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16 Beyond PEGylation “PEGylation andits Alternatives”
477
(c) Additionally, polypeptides can be customized with specic sequences and
lengths, allowing for precise control over their properties and interactions with
other molecules, making them valuable for tailoring drug delivery systems to
specic therapeutic needs.
(d) Polypeptides offer diverse functionalities, including amino acids with side
chains, which can be used for drug conjugation and targeting ligands.
(e) They are naturally compatible with biological systems, allowing them to inter-
act more effectively with cells, tissues, and biological molecules than synthetic
polymers.
(f) Some polypeptides, like β-sheet-forming peptides, can self-assemble into sta-
ble secondary structures, enhancing drug delivery and controlled release.
Polypeptides are particularly useful in applications like tissue engineering,
wound healing, and regenerative medicine, as they mimic extracellular matrix
components and are biocompatible with biological structures (Hosseinkhani
etal. 2013).
Excluding hydrophobic and highly polar amino acids from a polypeptide
sequence increases drug delivery or the system’s solubility. Taking advantage of this
benet, the circulation half-life of the drug can be enhanced by using homopolymers of genetically encoded amino acids (Bolze etal. 2016; Falvo etal. 2016). PAS,
a polypeptide composed of proline, alanine, and serine, was biodegradable and
hydrophilic, with a large hydrodynamic volume and surface charge. The highly
soluble formulation not only showed antihemolytic activity but was also distributed
and cleared similarly to PEG.PASylation is dened as “the genetic infusion of a
conformationally unfolded homopolymer of PAS with therapeutic proteins or
drugs” (Harari etal. 2014; Kuhn et al. 2016). In mouse models, the stability of
PASylated products was demonstrated in serum, with no organ distribution and
minimal immunogenicity and toxicity. Though this class of products is yet to be
investigated in the clinic, they have been widely employed to extend the systemic
circulation of leptins, antibody fragments, chemotherapeutics, interferons, and
growth hormones and for various therapeutic as well as diagnostic purposes
(Mendler etal. 2015; Morath etal. 2015; Schlapschy etal. 2013). Another study
reported an intriguing genetic fusion of XTEN, a polypeptide sequence, with a protein that resulted in a 60-fold increase in plasma half-life. XTEN is a hydrophilic,
stable homopolymer with an indenite structure. It is non-immunogenic and consists of certain amino acid sequences (alanine, glutamic acid, glycine, proline, serine, threonine). XTEN fusions have been further extended to glucagon, factor VII,
green uorescent protein, and human growth hormone to improve the efcacy of the
respective systems in diverse invivo models (Podust etal. 2016; Schellenberger
etal. 2009; Strohl 2015).
Polypeptides offer advantages like enzymatic degradation and structural stability, but may also face challenges in large-scale production. The choice between PEG
and polypeptides depends on the drug delivery system’s requirements and desired
properties, and researchers carefully consider these factors when selecting the most
suitable polymer (Fig.16.14).
478
Fig. 16.14 Chemical structure of cyclized polypeptide as an alternative to PEG
S. Mohanta et al.
Fig. 16.15 Structure of carbohydrate-based polymers
16.5.9 Carbohydrate-Based Systems
Carbohydrates, nucleic acids, and proteins are important natural macromolecules
for life. Synthetic carbohydrates can be good candidates for applications in polymer
and pharmaceutical research. They can have a linear, comb-type, branched, or
dendrimer- like structure (Tolstyka etal. 2016) (Fig.16.15).
Carbohydrate-based systems exhibit a PEG-like effect due to their hydrophilicity
and steric hindrance, which form a protective layer on drug delivery systems or
biomaterials. This layer minimizes protein adsorption, extending the circulation
time and enhancing bioavailability. Carbohydrate-based systems can also mimic
glycoproteins and glycolipids found on cell surfaces, effectively “camouaging”
themselves from the immune system. This molecular mimicry can reduce immune
responses and prevent immune-mediated clearance of the drug delivery system.
Carbohydrates are biocompatible, making them suitable for drug delivery reducing
the likelihood of adverse reactions or immunogenicity. The chemistry in their conjugation is crucial in understanding these mechanisms (Moros etal. 2012).
16 Beyond PEGylation “PEGylation andits Alternatives”
479
Carbohydrate-based systems can be conjugated to drug carriers, nanoparticles,
or other substrates through various chemical reactions. The specic chemistry used
depends on the functional groups on the carbohydrate and the substrate’s surface.
