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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5373_Библиотеки_им_академика_М_И_Перельмана.pdf
13 Multifunctional PEGylated Nanoparticles inTheragnosis
377
13.6.1 Cancer Diagnosis andTherapy
PEGylated NPs have been thoroughly investigated for cancer treatment and diagnostics. They have many benets, including increased tumor accumulation, extended
circulation duration, and regulated medication release. Several investigations in this
regard are reported with promising results. Choi etal. developed PEG-conjugated
hyaluronic acid NPs to deliver anti-cancer drugs doxorubicin and camptothecin.
The developed NPs were evaluated for their efcacy against the cancer cells SCC7
and MDA-MB-231 and the animal tumor model. In tumor-bearing mice, the
PEGylated NPs demonstrated selective uptake into the tumor site after systemic
administration. This can be attributed to PEG-mediated prolonged circulation time
and hyaluronic acid-mediated CD44 receptor targeting. No signicant increase in
tumor size was observed for up to 35days, suggesting anti-cancer activity (Choi
etal. 2011).
13.6.2 Imaging andContrast Agents
PEGylated NPs can be customized with imaging agents to serve as contrast agents
in a variety of imaging modalities, including CT, MRI, and uorescence imaging
(Mulder etal. 2009). Zhou et al. developed PEGylated AuNPs for the imaging of
tumor sites. The developed nanosystems explicitly accumulated in the tumor site
owing to the EPR effect and demonstrated better X-ray attenuation properties than
the marketed small molecular iodinated contrast agent and prolonged half-decay
time. The CT imaging has been successfully done using the above-developed
AuNPs, which hints towards the utility of PEGylated systems as contrast agents for
imaging applications (Zhou etal. 2014).
13.6.3 Gene Therapy andRNA Delivery
PEGylated NPs have also demonstrated potential in gene therapy and RNA delivery
applications. They can effectively transfer genetic material and RNA-based therapies to target cells, enabling gene editing and regulation. Santos etal. have developed liposomes of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene
glycol) (DSPE-PEG) with further surface modication with hexapeptide for the
delivery of SiRNA. The developed liposomes demonstrated increased uptake by
SCLC cells and HMEC-1 microvascular endothelial cells. PEG, in this case, can
ensure enhanced circulation time invivo, whereas hexapeptide has been used for
targeting purposes (Santos etal. 2010).
378
A. Tiwari et al.
13.7 Multifunctional PEGylated Nanoparticles
inTheragnosis
In theragnosis, which is the fusion of therapeutic and diagnostic activities within a
single platform, PEGylated NPs are frequently employed. These NPs have more
excellent stability, longer circulation times, and better drug delivery, among other
benets. A concise overview of multifunctional PEGylated NPs in theragnosis,
along with relevant examples, is given as follows.
13.7.1 PEGylation forEnhanced Stability
By minimizing nonspecic interactions with biological components, PEGylation
improves stability by adding PEG chains to NPs. This alteration prevents opsonization, which can cause the RES to clear substances quickly (Owens 3rd and Peppas
2006). PEGylation has been routinely used to increase the stability and circulation
time of theragnostic NPs. The PEG chains around the PEGylated NPs create a steric
barrier that prevents the aggregation of the NPs thereby imparting higher stability to
them. Adjusting the zeta potential of the NPs to meet the stability criteria can also
be employed along with steric stabilization via PEG to attain additional stability.
13.7.2 Prolonged Circulation Time
Longer circulation times are also a result of PEGylation, which is referred to as the
“stealth effect.” Because the hydrophilic PEG chains provide a steric barrier that
shields against immune system identication and uptake, NPs can circulate for a
longer time (Blanco et al. 2015). Conversely, PEGylation increases the overall
molecular weight of the PEGylated moieties, thereby reducing renal clearance
(Gupta etal. 2019). This characteristic is particularly essential for theragnostic NPs
since it enhances the possibility of accumulating at the target region. Hence,
increased molecular weight as well as reduced immune clearance due to PEG modication are jointly responsible for the prolonged circulation time.
