider interactions between different
components.
• Resistance Mechanisms: TME-mediated resistance mechanisms
can limit the efficacy of therapies. Understanding these mechanisms is crucial for developing combinatorial approaches that
enhance treatment outcomes.
10, 18].
7 Future Directions
8 Conclusions
• Combination Therapies: Integrating therapies that target multi-
ple components of the TME (e.g., immune cells, vasculature,
ECM) holds promise for overcoming resistance and improving
patient outcomes.
• Enhancing Specificity and Efficacy
improve the specificity and efficacy of therapies by optimizing
their binding affinity, internalization efficiency, and therapeutic
payload delivery.
• Personalized Medicine:
on individual tumor characteristics and patient immune profiles
could optimize treatment efficacy.
TME represents a critical determinant of cancer progression and
therapeutic response. Targeted therapies aimed at disrupting TME
interactions are advancing rapidly, offering new avenues for
Tailoring
: Continued
TME-targeted therapies based
research aims to
Drug Delivery to Cancer: Targeting the Tumor Microenvironment 225
improving cancer treatment outcomes and patient survival. The
field is moving toward developing site-directed anti-cancer strategies based on selective receptor expression on tumor cells and
vasculature. Synthetic peptides mimicking ligands for tumor overexpressed receptors represent a promising avenue for developing
next-generation cancer therapeutics. Continued research and clinical development are essential to harnessing the full potential of
TME-
targeted therapies in oncology. The ongoing research aims
to optimize therapeutic efficacy while minimizing side effects,
paving the way for innovative and personalized cancer treatments
in the future. The ability of tumor-homing
peptides to deliver
therapeutic cargo directly to target cells marks a significant
advancement in the evolution of cancer therapy strategies.
Tumor-homing peptides represent a promising approach in personalized medicine for cancer tre
atment and diagnostics, leveraging
their ability to selectively target and interact with tumor cells based
on unique molecular markers. The advancement of nanotechnology has indeed positioned nanoparticles as
a promising candidate
for controlled drug delivery systems (DDS). These nanoscale carriers offer several unique advantages that make them suitable for
precise, efficient, and safe drug delivery, particularly in the context
of complex diseases such as can
cer. Continued research and clinical
development are expected to expand their applications and improve
outcomes for cancer patients.
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Chapter 11
Biosensor-Based Drug Delivery Systems: Innovations,
Applications, and Future Perspectives
Disha Pant, A. H. Ahmad, and Kamal Pant
Abstract
Recent advancements in biosensor design and sensing effectiveness should be integrated with research on
responsive drug delivery systems to enhance health management and ensure patient compliance. Many
illnesses require continuous monitoring to enable timely intervention. Physicochemical changes in the body
can indicate the onset of illness before symptoms appear. Despite diagnostic and prognostic biosensors,
medical interventions still face challenges. Delayed detection can reduce therapeutic efficacy, and conventional treatments may cause side effects such as tissue damage and hepatic and renal toxicity. Drug delivery
systems offer a way to minimize side effects and improve patient adherence. Chronic illnesses necessitate
ongoing monitoring and effective treatment strategies.
Designing responsive systems that react to physicochemical changes can enhance therapeutic outcomes.
Integrating biosensors with drug delivery in implantable closed-loop systems allows for timely therapeutic
interventions triggered by illness biomarkers. Proper biomarker selection is crucial for accurate diagnosis
and effective responsive drug delivery. Detecting illness early based on biomarker levels can tailor therapeutic dosing to the severity of physiological changes. This review explores various biosensors and drug delivery
systems, highlighting challenges and future prospects for their integration in detecting and managing
chronic illnesses.
Key words Biosensor, Drug, Analyte, Nanoparticle, Artificial intelligence
1 Introduction
Targeted drug delivery is the crux of precise drug administration in
humans and animals. It plays a crucial role in drug delivery system
by providing a real-time, accurate, and reliable information about
the physiological state of the patient and monitor various parameters such as drug levels in patient’s body, altered levels of biomarkers, body pH, temperature, and other relevant parameters to
ensure effective drug delivery and precision medicine. While the
application of precision medicine is currently more focused on
humans, its concepts are equally applicable in the treatment of
veterinary patients.
227
228 Disha Pant et al.
In traditional delivery system, a drug to be effective needs
regular administration and continuous monitoring. The challenging part in therapy of diseases like cardiovascular dysfunctions,
diabetes mellitus, and cancers is monitoring of fluctuating in
blood pressure levels of lipids, sugars and cancerous cells in mitotic
phase of, need to be monitored regularly for titration of dose. A
biosensor is a device that combines a biological element with a
transducer to detect and measure a specific biological or chemical
analyte. It converts the biochemical signals produced by interactions between the biological element and the target analyte into
measurable electrical, optical, or other quantifiable signals.
Biosensor-integrated drug delivery systems have been studied
exhaustively for therapeutics of lifestyle ailments like cardiovascular
diseases, diabetes mellitus, and cancer.
Biosensors can detect changes in pH and temperature, which
are critical parameters in certain drug delivery applications. For
instance, pH-sensitive biosensors can be used in targeted drug
delivery systems to release drugs in response to specific pH conditions in a particular tissue or organ.
Biosensors enable real-time monitoring and data collection,
allowing for personalized medicine approaches. By tracking
patient-specific parameters, such as genetic factors or physiological
responses, biosensors can help optimize drug delivery and tailor
treatment plans to individual patients.
Overall, biosensors in drug delivery systems provide valuable
insights into patient health, drug efficacy, and treatment optimization. They enhance precision, control, and patient outcomes by
enabling real-time monitoring and feedback, thereby revolutionizing the field of drug delivery.
2 Materials
Biosensors are analytical devices composed of two main components: a bio-recognition element and a transducer (Fig.
1). The
bio-recognition element is the analyte and bioreceptor. The
Fig. 1 Functional components of a biosensor