Carbohydrates can be functionalized with specic reactive groups, such as amino
(-NH2), carboxyl (-COOH), or thiol (-SH) groups, during synthesis or chemical
modications. Chemical conjugation can occur through amidation, thiol-disulde
exchange, or carbodiimide-mediated coupling. If both carbohydrate and substrate
have compatible functional groups, they can be covalently linked to form a stable
bond. Some carbohydrate-based systems can be conjugated using enzymatic or glycosylation reactions, mimicking natural glycosylation processes in living organisms. The carbohydrate-based system and chemistry choice depend on the
application and desired drug delivery properties. Carbohydrate-based systems offer
an attractive alternative to PEG, providing similar benets in drug delivery and
biomaterials while aligning with the biocompatibility of natural carbohydrates (Su
etal. 2021).
Aside from their biological activities, they are suitable candidates for PEG substitutes due to intrinsic qualities that render them chemically well-dened, compact,
biocompatible, highly hydrated, synthetically exible, and less susceptible to aggregation and protein adsorption. Both polysaccharides (dextran, starch, hydroxyethyl
starch (HES), and hyaluronic acid) and oligosaccharides (from one to twelve sugar
units) have been widely investigated. Dextran-coated nanocarriers, like PEG and
HES, have demonstrated low protein adsorption and prolonged circulation durations (Besheer etal. 2007). Carbohydrates, combined with their active biological
role of interacting with cell surfaces or specic proteins, have emerged as desirable
candidates for biotherapeutic applications (Sizovs etal. 2013; Luyckx and Baudouin
2011). Trehalose is an exciting example of a naturally occurring disaccharide. It is
a nonreducing sugar with glucose units joined by α,α’-1,1-glucosidic bond, another
compelling example of a carbohydrate. It has shown fascinating biochemical properties, rendering them appealing for research in academia and industry (Gu
etal. 2014).
16.5.10 Hydrophilic Polymers
Hydrophilic polymers have numerous applications, including drug delivery (Knop
et al. 2010; Hildebrand et al. 2017), self-assembly (Willersinn et al. 2017), and
catalysis (Ge et al. 2007). As a result, research into hydrophilic polymers is an
essential aspect of polymer science. Signicant areas of investigation have been
structure-property relationships and their interactions with biological entities
(Rudolph etal. 2013; Takahashi etal. 2018; Cuomo etal. 2012). Synthetic polymer
chemistry offers new possibilities for advanced characteristics and prospects using
innovative hydrophilic polymers and structures (Liu etal. 2018; Mccormick and
Lowe 2004). Hydrophilic polymers have essential features not just when dissolved
but also when crosslinked, as in the case of hydrogels. This class of materials has
various intriguing features as well as customizable size and morphology, which are
480
S. Mohanta et al.
of great importance for pharmaceutical applications (Thiele etal. 2014). Hydrophilic
polymers include poly(acrylamide) and poly(ethylene glycol) (PEG). It has to be
noted that some polymers, such as poly(2-hydroxyethyl methacrylate), are hydrophilic and water-swellable albeit with poor aqueous solubility. Even for hydrophilic
polymers, water solubility varies according to polymer concentration, type, and
molecular weight. As a result, they may not be distinguished based just on solubility
(Schmidt 2019) (Fig.16.16).
Hydrogels are hydrophilic polymer materials known for their biocompatibility,
swelling, and soft texture. They nd applications in areas such as tissue engineering
and implants. Reports have described polymer self-assembly combined with hydrogel formation has been described, with the double hydrophilic block copolymer
poly(N-vinylpyrrolidone)-b-poly (oligo ethylene glycol methacrylate) coupled with
α-cyclodextrin (α-CD). This results in thermo-responsive hydrogels that exhibit distinct mechanical properties upon cooling to room temperature (Jiang etal. 2016).
Cyclic cyclodextrin (CD) can not only be applied for gelation but can also be utilized in stimulus-responsive hydrogels for drug entrapment. Bian etal. synthesized
an amphiphilic polymer by combining hydrophilic acrylamide, hydrophobic
N-dodecyl acrylamide, and sodium acrylate, which delayed the formation of phenolic network crosslinking points (Xu etal. 2019). Cuomo and coworkers described a
Fig. 16.16 Chemical structure of epoxy poly(AAG-AA), a hydrophilic polymer
16 Beyond PEGylation “PEGylation andits Alternatives”
481
hydrogel based on an emulsion of alginate and lemon grass essential oil, which was
studied for mechanical properties.
Thiele and coworkers reported a polysaccharide hydrogel targeting microgels via
microuidics (Hauck etal. 2018). Combining chitosan or hyaluronic acid with tertbutyl isocyanide and a PEG crosslinker allowed for the fabrication of mono- disperse
microgels with sizes in the 70–100μm range. Functional microgels were formed by
adding functional carboxylic acids in the Ugi crosslinking reaction, potentially
valuable for drug delivery. Lensen and coworkers described the microstructure of
PEG-based hydrogels, revealing the strong effect of the polymerization process on
the size of crystalline domains. With this understanding, crystallization behavior in
PEG-based hydrogels can be ne-tuned to improve material properties (Zhang
etal. 2018).