13.7.3 Improved Drug Delivery
Multifunctional PEGylated NPs can effectively transport therapeutic materials,
such as medicines or genes, to the appropriate location by encapsulating them. By
enhancing stability during circulation and avoiding early drug release and degradation, the PEG coating enhances the overall pharmacokinetic behavior of the
PEGylated NPs. Furthermore, targeting ligands can be functionalized onto the surface of PEGylated NPs to enable selective identication and binding to the intended
cells or tissues (Peer etal. 2007). This active targeting increases the effectiveness of
medicine delivery. Nanocarriers that target specic receptors can be used to treat
13 Multifunctional PEGylated Nanoparticles inTheragnosis
diseases that show overexpression of certain receptors. For instance, folate receptors and CD44 receptors have been widely exploited for the targeted therapy of various cancers (Kesharwani etal. 2021).
379
13.7.4 Diagnostic Functionality
Theragnostic NPs combine drug delivery with diagnostic capabilities, enabling
simultaneous imaging and therapy. These NPs can transport imaging agents like
uorescent dyes or contrast agents in various imaging modalities such as MRI, CT,
or optical imaging (Han etal. 2019). The diagnostic element aids in dening the
target site, tracking therapy effectiveness, and directing therapeutic choices.
Multifunctional PEGylated NPs have considerable potential for diagnosis because
they combine better stability, prolonged circulation time, improved drug delivery,
and diagnostic capabilities. However, theragnosis has many limitations that need to
be addressed, even if it offers a lot of potential for individualized therapy and better
patient outcomes.
13.8 Technical Challenges
Theragnosis entails creating cutting-edge imaging and sensing technologies that
can precisely identify and track the course of disease. However, these methods have
technological constraints, including sensitivity, resolution, and specicity, which
can impact the precision and dependability of diagnostic data. To address these
technical problems, more research and development is required. The following section enlists the various technical challenges associated with the clinical applications
of the PEGylated NPs in theragnosis.
13.8.1 Limited Availability ofTargeted Therapies
By locating certain molecular targets linked to diseases, theragnosis aims to provide
targeted therapeutics. Targeted treatments are, however, currently scarce for many
illnesses. More tailored treatment drugs that diagnostic data can lead must be developed for theragnosis to realize its full potential. Developing theragnostic modalities
for all diseases is not practically possible. This puts reasonable restrictions on the
broad-scale application of the theragnostic NPs.
13.8.2 Cost andAccessibility
The use of pricy diagnostic imaging techniques and specialized therapeutic drugs
during the implementation of the theragnosis could considerably raise the expense
of treatment (Mangalath etal. 2014). This might make theragnosis less available to
380
patients, especially in places with limited access to healthcare resources. To guarantee wider access, efforts must be made to lower the price and increase the availability of theragnostic technology.
A. Tiwari et al.
13.8.3 Ethical andRegulatory Considerations
The use of personal health information, patient privacy, and informed permission
are all crucial ethical and legal issues that are raised by the theragnosis (Coletta
etal. 2020). The integration of diagnostic and therapeutic activities also questions
the proper use and interpretation of diagnostic data for treatment decisions. The
widespread implementation of theragnostic methods depends on creating precise
rules and laws to address these moral and legal concerns.
13.8.4 Limited Clinical Validation
Although encouraging preclinical and early clinical research has shown theragnosis’ potential, additional clinical validation is required to prove its efcacy and utility in treating various diseases and patient demographics. Extensive clinical studies
and meticulous evaluation are needed to assess the clinical advantages, nancial
viability, and long-term effects of theragnostic techniques (Fogel 2018). It is crucial
to remember that theragnosis is a rapidly developing discipline, and future technological improvements and continuing research are expected to resolve some of these
limits. Theragnosis has the potential to transform customized medicine and enhance
patient care with ongoing innovation and cooperation..
