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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5615_Библиотеки_им_академика_М_И_Перельмана.pdf
Multifunctional PEGylated
Nanoparticles inTheragnosis
AkhileshTiwari, MuktikaTekade, ShubhamRamdasMule,
GirishMeravanigeBasavarajappa,
andRakeshKumarTekade
Abstract
Target-specic therapeutic modalities solve shortcomings associated with tradi-
tional medication administration and therapy. The success of liposomes, poly-
meric nanoparticles (NPs), dendrimers, micelles, protein-drug conjugates, and
other nanoplatforms in improving the pharmacokinetics and biodistribution of
the therapeutic after systemic administration has led to promising results in clini-
cal settings and market traction. NPs have been the gold standard for medication
administration for millennia; however, this conventional method still faces prob-
lems with drug solubility, sustained payload release, and getting the necessary
treatment to the targeted sickness site. NPs-mediated drug administration and
targeting are further improved by encasing nanoformulations in a stealth coating
made of hydrophilic polymers authorized by the FDA, such as PEG, chitosan,
polyacrylamides, etc. The NPs are protected by this surface layer against opso-
13
A. Tiwari (*)
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak,
Anuppur, Madhya Pradesh, India
M. Tekade
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshila Campus,
Indore, Madhya Pradesh, India
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
S. R. Mule · R. K. Tekade
National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, An
Institute of National Importance, Government of India, Department of Pharmaceuticals,
Ministry of Chemicals and Fertilizers, Palaj, Opposite Air Force Station, Gandhinagar,
Gujarat, India
G. M. Basavarajappa
Department of Biomedical Sciences, College of Medicine, King Faisal University,
Al-Ahsa, Saudi Arabia
367
368
A. Tiwari et al.
nization, immune system recognition, and aggregation. The benets and require-
ments for the PEGylation of NPs are discussed in this chapter. Here, the focus is
on NPs as a means of drug administration and how the PEGylation of NPs
enhances their therapeutic utility. Several PEGylated NPs that have demonstrated
promising outcomes for both systemic and nonsystemic drug delivery have also
been highlighted.
Keywords
PEG · PEGylated · Theragnostic · Nanoparticles · Pharmacokinetic ·
Biodistribution
13.1 Introduction
The term “theragnosis” in medicine refers to the simultaneous diagnosis and treatment of disorders. Combining therapeutic and diagnostic procedures makes this
possible. It combines the elds of therapeutics and diagnostics to improve patient
care and outcomes. This technique has drawn a lot of interest in the eld of customized medicine, where therapies may be modied based on specic patient features.
The term “theragnosis” refers to various methods and tools that make it possible to
nd specic biomarkers associated with particular disease conditions, provide customized medications, and track the efcacy of treatments in real time. Several theragnostic elements are being developed in recent years.
Genetic testing, also referred to as molecular diagnostic technologies, is crucial
to the diagnosis since it can identify distinctive biomarkers connected to diseases.
Genetic or epigenetic components may be included in these biomarkers. Several
molecular diagnostic methods are used to nd and assess these biomarkers, including polymerase chain reaction (PCR), next-generation sequencing (NGS), and
microarray technologies (Arora etal. 2023). Breast cancer can be diagnosed with
molecular diagnostic tools such as PCR, NGS, and gene proling, which help identify altered biomarker expression levels and genetic mutations (Litton etal. 2019).
Imaging technologies used for the noninvasive visualization and characterization of
illnesses and advanced imaging methods are crucial components of theragnostic
endeavors. Theragnosis frequently employs methods including magnetic resonance
imaging (MRI), positron emission tomography (PET), computed tomography (CT),
and ultrasound. These imaging techniques can reveal essential details of the location, severity, and treatment response of the disease (Weissleder and Pittet 2008).
In order to administer therapeutic medications to injured tissues with the fewest
side effects on healthy tissues, theragnosis employs tailored drug delivery devices.
The nanoparticles (NPs), liposomes, and other drug carriers can be functionalized
with unique ligands that target disease-specic receptors or biomarkers. This targeted approach reduces systemic toxicity and enhances treatment efcacy.