Reinforcement via nanoparticles has also been explored to investigate the formation and mechanical properties of Laponite/cellulose-based hydrogels (Xie etal.
2018). When Laponite was combined with silanized hydroxypropyl methylcellu-
lose, a signicant reinforcement effect was observed, increasing the storage modulus by an order of magnitude. Fluorescent microsphere tracking analysis was used
to investigate the hydrogel architecture, revealing two domains: loose aggregates in
the periphery and dense Laponite structures in the core.
Hydrophilic polymers have been applied in the biomedical eld with advances in
drugs and vaccines in the form of polymeric nanomaterials. These nanoparticles
exhibit targeted delivery and sustained release (Secker etal. 2015). Poly(peptoids)
have gained attention, with Barz et al. developing siRNA polyplexes with
poly(sarcosine) as a shielding agent. They reported the formation of lipo-oligomer
structure and siRNA polyplexes, with the oligomer consisting of cholanic acids
coupled through a bioreducible disulde linker. The ability to shield was tested
using invivo imaging and biophysical assays, revealing prolonged systemic circulation time on par with the gold standard PEG (Klein etal. 2018) (Table16.1).
16.5.11 Non-PEGylated Nanoparticles
Non-PEGylated microparticles and nanoparticles (Fig. 16.17), mainly inorganic
nanoparticles such as iron, gold, silver, hafnium, ceramic silica, and carbon nanotubes, have sparked considerable interest in tissue engineering, drug delivery, and
diagnostic formulations (Anselmo and Mitragotri 2015, 2016). Metal nanoparticles
with about 1–100nm diameters are appealing owing to their distinct physicochemical characteristics, such as enhanced surface-area-to-volume ratio, small size, and
conductivity. They are also amenable to surface modication and can be designed to
respond to external stimuli with pharmacokinetics suitable for systemic delivery
(Huang etal. 2011). Because of their increased permeability and retention, nanoparticles preferentially concentrate at malignant tumor sites.
Non-PEGylated nanoparticles can be modied to achieve a PEG-like effect
through chemical reactions and surface functionalization. These methods include
hydrophilic coating, ligand attachment, surface modication, and stealth coatings.
482
Table 16.1 Comparison between different alternative polymers for PEG
Name of Polymer
Polyzwitterions Chemical exibility,
Polyglycerols (PGs) Biocompatibility, easy
Polyvinyl pyrolidones
(PVP)
Polyoxazolines (Pox) Low PDI values,
Polyacrylamides Easy functionalization
Poly[oligo(ethylene
glycol) methyl ether
methacrylate]
(POEGMA)
Polyamino acids Biodegradable,
Carbohydrate-based Biodegradable, low
Advantages Disadvantages
Nondegradable, high
zwitterionic nanovectors,
biocompatibility,
non-fouling, prolonged
blood circulation, and
multifunctionality
synthesis, immune
invasion, and prolonged
circulation due to
hyperbranched
polyglycerol (HPG)s
Biocompatible and
stabilizer
exible end-group
chemistry,
biodegradability, and
biocompatibility
due to hydroxyl groups,
Biocompatible and
fouling
Biocompatible, Easy
chemical modication,
Thermoresponsive,
Biodegradable
Decreased ABC
phenomenon,
Biocompatible
immunogenicity,
nontoxic, easy chemical
modication,
biocompatible
synthesis and
modication cost
Nonbiodegradability,
accumulation in tissues
Enhanced protein
adsorption, slower
biodegradation
Higher synthesis cost
and no FDA approval
Nonbiodegradability,
degradation by thermal
and photolytic effect,
resultant monomer gives
neurotoxic effect
Microbial
contamination, excessive
hydration, and reduced
viscosity on storage
Variable chemistry,
broad or mixed
molecular weights
S. Mohanta et al.
Reference
Qian etal.
(2022), Zheng
etal. (2017)
Hoang Thi etal.
(2020)
Hadjesfandiari
and Parambath
(2018), Knop
etal. (2010)
Hoang Thi etal.
(2020)
Hadjesfandiari
and Parambath
(2018), Knop
etal. (2010)
Lutz (2008)
Boddu etal.
(2021)
Barclay etal.
(2019), Hoang
Thi etal. (2020)
Hydrophilic polymers like dextran, chitosan, or albumin can be conjugated to the
nanoparticle’s surface through covalent bonding (Salatin and Yari Khosroushahi
2017). Ligands, peptides, or biomimetic materials can enhance biocompatibility
and enable targeted drug delivery. Surface modications, such as adsorption or
encapsulation of hydrophilic materials, create a hydrophilic shell around the
nanoparticles. Stealth coatings can be formed using materials like zwitterions or
synthetic polymers.