13.9 Regulatory Requirements ofTheragnosis
The term “theragnosis” refers to the fusion of treatment and diagnosis, in which
therapeutic actions are individualized and guided by diagnostic ndings. It entails
the discovery of certain biological targets or biomarkers that assist in choosing the
best course of action for every patient. To the best of our knowledge, theragnosis is
not the subject of any specic regulatory requirements. Regulatory standards for
diagnostics and personalized treatment may differ by nation or location. Through
the Food and Drug Administration (FDA) in the United States, specically the
Center for Devices and Radiological Health (CDRH) and the Center for Biologics
Evaluation and Research (CBER), controls diagnostic procedures and equipment.
The FDA oversees diagnostic procedures, including those used in diagnosis, to verify their efcacy and safety (Genzen 2019).
The FDA classies typically diagnostic tests as either invitro diagnostic (IVD)
tools or laboratory-developed tests (LDTs) (Sarata and Johnson 2014). LDTs are
tests created and carried out within a single laboratory, whereas IVD devices are
commercially distributed tests. For each of these categories, the FDA has a different
13 Multifunctional PEGylated Nanoparticles inTheragnosis
381
regulatory process, such as premarket approval (PMA), 510(k) clearance, and the
laboratory-developed test (LDT) policy (Sarata and Johnson 2014). Customized
medication and diagnostics are subject to regulatory oversight in the European
Union (EU). IVDs are governed by the in vitro Diagnostic Regulation (IVDR)
2017/746, which became effective in May 2022 (Sarata and Johnson 2014). The
IVDR establishes standards for the reliability, efciency, and clinical validity
of IVDs.
It is vital to remember that regulatory requirements are subject to periodic
changes. For the most up-to-date and correct information on the regulatory requirements for theragnosis in particular, it is recommended to keep a tab of all the regulatory changes.
13.10 Conclusion
The quest for the development of enhanced therapeutic and diagnostic techniques
fuels the research endeavors in the realm of drug delivery. One of the most important outcomes of these efforts is the development of PEGylated NPs in theragnosis,
a domain dealing with both therapeutics and diagnostics. PEGylated NPs demonstrate remarkable properties such as reduced immunogenicity, increased stability,
and increased circulation time, enabling them to deliver drugs precisely, minimize
the off-target effects, and maximize therapeutic efcacy.
Targeted PEGylated NPs thereby reduce the need for high drug doses, ultimately
reducing the systemic toxicity of drugs. The unique surface properties of PEGylated
NPs allow the attachment of various ligands, such as targeting moieties and imaging
agents, allowing them to attain therapeutic as well as diagnostic functions simultaneously. This helps in the early detection of cancers, wherein an early intervention
can bring signicant patient outcomes in terms of survival rates. Despite the advantages that PEGylated NPs offer, they present themselves with many technical challenges, such as achieving precise control over the size of NPs and their surface
properties, which signicantly affect the pharmacokinetic behavior of NPs.
Achieving multifunctionality while tackling the challenge of increased complexity
is another prime challenge associated with developing PEGylated NPs. Furthermore,
there is a need to have clear regulatory guidelines and standardized protocols for the
development of theragnostic modalities such as multifunctional PEGylated NPs.
Overall, the PEGylated NPs offer various advantages in the domain of theragnostic
intervention of various diseases, which hints towards their potential clinical utility.
