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Smart Drug Delivery Systems
41
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of oncology. The main objective of these nanodevices is to avoid the adverse drug
reaction, decrease unwanted side effects as well as reducing cytotoxicity during
chemotherapy. Further, these newer drug delivery systems will reduce dose frequency due to the nature of their controlled and sustained release or preprogramed
drug release pattern in different time intervals, so that these nanodevices enhance
therapeutic efficacy as well as reach in therapeutic range for recovery of the patients.
Due to very small or nanosize they can easily entrap by malignant cells due to nature
of leaky vasculature of basement membrane and so therefore easily applicable for
passive targeting. Ligand molecules such as antibody or aptamer can be attached to
the surface of nanocarrier so that they can easily recognize the tumor cells or may be
applied for active targeting purposes.
Several researches have been carried out by using various anticancer drug loaded
nanocarriers and has been studied for cellular uptake in different cancer cell lines via
passive and active targeting. It is important to note that several nano drug delivery
systems should apply for approval via clinical trial and may be started in commercial
use of human beings in future field of cancer treatment. This may be beneficial for
minimizing the cytotoxicity as well as enhance the pharmaceutical elegance for
human health care.
– Futuristic Window in Cancer Therapy

Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
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Chapter 3
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Fluorescence Guided Activatable
Cancer Theranostics: Its
Dev
elopment and Prospect
ShayeriBiswas and SankarprasadBhuniya
Abstract
Since the prehistorical period, cancer has been a pervasive affliction in the
human body, representing one of the most formidable challenges to human health
and well-being. Its insidious presence in the human body commands the highest
mortality rate among those who succumb to its grasp. Epigenetic factors often play
a critical role as the primary caretakers orchestrating the transformation from an
innocuous, rudimentary stage to the formidable and often fatal metastasis phase. In
the battle against this lethal illness, the concept of theranostics was embraced in the
early twenty-first century, combining both treatment and diagnostic techniques.
This prompt data on treatment methods could pave the way for the advancement of
tailored medicine, potentially curbing medication misuse as well. The use of fluorescence as a partially invasive method has been adapted for diagnostic purposes in
the field of intelligent medicine. Within this approach, the overexpression of unique
elements (ROS, thiols, enzymes, proteins, etc.) within cancer cells facilitates the
cleavage of the theranostic agent, resulting in the immediate release of drugs exclusively in cancer cells. This approach rapidly offers temporal data on the activation of
therapies and their effects at the subcellular level in animal models, as demonstrated
through in situ biopsies.
Keywords: endogenous stimulators, theranostics, prodrug, fluorescence, cancer
. Introduction
Cancer represents a potentially life-threatening condition within human society,
with its various types categorized based on their origin and location [1]. Alterations in
the genes responsible for cellular signaling, particularly the malfunctioning of protein
kinases, can lead to the growth of cancer [2]. The unveiling of the human genome
sequence has spurred the development of novel treatment protocols for this ailment.
In 2004, the U.S. Food and Drug Administration (FDA) promoted the exploration
of innovative products for cancer treatment, specifically emphasizing personalized
medicine to mitigate drug misuse and encourage targeted therapy. The pharmaceutical industry views the “Trojan horse” approach, in conjunction with therapeutic and
diagnostic tools, as a potential solution for precise treatment. The term “theranostic”

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was initially coined by John Funkhouser, the Chief Executive Officer of PharmaNetics,
in 1998, and has since become a widely searched keyword in cancer research.
Parallel advancements in chemistry, biotechnology, nanotechnology, pharmacy,
medicine, and imaging have led to the continual development and assessment of
theranostic nanomedicine and its clinical significance in recent years [3]. Engineered
nanoparticles and devices have been crafted to meet the current demands for personalized treatment. Research in the realm of theranostic tools for cancer treatment has
resulted in the development of various anticancer drugs and carriers, such as polymers, liposomes, and diverse nanoparticles.
In the initial stages of theranostic nanomedicine development before 2005, therapeutic and diagnostic tools were incorporated into polymer vehicles that passively
entered the target site due to the enhanced permeability and retention (EPR) effect.
Subsequently, theranostic nanomedicines were devised with specific ligands capable
of targeting particular cancer types based on their genetic signatures or the expression
of specific proteins in tumor cells. This approach capitalizes inherent variance between
normal and cancer cells to enhance cancer cell-specific uptake. The technologies
behind targeted theranostic nanocarriers have exhibited desirable improved properties at the treatment site, localizing specifically to affected areas, providing targeted
therapeutic release, and enabling noninvasive monitoring with diagnostic tools [4].