16 Beyond PEGylation “PEGylation andits Alternatives”
Fig. 16.17 Structure of a
non-PEGylated
nanoparticle
483
Non-PEGylated nanoparticles should be synthesized and characterized to meet
high standards of quality, purity, and consistency. Biocompatibility testing should
be conducted to evaluate safety and interactions with biological systems. Sterility
should be maintained during preparation and handling, especially in medical and
biological applications. Chemical compatibility should be veried to avoid degradation, reduced efcacy, or undesired by-products. Dosage optimization should be
determined for each specic application, as excessive amounts may not improve
effectiveness or lead to undesirable side effects.
Non-PEGylated gold nanoparticles are used in cancer therapeutic applications
like drug delivery and photothermal therapy due to their high biocompatibility, minimal cytotoxicity, and low immunogenicity. They are compatible with biological
systems and have limited inammation and foreign body responses. Toxicity studies show no acute toxicity, but thorough characterization and purication are crucial. Sterile handling is essential to prevent contamination. The optimal dosage and
concentration should be determined for each cancer therapeutic application. The
safety prole varies depending on the nanoparticles used and their application, and
comprehensive safety assessments and studies are essential. Researchers should reference peer-reviewed sources for safety assessments and research (Gamucci
etal. 2014).
Metal nanoparticle-based therapeutic systems are being investigated in various
stages of preclinical and clinical development for the therapy as well as diagnosis of
diseases such as cancer, liver cirrhosis, and anemia. While more research is warranted to understand the long-term effects of nanoparticles, current treatment
options can be improved by enhancing bioavailability and efcacy via an approach
that combines inorganic metal nanoparticles conjugated to small molecule entities
(Na etal. 2009).
16.6 Future Prospects
Although the FDA has approved natural polymers such as polypeptides, polysaccharides, and nucleotides for various indications, scientists have tried to develop
synthetic polymers that can perform better. Among other synthetic polymers, linear
PEG has been demonstrated to be superior for multiple applications.
484
S. Mohanta et al.
Even though PEGylation provides numerous benets, new research has shown
critical shortcomings such as immune activation, poor degradability, and potential
aggregation. The enormous advances in macromolecular engineering and polymer
chemistry have aided in exploring substitutes for PEG that can address the abovementioned limitations. Polymeric systems such as poly(glycerol)s,
poly(vinylpyrrolidone), poly(amino acid)s, poly(N-(2-hydro-xypropyl) methacrylamide), and poly(2-oxazoline)s have shown potential as far as hydrophilicity, aqueous solubility, stealth properties, and biocompatibility are concerned. However,
none of them have been approved by the FDA yet, and further research is required
to properly evaluate and compare them with PEG through a comprehensive analysis
of polymer structure as well as cellular interactions.
16.7 Conclusion
PEGylation is, without a doubt, a very versatile and effective bioconjugation
method. PEGylation of nanoparticles allows for effective transport of hydrophobic
medicines, prolongs systemic circulation, enhances mucus penetration, and
improves the stability of biotherapeutics. As a result, PEGylation has emerged as an
invaluable technique for nanomedicine modication to enable the development of
safe and efcacious drug delivery systems. Nonetheless, the anti-PEG immune
response is a vexing problem that compromises the safety of drugs. So far, potential
PEG alternatives are yet to be successfully translated to the clinic. Studies investigating the immunogenic potential of PEG have demonstrated that the clearance of
subsequent doses of the drug can be primarily attributed to the anti-PEG antibodies
produced after the rst dose. If the patient has preexisting antibodies due to prior
exposure to PEG in domestic or cosmetic goods, the rst dose can elicit an immune
response. It is, therefore, critical to understand the parameters that inuence the
development of anti-PEG antibodies to design innovative drug vectors or change the
injection schedule and/or administration route and achieve therapeutic efcacy.
While PEG alternatives will be aggressively investigated in the near future, we
believe that PEG will continue to be extensively used for bioconjugation to enable
effective drug delivery.
Acknowledgments The author RKT acknowledges the Department of Pharmaceuticals, Ministry
of Chemicals and Fertilizers, India, for supporting the drug discovery and formulation research at
NIPER Ahmedabad. R.K.T also acknowledges the Department of Science and Technology,
Government of India, for a Core Research Grant funding (File No. CRG/2021/005402) and also
acknowledges the Indian Council of Medical Research (ICMR), New Delhi, for the grant File Id:
2021-14161 and grant File Id: IIRP-2023-4849/F1 for supporting research in RKT lab.
16 Beyond PEGylation “PEGylation andits Alternatives”
485
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