References
Ahmad Z, Shepherd JH, Shepherd DV, Ghose S, Kew SJ, Cameron RE, Best SM, Brooks RA,
Wardale J, Rushton N (2015) Effect of 1-Ethyl-3-(3-Dimethylaminopropyl) Carbodiimide and
N-Hydroxysuccinimide concentrations on the mechanical and biological characteristics of
cross-linked collagen Fibres for tendon repair. Regen Biomater 2:77–85
382
Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodis-
tribution of polymeric nanoparticles. Mol Pharm 5:505–515
Arora N, Chaudhary A, Prasad A (2023) Editorial: methods and applications in molecular diagnos-
tics. Front Mol Biosci 10:1239005
Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological
barriers to drug delivery. Nat Biotechnol 33:941–951
Choi KY, Chung H, Min KH, Yoon HY, Kim K, Park JH, Kwon IC, Jeong SY (2010) Self-
assembled hyaluronic acid nanoparticles for active tumor targeting. Biomaterials 31:106–114
Choi KY, Yoon HY, Kim J-H, Bae SM, Park R-W, Kang YM, Kim I-S, Kwon IC, Choi K, Jeong
SY, Kim K, Park JH (2011) Smart Nanocarrier based on Pegylated hyaluronic acid for cancer
therapy. ACS Nano 5:8591–8599
Coletta RD, Yeudall WA, Salo T (2020) Grand challenges in oral cancers. Front Oral Health 1:3
Fogel DB (2018) Factors associated with clinical trials that fail and opportunities for improving the
likelihood of success: a review. Contemp Clin Trials Commun 11:156–164
Genzen JR (2019) Regulation of laboratory-developed tests: a clinical laboratory perspective. Am
J Clin Pathol 152:122–131
Goldberg M, Langer R, Jia X (2007) Nanostructured materials for applications in drug delivery
and tissue engineering. J Biomater Sci Polym Ed 18:241–268
Grabarnick Portnoy E, Andriyanov AV, Han H, Eyal S, Barenholz Y (2021) Pegylated liposomes
remotely loaded with the combination of doxorubicin, quinine, and indocyanine green enable
successful treatment of multidrug-resistant tumors. Pharmaceutics 13:13
Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Biodegradable
long-circulating polymeric Nanospheres. Science 263:1600–1603
Gupta V, Bhavanasi S, Quadir M, Singh K, Ghosh G, Vasamreddy K, Ghosh A, Siahaan TJ,
Banerjee S, Banerjee SK (2019) Protein Pegylation for cancer therapy: bench to bedside. J Cell
Commun Signal 13:319–330
Han X, Xu K, Taratula O, Farsad K (2019) Applications of nanoparticles in biomedical imaging.
Nanoscale 11:799–819
Jin H, Pi J, Zhao Y, Jiang J, Li T, Zeng X, Yang P, Evans CE, Cai J (2017) Egfr-targeting Plga-
peg nanoparticles as a curcumin delivery system for breast cancer therapy. Nanoscale
9:16365–16374
Kesharwani P, Chadar R, Sheikh A, Rizg WY, Safhi AY (2021) Cd44-targeted Nanocarrier for
cancer therapy. Front Pharmacol 12:800481
Kharkar PM, Rehmann MS, Skeens KM, Maverakis E, Kloxin AM (2016) Thiol-Ene click hydro-
gels for therapeutic delivery. ACS Biomater Sci Eng 2:165–179
Kim J, Park S, Lee JE, Jin SM, Lee JH, Lee IS, Yang I, Kim J-S, Kim SK, Cho M-H, Hyeon
T (2006) Designed fabrication of multifunctional magnetic gold nanoshells and their appli-
cation to magnetic resonance imaging and photothermal therapy. Angew Chem Int Ed Engl
45:7754–7758
Li Y, Pei Y, Zhang X, Gu Z, Zhou Z, Yuan W, Zhou J, Zhu J, Gao X (2001) Pegylated Plga nanopar-
ticles as protein carriers: synthesis, preparation and biodistribution in rats. J Control Release
71:203–211
Li Y, Kröger M, Liu WK (2014) Endocytosis of Pegylated nanoparticles accompanied by
structural and free energy changes of the grafted polyethylene glycol. Biomaterials
35:8467–8478
Litton JK, Burstein HJ, Turner NC (2019) Molecular testing in breast cancer. Am Soc Clin Oncol
Educ Book 39:E1–E7
Liu Z, Gao X, Kang T, Jiang M, Miao D, Gu G, Hu Q, Song Q, Yao L, Tu Y, Chen H, Jiang X, Chen
J (2013) B6 peptide-modied peg-Pla nanoparticles for enhanced brain delivery of neuropro-
tective peptide. Bioconjug Chem 24:997–1007
Maeda H, Bharate GY, Daruwalla J (2009) Polymeric drugs for efcient tumor-targeted drug deliv-
ery based on Epr-effect. Eur J Pharm Biopharm 71:409–419
Mangalath U, Aslam SA, Abdul Khadar AH, Francis PG, Mikacha MS, Kalathingal JH (2014)
Recent trends in prevention of Oral cancer. J Int Soc Prev Community Dent 4:S131–S138