Theragnosis enables real-time treatment response monitoring, enabling any required
adjustments to be made to therapy. Biomarkers, imaging techniques, and wearable
technologies may all be used to assess the progression of a disease, the effectiveness
of treatment interventions, and to help make well-informed decisions. The
13 Multifunctional PEGylated Nanoparticles inTheragnosis
Fig. 13.1 Multifunctional PEGylated NPs
369
identication of compounds having multiple uses that have both medicinal and
diagnostic capabilities is referred to as theragnostic. For instance, medicines and
imaging agents for disease visualization for specialized medical treatment can both
be transported by diagnostic NPs. These agents assist individualized therapy by
delivering medication and real-time disease information at the same time. The theragnosis concept can potentially revolutionize the healthcare sector by improving
disease detection, treatment efcacy, and patient outcomes. By enabling doctors to
base decisions on the specics of each patient, it allows them to perform medicine
more accurately and personally. The schematic representation of multifunctional
PEGylated NPs is given in Fig.13.1. In this chapter, the details of PEGylated NPs
in the theragnostic domain are discussed thoroughly, emphasizing their therapeutic
applications.
13.2 Development ofDifferent PEGylated Nanoparticles
forTheragnosis
PEGylated NPs have shown promise as theragnostic platforms since they combine
therapy and diagnostics into one device. These NPs boost medication transport,
increase therapeutic efcacy, and enable noninvasive imaging for diagnostics by
fusing the benets of nanotechnology with those of polyethylene glycol (PEG).
Herein, a succinct summary of how various PEGylated NPs for theragnosis has
been well elaborated.
13.2.1 PEGylated Lipid-Based NPs
Using lipid-based NPs like liposomes and solid lipid NPs (SLNs), theragnosis has
been extensively studied. These NPs are more stable, have longer circulation times,
370
and are less absorbed by the reticuloendothelial system (RES), thanks to the addition of PEG.PEGylated liposomes have been investigated for the combined delivery of therapeutic medicines and imaging agents. For instance, doxorubicin, a
chemotherapeutic drug, and indocyanine green, a uorescent dye, have been delivered together via PEGylated liposomes for combined chemotherapy and uorescence imaging (Grabarnick Portnoy etal. 2021).
A. Tiwari et al.
13.2.2 PEGylated Polymeric Nanoparticles
When it comes to design and functionalization, polymeric NPs are exible.
Polymeric NPs that have been PEGylated are more stable, biocompatible, and have
longer circulation times. For theragnosis, a variety of polymers have been utilized,
including poly (lactic-co-glycolic acid) (PLGA), polyethyleneimine (PEI), and
polymeric micelles. It has been looked at using PEGylated PLGA NPs to simultaneously deliver medicinal and imaging agents. For instance, PEGylated PLGA NPs
loaded with the uorescent probes quantum dots and the chemotherapeutic drug
paclitaxel have been created for combination therapy and uorescence imaging (Li
etal. 2001).
13.2.3 PEGylated Metal-Based Nanoparticles
Gold nanoparticles (AuNPs) and iron oxide nanoparticles (IONPs) are two examples of metal-based NPs with distinctive optical and magnetic properties appropriate for therapy and imaging. Metal-based NPs can be surface functionalized, which
increases their stability and biocompatibility. For combination of photothermal
therapy and photoacoustic imaging, PEGylated AuNPs have been used. For instance,
PEGylated AuNPs have been used to administer paclitaxel and photothermal agents
such as indocyanine green simultaneously for the purposes of imaging and synergistic therapy (Kim etal. 2006).
13.2.4 Multifunctional PEGylated Nanocarriers
Multifunctional PEGylated nanocarriers used in combination therapy have drawn
much interest from the drug delivery community. These nanocarriers have several
benets, including increased drug solubility, longer circulation times, targeted
administration, and the capacity to incorporate several therapeutic agents. Several
research activities highlighting the utility of multifunctional PEGylated nanocarriers in managing various diseases have been undertaken in the past few years.
Interestingly, multifunctional PEGylated NPs that can simultaneously transport
diagnostic modalities such as MRI contrast agents and anticancer medications have
been well explored. The successful encapsulation of chemotherapeutic drugs and
NPs within the nanocarriers with targeting capabilities such as receptor-mediated
13 Multifunctional PEGylated Nanoparticles inTheragnosis
371
targeting or magnetic targeting has been demonstrated by many researchers independently. The multifunctional nanocarriers have demonstrated improved treatment
efcacy and the potential for imaging-based real-time drug delivery monitoring.