While targeted therapy has demonstrated effective therapeutic efficacy, various
imaging modalities, including magnetic resonance imaging (MRI), positron emission
tomography (PET), ultrasound, fluorescence, and computed tomography, have shed
light on the underlying disease mechanisms and facilitated assessment in pre-and
post-treatment stages [5–9].
Newly developed materials, including upconversion nanoparticles, graphenebased nanodevices, and other theranostic prodrugs, have been introduced as innovative solutions to address various forms of sporadically mutated cancer. Contrarily,
the primary obstacle lies in surpassing the limitations of imaging for seamless in vivo
visualization. Ultimately, the overall aim of nanomedicine is to fulfill the objective of
providing personalized medicine [10].
Considerable efforts have been dedicated to the creation of theranostic tools,
although most of these tools rely on nanoparticle technology. Regrettably, none of the
existing nanoparticles are capable of offering real-time insights into the process of
drug release and its activation. Currently, advanced techniques, such as small molecular optical-modulated theranostics, appear to be resolving this issue and instilling
confidence in tailoring suitable treatments for individual patients. These newer
methodologies, particularly those involving ROS-activatable systems, enzymes, and
similar agents, facilitate the precise delivery of therapeutic agents to specific tumor
regions [11]. In this approach, chemotherapeutic agents are linked to a tumor-guiding
group via a self-immolative linker, allowing them to enter tumor tissues and activate
within. The structural framework of these systems is relatively straightforward,
compact, reproducible, and biocompatible, enabling easy modifications to achieve
the desired effectiveness in chemotherapy and displaying enhanced cellular uptake,
making them preferred candidates for chemotherapy compared to nano-theranostics.
Discussions within the review encompass the causes of cancer formation and their
variant, early drug development and delivery strategies, the design approaches of
small conjugate-based theranostics, the underlying mechanisms of drug activation,
and various imaging techniques used for precise cancer diagnosis. The review is
structured to explore diagnostic methods and the mechanisms involved in activating
theranostics at the tumor site.

Fluorescence Guided Activatable Cancer Theranostics: Its Development and Prospect
DOI: http://ITexLi.115104
. Cancer formation and their properties
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Cancer is characterized by the fundamental anomaly of unregulated cell growth
across various cell types. This irregularity is manifested through the modification
of normal cellular signaling pathways, invasion into healthy cells and tissues, and
eventual dissemination throughout the body, often in the form of metastasis.
Essentially, modifications in epigenetics profoundly influence the expression
of genes, which serves as the inception of cancer [12]. Gene mutations are greatly
impacted by changes in DNA, including modifications like DNA methylation and
hydroxymethylation, as well as alterations in histone acetylation, histone methylation, and variations in small noncoding RNAs. Consequently, these changes give
rise to unregulated cell division, ultimately resulting in the expansion of tumor cell
population which originate from a single clone. Frequently, cancer-causing substances,
including arsenic and its derivatives, asbestos, benzo(a)pyrene, polyaromatic,
dimethylnitrosamine, nickel compounds, and others harm the DNA, leading to gene
mutations. These altered genes foster the invasion of tumors and diminish the function
of tumor suppressor genes [13]. Apart from the cancer-causing agents, tumor growth
stimulants are also triggered during the initial phase of cancer prognosis through the
activation of protein kinase C induced by phorbol ester [14]. Furthermore, epigenetic
suppression entails an overabundance of methylation on the DNA repair protein
O6-methylguanine DNA methyltransferase (MGMT), resulting in the deactivation of
MGMT for DNA repair, a process frequently observed in cancerogenesis. Within cancer
cells, micro-RNAs, a type of noncoding RNA comprising around twenty bases, bind
to messenger RNAs, leading to their degradation or the inhibition of translation. This
process significantly influences the growth and spread of numerous cancer types [15].
The unrestricted proliferation of cancer cells leads to numerous alterations in
cellular communication, the cell cycle, cell adhesion, and the extracellular matrix.