A. Tiwari et al.
13 Multifunctional PEGylated Nanoparticles inTheragnosis
Martínez-Jothar L, Doulkeridou S, Schiffelers RM, Sastre Torano J, Oliveira S, Van Nostrum
CF, Hennink WE (2018) Insights into Maleimide-thiol conjugation chemistry: conditions for
efcient surface functionalization of nanoparticles for receptor targeting. J Control Release
282:101–109
Mourdikoudis S, Pallares RM, Thanh NTK (2018) Characterization techniques for nanopar-
ticles: comparison and complementarity upon studying nanoparticle properties. Nanoscale
10:12871–12934
Mulder WJ, Strijkers GJ, van Tilborg GA, Cormode DP, Fayad ZA, Nicolay K (2009)
Nanoparticulate assemblies of Amphiphiles and diagnostically active materials for multimo-
dality imaging. Acc Chem Res 42(7):904–914. https://doi.org/10.1021/ar800223c
Owens DE 3rd, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of poly-
meric nanoparticles. Int J Pharm 307:93–102
Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerg-
ing platform for cancer therapy. Nat Nanotechnol 2:751–760
Rahme K, Dagher N (2019) Chemistry routes for copolymer synthesis containing peg for target-
ing, imaging, and drug delivery purposes. Pharmaceutics 11:11
Ren Y, Wang X, Liang H, He W, Zhao X (2021) Mechanism of Mir-30b-5p-loaded Peg-Plga
nanoparticles for targeted treatment of heart failure. Front Pharmacol 12:745429
Salmaso S, Caliceti P (2013) Stealth properties to improve therapeutic efcacy of drug nanocarri-
ers. J Drug Deliv 2013:374252
Santos AO, Da Silva LCG, Bimbo LM, De Lima MCP, Simões S, Moreira JN (2010) Design
of peptide-targeted liposomes containing nucleic acids. Biochim Biophys Acta Biomemb
1798:433–441
Sarata AK and Johnson JA (2014) Regulation of clinical tests: In Vitro Diagnostic (Ivd) Devices,
Laboratory Developed Tests (Ldts), and genetic tests
Suk JS, Xu Q, Kim N, Hanes J, Ensign LM (2016) Pegylation as a strategy for improving
nanoparticle- based drug and gene delivery. Adv Drug Deliv Rev 99:28–51
Torchilin VP (2007) Targeted pharmaceutical Nanocarriers for cancer therapy and imaging. AAPS
J 9:E128–E147
Veronese FM, Harris JM (2002) Introduction and overview of peptide and protein Pegylation. Adv
Drug Deliv Rev 54:453–456
Weissleder R, Pittet MJ (2008) Imaging in the era of molecular oncology. Nature
452(7187):580–589. https://doi.org/10.1038/nature06917
Wu J (2021) The enhanced permeability and retention (Epr) effect: the signicance of the concept
and methods to enhance its application. J Pers Med 11:771
Yim MS, Hwang YS, Bang JK, Jung D-W, Kim JM, Yi G-R, Lee G, Ryu EK (2021) Morphologically
homogeneous, Ph-responsive gold nanoparticles for non-invasive imaging of Hela cancer.