Yim etal. formulated pH-responsive PEGylated gold NPs, which were further conjugated with an anticancer drug, doxorubicin via citraconic anhydride linkage. The
123
NPs were additionally labeled with radioisotopes
124
I or
I for detection using
PET.The citraconic anhydride linkage degraded in response to the acidic conditions
at cancerous cells, releasing the doxorubicin intracellularly. Clear PET images of
the cellular accumulation of gold NPs were obtained along with the PET images of
the clearance pattern of the gold NPs, and signicant cell mortality was achieved
due to the presence of doxorubicin (Yim etal. 2021).
Hence, it can be concluded that the development of PEGylated NPs for the theragnostic applications opens a new avenue of opportunities for managing various
diseases. Persistent research in this domain is required to develop clinically applicable theragnostic modalities.
13.2.5 Targeted PEGylated Nanocarriers
A fundamental difculty in the clinical treatment of cancer is the effective and sitespecic administration of therapeutic medicines. Researchers have studied a range
of liposomes, micelles, and polymeric NPs as nanoscale carriers to improve the
bioavailability and pharmacokinetic properties of medications. One such process is
the increased permeability and retention effect (EPR effect) (Wu 2021). It might be
possible to improve treatment by attaining targeted delivery to the cancer cells or
the tumor vasculature by conjugating targeting ligands onto nanocarriers. It has
been demonstrated that the administration of receptor-targeted nanocarriers
enhances therapeutic benets both invitro and invivo. There have been studies on
several different ligands, such as folate, transferrin, antibodies, peptides, and
aptamers.
NPs can be made to perform a wide range of tasks, including intracellular medication release and imaging. It is crucial to remember that the choice of ligands for
PEGylated nanocarriers’ surface functionalization depends on the precise target tissues or cells and the intended therapeutic outcomes. Jin etal. developed PLGAPEG NPs with further surface modication with the GE11 peptide, an EGFR-targeting
peptide. The NPs so prepared were utilized to deliver curcumin to the breast cancer
cells. Upon invitro and in vivo examination of the NPs, it was reported that the
phosphoinositide 3-kinase signaling was signicantly reduced along with reduced
viability of cancer cells and suppressed tumor burden compared to free curcumin
and nontargeted NPs (Jin etal. 2017).
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A. Tiwari et al.
13.3 Chemistry ofPEGylated NPs
The eld of nanomedicine frequently employs PEGylated NPs, also referred to as
PEG NPs, as a form of drug delivery platform. PEGylation is the technique of creating a PEG corona around NPs by covalently connecting PEG chains to the surface
of the NPs (Li et al. 2014). The PEGylated NPs have many benecial qualities,
including increased stability, longer circulation times, less immunogenicity, and
more effective drug delivery.
It is crucial to understand the chemistry behind developing and evaluating
PEGylated NPs to formulate the PEGylated NPs with desired physicochemical
properties and therapeutic outcomes. In this section, the chemistry of PEGylated
NPs has been discussed thoroughly.
13.3.1 Surface Modification Chemistry
PEG chains are covalently attached to the NPs’ surface through various chemical
processes during the surface modication of NPs with PEG. Thiol-ene, aminecarboxylic acid, and maleimide-thiol reactions are typical techniques used for surface modication with PEG (Kharkar etal. 2016). In the amine-carboxylic reaction,
the carboxylic group on the surface of NPs and the amine group in the structure of
PEG react to form stable amide bonds (Rahme and Dagher 2019). The aminecarboxylic reactions are carried out using carbodiimide chemistry such as
N-hydroxysuccinimide (NHS) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
(EDC) (Ahmad etal. 2015).
In the thiol-maleimide reaction, maleimide-modied NPs are conjugated with
thiol-functionalized PEG to form the stable thioether bond (Martínez-Jothar etal.
2018). These processes enable the attachment of PEG molecules with various func-
tional groups and lengths to the surface of NPs. The method of PEGylation is primarily governed by reaction parameters such as temperature, pH, and reaction time
(Suk etal. 2016). Serious consideration of all these factors must be given to obtain
the nal product with the desired attributes.
13.3.2 Polymer Chemistry
The creation, evaluation, and subsequent conjugation of PEG polymers to the surface of NPs all depend heavily on polymer chemistry. PEG polymers with various
MWs and structural types are used in the PEGylation of NPs. The preferred characteristics of the NPs, such as stability, drug-loading capacity, and release kinetics,
will determine which PEG polymer is used (Suk etal. 2016; Zielińska etal. 2020).
