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14 Reversible PEGylation ofNanocarriers
417
14.5.5 Immunogenicity
Despite PEG’s well-known low immunogenicity, some researchers have reported
experiencing immunological reactions. Reversible PEGylation may cause an immunological reaction when exposed to PEG repeatedly, which could eventually
decrease the medicinal agent’s effectiveness (Shiraishi and Yokoyama 2019;
Veronese 2001).
14.5.6 Scale-up Difficulties
The shift from laboratory-scale synthesis to large-scale production may pose difculties with cost-effectiveness, scalability, and reproducibility. For larger-scale
applications, the synthesis and purication techniques developed on a small scale
might need to be optimized.
14.5.7 Influence onDrug Bioavailability
PEG concentrations can affect a drug’s bioavailability. The advantages of extended
circulation times must be carefully weighed against possible changes in drug
absorption, distribution, metabolism, and excretion (ADME) patterns in reversible
PEGylation systems.
14.5.8 Cost
A major determinant of their uptake may be the expense of synthesizing and producing reversible PEGylation conjugates. One crucial factor to take into account is
the expense of synthesis, purication, and regulatory compliance in relation to the
possible advantages of better therapeutic outcomes (Tao etal. 2009).
Addressing these challenges requires interdisciplinary efforts, combining expertise in chemistry, biology, and materials science. Despite these obstacles, reversible
PEGylation holds promise for enhancing the pharmacokinetics and therapeutic outcomes of various bioactive molecules (Pomroy and Deber 1998). Ongoing research
aims to overcome these challenges and unlock the full potential of reversible
PEGylation in medical and biotechnological applications.
14.6 Conclusion
To sum up, reversible PEGylation of nanocarriers offers a viable path towards drug
delivery system optimization. Reversible PEGylation provides a careful balance
among biocompatibility and effective payload delivery by addressing the drawbacks
of irreversible PEGylation, including reduced cellular absorption and clinical
418
M. Mishra et al.
efcacy. Stimuli-responsive polymers along with cleavable linkers provide controlled dissociation of PEG chains from nanocarrier, activated by specic physiological circumstances, thereby improving targeted release at a particular site of
action. Reversible PEGylation techniques, such as pH-sensitive, temperature-triggered formulations, and enzyme-responsive, are highly versatile and can be used to
achieve more precise drug release kinetics and better therapeutic results. Expanding
up reversible PEGylation methods, maintaining stability in storage and transit, and
negotiating regulatory processes for clinical approval are still difcult tasks. In
order to fully realize the ability of reversible PEGylation to revolutionize drug delivery and ultimately result in less hazardous more efcient treatments for a variety of
disorders, it will be imperative to address these obstacles.
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421
Stimuli-Responsive PEGylated Nanocarriers
SamahHamedAlmurisi,
PrasanthiSriNaginderaRao,
andThiagarajanMadheswaran
Abstract
Compared to traditional medication dosage forms, nanocarrier-based delivery
systems confer several benets, including drug protection, improved bioavail-
ability, and tailored administration to disease sites. With increased availability in
the body, better drug loading values, improved intracellular transport, and supe-
rior physiological outcomes, nanocarriers are reported to improve targeted drug
delivery to cells and tissues. Stimuli-responsive nanocarriers with unique design
characteristics can adapt to exogenous and endogenous stimuli; their structure
and physicochemical properties change in response to various factors. This
results in the release of drugs at a specic target site when triggered by certain
physiological or external triggers. Numerous therapeutic and diagnostic pro-
cesses can be made substantially more effective by creating pharmaceutical
nanocarriers with multiresponsive systems. The most popular technique for giv-
ing drug nanocarriers stealthy characteristics is PEGylation. The PEG molecules
have been altered to improve their uptake by particular targets and to allow con-
trolled drug release. This chapter highlights the most recent developments in
nanocarriers with multifunctional properties and stimuli sensitivity for therapeu-
tic drug delivery applications. By delivering the drugs specically to the disease
cells, there is a pronounced enhancement in the efcacy of the treatment, improv-
ing the incidence of unwanted effects on nontarget cells, tissues, and organs.
15
S. H. Almurisi · P. S. NaginderaRao · T. Madheswaran (*)
Department of Pharmaceutical Technology, School of Pharmacy, International Medical