Nanomedicine 34:102394
Younis U, Rahi AA, Danish S, Ali MA, Ahmed N, Datta R, Fahad S, Holatko J, Hammerschmiedt
T, Brtnicky M, Zarei T, Baazeem A, Sabagh AE, Glick BR (2021) Fourier transform infrared
spectroscopy vibrational bands study of Spinacia Oleracea and Trigonella Corniculata under
biochar amendment in naturally contaminated soil. PLoS One 16:E0253390
Zhou B, Zheng L, Peng C, Li D, Li J, Wen S, Shen M, Zhang G, Shi X (2014) Synthesis and char-
acterization of Pegylated Polyethylenimine-entrapped gold nanoparticles for blood Pool and
tumor Ct imaging. ACS Appl Mater Interfaces 6:17190–17199
Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, Durazzo A, Lucarini M,
Eder P, Silva AM, Santini A, Souto EB (2020) Polymeric nanoparticles: production, character-
ization, toxicology and ecotoxicology. Molecules 25:3731
383
Reversible PEGylation ofNanocarriers
MahimaMishra, SweetyShah, GagandeepKaur,
AniketNavale, HeetJani, VaishnaviChinkure,
andRakeshKumarTekade
Abstract
Nanocarriers have transformed drug delivery by providing targeted and regulated
distribution of therapeutic agents, as a result increasing efcacy and decreasing
side effects. Among the various approaches used to maximize the performance of
nanocarriers, polyethylene glycol (PEG)ylation has attracted a lot of interest due
to its capacity to improve biocompatibility and extend the duration of circulation
invivo. Conventional PEGylation, often result in unsatisfactory therapeutic pay-
load delivery and less cellular absorption. A potential solution to these issues is
reversible PEGylation, which preserves effective drug release with cellular
incorporation while providing the advantages of extended circulation. This
review examines the principles and uses of reversible PEGylation in drug deliv-
ery and nanocarrier design. At one point, the review also examines the effects of
reversible PEGylation concerning the pharmacokinetics, biodistribution and col-
loidal stability of nanocarriers. A discussion on the translational opportunities
and difculties related to reversible PEGylation, including stability, scalability,
and regulatory issues is also incorporated.
14
M. Mishra · S. Shah · G. Kaur · A. Navale · H. Jani · V. Chinkure
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, Opp. Air force station, Gandhinagar,
Gujarat, India
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, Opp. Air force station, Gandhinagar,
Gujarat, India
e-mail: rakeshtekade@niperahm.res.in
385
386
Keywords
M. Mishra et al.
Reversible PEGylation · Nanocarriers · Polyethylene glycol (PEG) · Stimuli-
responsive polymers · Cleavable linkers · pH-sensitive
14.1 Introduction
14.1.1 Nanocarrier inDrug Delivery
Pharmaceutical nanocarriers are extremely versatile, nanosized drug delivery system comprising liposomes, nanotubes, nanocomplexes, niosomes, polymeric,
lipidic, and inorganic nanoparticles, among many more. Drug delivery systems
using nanocarriers offer a cutting-edge approach for enhancing the effectiveness
and accuracy of medication delivery (Alshawwa etal. 2022). These nanoscale carriers are intended to carry and distribute pharmaceutical substances, such as medications or genetic material, to particular target locations within the body. The
principal objective is to optimize the therapeutic outcome while mitigating adverse
reactions and lowering the treatment’s overall toxicity. While nanocarrier-based
drug delivery systems seem promising, there are still issues to be resolved, such as
concerns regarding their long-term safety, their ability to be scalable for mass production, their possible toxicity, and their uptake by the reticuloendothelial system
(RES) (Sun etal. 2015a).
14.1.2 PEGylation ofNanocarriers andIts Role
Nanostructures like solid lipid nanoparticles, polymeric nanoparticles, liposomes,
micelles, and dendrimers offer several benets, including the ability to deliver drugs
to particular sites, defense against enzymatic degradation, low toxicity, stability,
enhanced drug solubility, and the possibility of controlled release (Veronese and
Pasut 2005). When creating sophisticated drug delivery systems, one typical tactic
is to coat the surface of nanocarriers with substances that improve therapeutic delivery behavior. Although the synthesis of nanocarriers has advanced, little is understood about how they behave in intricate biological systems (Shete etal. 2022). The
creation of a protein corona, primarily made up of plasma proteins like albumin,
causes alterations in the surfaces of nanocarriers upon exposure to biological uids.
The properties of nanomedicines, including as size, surface charge, aggregation
resistance, and hydrodynamic size, can all be strongly impacted by this corona.
Thus, these modications could affect biodistribution, targeting ability, and biocompatibility—underscoring the need to take the protein corona into account when
developing “smart” nanomedicines (Vllasaliu etal. 2014). Opsonization and absorption by the RES frequently result in unaltered nanostructures having short plasma
half-lives (Thakur etal. 2015).