The higher molecular weight PEGs offer better steric hindrance and enhance stealth
properties (Salmaso and Caliceti 2013). This ultimately increases the circulation
time of NPs in the bloodstream. However, the higher MWs of PEG affect the tissue
penetration of the PEG-modied NPs, which necessitates the thorough
13 Multifunctional PEGylated Nanoparticles inTheragnosis
determination of polymer selection criteria. The functional groups on the surface of
PEG, such as thiol, amine, maleimide, and carboxyl, govern the choice of chemistry
for further modication of NPs with PEG. For instance, using thiol maleimide
chemistry, thiol-terminated PEG can be conjugated with maleimide-modied NPs.
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13.3.3 Synthesis ofNPs
PEGylated NPs generation depends heavily on the chemistry involved in the synthesis of NPs. Various techniques are used to create NPs with diverse sizes, shapes, and
surface qualities, including nanoprecipitation, emulsion/solvent evaporation, and
self-assembly. The effectiveness and stability of the PEGylated NPs are inuenced
by the chosen method of NP synthesis. Hence, the selection of the process of synthesis of PEGylated NPs is a crucial aspect to consider to generate NPs with desired
pharmacokinetic attributes (Goldberg etal. 2007).
13.3.4 Characterization Techniques
PEGylated NPs are characterized by utilizing a variety of analytical techniques.
These include transmission electron microscopy (TEM), which gives insights into
the morphological characteristics of the NPs, and dynamic light scattering (DLS) is
used to measure the particle size and zeta potential of the NPs. Fourier-transform
infrared spectroscopy (FTIR), a well-known technique for functional group detection, can be utilized to determine the surface modication of the NPs and the conjugation of PEG with the desired entity of interest (Younis et al. 2021). Nuclear
magnetic resonance (NMR) is a preferred technique for detecting the conjugation of
the PEG with the molecules of interest. The NPs can be further characterized by
X-ray diffraction analysis, which determines the crystallinity of the prepared formulation (Mourdikoudis etal. 2018). In the case of metallic PEGylated NPs, the identication and determination of the metallic content of the NPs is necessary. This can
be achieved using energy-dispersive X-ray (EDX) analysis and inductively coupled
plasma-mass spectrometry (ICP-MS).
13.4 Mechanism ofEnhanced Drug Delivery Through
PEGylated NPs
PEGylation is the term used to describe the process of attaching PEG chains to NPs’
surfaces. Utilizing PEGylated NPs to enhance drug pharmacokinetics and therapeutic efcacy is known to enhance the therapeutic aspects of drug delivery by various
mechanisms. Some crucial outcomes associated with the PEGylation of NPs that
signicantly impact the invivo behavior of the prepared PEGylated NPs are shown.
The mechanisms of enhanced drug delivery through PEGylated NPs are shown in
Fig.13.2.
374
Fig. 13.2 Mechanism of enhanced drug delivery through PEGylated NPs
A. Tiwari et al.
13.4.1 Longer Circulation Time
PEGylation reduces the RES’s ability to recognize and opsonize NPs, giving them
a stealth effect. The hydrophilic PEG chains form a steric barrier that delays opsonization and subsequent clearance by the RES (Gref etal. 1994). This prolongs the
circulation period of NPs in the bloodstream. The effectiveness of medication delivery is improved by the accumulation of NPs at the target site due to the lengthened
circulation duration.
The PEG coating on the surface of NPs reduces nonspecic interactions with
plasma proteins and cell surfaces, limiting absorption by macrophages and other
immune cells, resulting in decreased clearance and enhanced biodistribution (Alexis
etal. 2008). This decrease in nonspecic interactions promotes the availability of
NPs at the target site and slows down fast clearance. The EPR effect, which passively permits PEGylated NPs to collect in tumor tissues with leaky vasculature,
further improves drug delivery to solid tumors (Maeda etal. 2009).
13.4.2 Enhanced Cellular Uptake
By removing numerous obstacles, PEGylation can enhance the cellular uptake of
NPs. PEGylation is a proven technique to lessen the serum proteins’ ability to
13 Multifunctional PEGylated Nanoparticles inTheragnosis
adhere to the surface of NPs, which can impede cellular uptake (Veronese and
Harris 2002). Depending on the ligands connected to the PEG chains, the presence
of PEG on the surface of NPs can also promote endocytosis by engaging with particular cell surface receptors, such as the asialoglycoprotein receptor or folate receptor (Torchilin 2007). This active targeting strategy enhances the specicity and
effectiveness of drug delivery to specic cell types. PEGylation combined with further surface modication with the targeting ligand will enhance the cellular uptake
multifold owing to the improved circulation time due to PEGylation and receptormediated cellular uptake due to the targeting ligand.