Typically, the growth pattern of normal cells is tightly regulated, with densitydependent inhibition restricting further cell growth, overseen by cell growth regulators. However, during the progression of cancer cells, the phenotype of extracellular
growth factor receptors changes, and the density-dependent inhibition process
becomes ineffective. Occasionally, cancer generates fresh growth factors to promote
unregulated growth, a process known as autocrine growth stimulation, making it
independent of the usual growth factors that regulate the growth of normal cells [16].
Consequently, cellular growth signaling varies in cancer cells, where the intracellular
signaling pathway is disrupted by the deactivation of growth factor receptors or other
critical proteins, such as Ras proteins or protein kinases [17].
The adhesion between cells and their attachment to the matrix is notably weaker
in cancer cells. Within these cells, the primary adhesion function of E-cadherin in
cell-matrix interactions is compromised, resulting in decreased activity. Receptors
responsible for cell-cell attachment are downregulated, while those associated with cell
motility are upregulated. Additionally, this process stimulates the activation or overexpression of surface metalloproteases, leading to the degradation of the extracellular
matrix. This degradation facilitates the movement of cells with mesenchymal traits,
which is crucial for metastasis. Also, increased secretion of collagenase has enhanced
the capacity of carcinomas to break down and penetrate basal laminae, facilitating
the invasion of underlying connective tissue. Moreover, the heightened expression of
vascular endothelial growth factor receptors fosters the creation of fresh blood vessels.
Importantly, within tumor cells, the process of apoptosis, which typically serves
as a tightly controlled mechanism for cell death in the development and sustenance

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of a normal cell population in mature organisms, is also disrupted. Anomalies in the
apoptosis process are also a prominent characteristic of carcinogenesis. In certain
types of cancer, the natural intrinsic apoptosis pathway is hindered by regulators like
X-linked inhibitor of apoptosis protein (XIAP) and the B-cell lymphoma 2 family of
proteins [18]. Similarly, the proteins FLIPL and FLIPS also impede alternative extrinsic pathways [19].
Numerous notable distinctions between cancer and normal cells contribute to
their accelerated growth rates and enhanced migratory capabilities.
. Anticancer drugs and delivery
During the sixteenth-century, the pioneering physician Paracelsus was among
the first to utilize medicine and minerals in the treatment of cancer. Up until 2020,
the FDA had approved approximately 89 medications intended for the treatment of
cancer [20]. These medications are categorized as alkylating agents, antimetabolites,
anthracyclines, plant alkaloids, microtubule inhibitors or modulators, topoisomerase inhibitors, chromosome binding agents, and other antitumor treatments.
These drugs exhibited anticancer effects by causing DNA fragmentation, inhibiting
topoisomerase activity, and inducing apoptosis through different mechanistic pathways. In more than 90% of instances, chemotherapy is prescribed with the primary
goal of providing palliative care, aiming to either stabilize the disease or enhance
the patient’s quality of life. Regrettably, the limited rate of drug accumulation
within cancer cells is insufficient to manage the rapid growth of tumors effectively.
Therefore, combination therapy might be more effective in controlling the swift and
proliferative cancer growth. Nonetheless, the intrinsic heterogeneous characteristics
and hypoxic conditions significantly disrupt the effectiveness of anticancer drugs in
chemotherapy. Even during advanced stages, various factors such as multidrug resistance, changes in drug activation mechanisms, detoxification, activation of cellular
efflux, and delayed apoptosis further diminish the anticancer efficacy of chemotherapy [21]. The idea of drug delivery emerges as a means to expand the therapeutic
window, which is presently limited. In general, micro/macro encapsulated particles,
polymer-bound micro drug delivery systems, and prodrug-linked low molecular
weight drug delivery systems are frequently utilized. Ligand-receptor interactionbased targeted delivery system is the key strategy behind the effective transport of
chemotherapeutics agents to the cancerous region. Generally, integrin-binding RGD
peptide, folic acid, monoclonal antibody, glycoside, D-biotin, and similar substances
are commonly employed for targeting different forms of cancer [22, 23]. Several
thousand publications concerning drug delivery systems illustrate their internalization through either receptor-ligand interaction within the endocytosis pathway or
passively through the concept of the enhanced permeable retention (EPR) effect.
These endeavors are essential from the standpoint of patient care, reducing drug
misuse, and minimizing mortality.
. Theranostics and importance of self-immolative linker
The ongoing management of cancer in the modern era motivates the development of inventive protocols for delivering anticancer drugs, aiming to enhance
the therapeutic window. In light of this, the concept of theranostics emerges in the
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