University, Bukit Jalil, Kuala Lumpur, Malaysia
e-mail: Thiagarajan@imu.edu.my
423
424
Keywords
S. H. Almurisi et al.
Nanocarriers · Stimuli-responsive · Drug targeting · PEGylated · Theragnostic
applications
Abbreviations
ABC Ammonium bicarbonate
AMF Magnetic eld
CAFs Cancer-associated broblasts
CAT Catalase
CPs Conductive polymers
CS Chitosan
CST Critical solution temperature
CUR Curcumin
Cys Cysteine
DOX Doxorubicin
DTT Dithiothreitol
ECs Endothelial cells
EPR Enhanced permeability and retention
Gox Glucose oxidase
GPx Glutathione peroxidase
GSH Glutathione
HA Hyaluronic acid
LCST Lower critical solution temperature
MBs Microbubbles
MC Merocyanine
MHT Magnetic hyperthermia
MMA Methyl methacrylate
MMPs Matrix metalloproteinases
MNPs Magnetic nanoparticles
MoS2 Molydenum disulde
NADPH oxidase Nicotinamide adenine dinucleotide phosphate oxidase
NBs Nanobubbles
NIR Near-infrared
NPs Nanoparticles
NR Nile red
OG Oil-soluble uorescent green
PCL Polycaprolactone
PEG Polyethylene glycol
PEGylation The process of polyethylene glycol (PEG)-based modication
of molecules for biomedical application
PEI Polyethyleneimine
pNIPAm Poly(N-isopropylacrylamide)
15 Stimuli-Responsive PEGylated Nanocarriers
425
PNIPAm Poly(N-isopropyl acrylamide
PTX Paclitaxel
RES Reticuloendothelial system
ROS Reactive oxygen species
Se Selenium
Se-Se Diselenide
SOD Superoxide dismutases
SP Spiropyran
S-S Disulde
US Ultrasound
UV Ultraviolet
γ-GCS γ-glutamyl cysteine
γ-PGA Poly-γ-glutamic acid (γ-PGA)
15.1 Introduction
New technologies incorporating advanced nanomaterials that are applicable to theranostics have evolved to address the obstacles posed by conventional dosage forms
and the adverse effects associated with pharmaceuticals. These new technologies
have dual properties, including bioimaging for diagnostic purposes and targeted
drug release for therapeutic function (Pham etal. 2020a). Engineers and researchers
have been putting more effort into designing and producing stimuli-sensitive nanomaterials with combined therapy and diagnostic functions. This is being done to
maximize the scope of nanotechnology applications for precise drug delivery and
disease diagnosis in the human tissue while maintaining a higher level of safety and
biocompatibility (Oladipo etal. 2023). These intelligent nanomaterials, utilized in
controlled drug delivery strategies, are formulated to react primarily to external
stimuli when required. Another way to implement this requirement is to trigger it
when necessary (Ahmad and Packirisamy 2020).
In contrast to conventional nanocarriers, new-generation drug nanocarriers with
stimuli-sensitive properties can recognize the environment in which bacteria are
located and the site of the infection. Furthermore, these nanocarriers respond
dynamically to specic triggers from outside factors (Bag etal. 2023). In addition
to this, they can control drug delivery patterns by preventing drug leakage before
reaching the target site to improve the delivery of loaded drugs at the target site
while simultaneously reducing the likelihood of unwanted side effects. Therefore,
nanocarriers created with nanomaterials with stimuli-sensitive properties present
distinct, improved therapeutic action and more targeted delivery. Additionally, these
nanocarriers have a superior capacity for cell penetration, which is necessary to treat
various cancers effectively (Gessner and Neundorf 2020).
In the last 10years, strategies for successfully delivering therapeutic drugs have
been developed, including polymer-based nanomaterials sensitive to stimuli. The
nanocarriers are designed to allow the release of drugs in the presence of selected
stimuli across polymer, lipid, or metal nanoparticles. These stimuli can be internal
or external or triggered by dual or multiple factors. The design of the material can
426
S. H. Almurisi et al.
be employed. The term “stimuli-responsive smart biomaterials” refers to materials
triggered in response to the local microenvironment’s pH, enzymes, physical force,
or redox stimuli to release drugs loaded into the nanocarriers. A myriad of potential
applications are associated with these biomaterials (Alves etal. 2021).
Redox potential, pH, enzymes, ions, and oxygen and glucose levels are all examples of endogenous stimuli, also known as internal or biological stimuli. These
stimuli are mostly peculiar to sick tissue and have the potential to accumulate at the
target site. They also have the potential to disrupt the structure of nanocarriers and
change the functions they perform. These stimuli-responsive drug delivery systems
observe various expression proles in response to specic cells or tissues. The
nanocarriers interact with antibodies and antigens and can detect host-guest products in a particular state to release the drug. An example of a highly specic potential trigger includes processes catalyzed by enzymes specic to particular substrates
and catalytic properties (Sheshala etal. 2022). Enzymatically catalyzed processes
possess high specicity and high catalytic properties, making them suitable as triggers for drug release. A critical challenge in drug release is an unspecic time and
nontargeted release; to overcome this, careful design and selection of stimulisensitive biomaterials is necessary. This requirement must be met to fabricate nanocarriers (Joseph etal. 2023).
In many stimuli-based drug delivery strategies, exogenous or external stimuli are
applied as chemical, biological, or physical techniques to allow the nanocarriers to
release their therapeutic drug payloads in a regulated and targeted manner, as illustrated in Fig.15.1. Exogenous triggers such as light, heat, ultrasound, and electrical
and magnetic elds can all trigger controlled drug delivery. The benets of applying
external stimuli to disrupt the structure of stimuli-sensitive nanocarriers include the
Fig. 15.1 Illustration of exogenous and endogenous stimuli-responsive systems