375
13.4.3 Controlled Drug Release
PEGylation can alter how quickly medications are released from NPs. Because PEG
chains are hydrophilic, they prevent medication from diffusing out of the NPs
matrix, producing a prolonged release prole. PEG layers on the surface of NPs
prevent the rapid diffusion of the drug, thereby prolonging the release rate. To netune the release rate and obtain the desired therapeutic results, the size and structure
of the PEG chains can be changed to achieve the desired drug release pattern.
13.5 Application ofTheragnosis inDifferent Therapies
A new area of medicine known as theragnostic combines therapy and diagnostics,
intending to create individualized treatments based on the unique features of each
patient’s ailment. It entails using diagnostic tools to pinpoint specic molecular
targets or biomarkers, followed by administering therapeutic therapies explicitly
made for those targets. Some of the theragnostic use in various therapy are accompanied by pertinent sources.
13.5.1 Cancer Theragnostic
The goal of cancer prognosis is the creation of patient-specic tailored medicines.
Specic tumor biomarkers can be seen and measured utilizing molecular imaging
techniques like PET or single-photon emission computed tomography (SPECT).
This makes it possible to choose the best treatments, including radiotherapy or tailored drug administration. Choi etal. developed the PEG-hyaluronic acid (HA) NPs
to target CD44 receptors overexpressing cancer cells. The NPs were further labeled
with cyanine 5.5 for the uorescence-based detection of the localization of the NPs
(Choi etal. 2010). It was reported that a signicant number of the administered NPs
were localized at the tumor site, which suggests the high tumor targetability of the
prepared NPs. These results suggest the possible application of the PEGylated NPs
for the theragnosis of cancer.
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A. Tiwari et al.
13.5.2 Cardiovascular Theragnostic
Cardiovascular theragnostics aim to create individualized treatments for heart failure and atherosclerosis, two cardiovascular illnesses. Determining the extent of disease progression and prospective therapy targets is possible using noninvasive
imaging methods like CT or MRI. Gene therapy and targeted drug delivery are
examples of therapeutic approaches. Ren et al. formulated the PEG-PLGA NPs
loaded with miR-30b-5p for targeted therapy of cardiac failure. Echocardiography,
HE/Masson staining, and immunouorescence were utilized to assess the effects of
the therapy on the cardiac structure and function. Western blotting and reverse
transcription- polymerase chain reaction (RT-PCR) were done to evaluate the expression of markers associated with inammation and cardiac hypertrophy. The
miR-30b-5p-loaded PEG-PLGA NPs improved cardiac function, myocardial injury,
and regulated markers related to inammation and cardiac hypertrophy (Ren
etal. 2021).
13.5.3 Theranostics forNeurological Conditions
This eld focuses on the detection and treatment of neurological conditions like
brain tumors, Parkinson’s disease, and Alzheimer’s disease. Functional MRI (fMRI)
and PET are the two examples of molecular imaging techniques that can be used to
identify specic molecular targets or gauge the effectiveness of a treatment.
Therapeutic approaches include gene therapy, deep brain stimulation, and targeted
drug delivery. Liu etal. developed PEG-poly(lactic) acid NPs and imparted surface
modication using B6 peptides to target clathrin-mediated and lipid-raft-mediated
endocytosis. The prepared NPs were loaded with the neuroprotective peptide
NAPVSIPQ (NAP) for the management of the Alzheimer’s disease. B6-decorated
NPs demonstrated higher accumulation in brain capillary endothelial cells. The
administration of the NPs in mouse models of AD showed improvement in learning
functions and amelioration of hippocampal neuronal loss and cholinergic disruption. This suggests the utility of PEGylated NPs in managing neurological conditions (Liu etal. 2013).
13.6 Diagnosis andTherapy Through PEGylated NPs
PEGylated NP-based diagnosis and treatment have drawn much interest from the
medical community. Considering PEG’s advantages, such as longer circulation time
and targeting ability with surface modication with targeting ligands, the PEGylated
NPs offer signicant promise as a theragnostic platform for various diseases.
Hereby, the uses and advantages of PEGylated NPs in treatment and diagnostics
have been thoroughly discussed in this section.