PEGylation in anti-cancer therapy: an overview (original) (raw)
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Nanoparticle PEGylation for Cancer Therapy
Nanoparticles (NPs) are particles between 1 and 100 nanometers in size. They are currently the most sought-after and studied field of science, and have become the materials of choice in various nanomedicine applications due to their uniqueness in interacting with a plethora of materials including polyethylene glycol (PEG). This revie discusses the nature, uses, benefits and challenges of using PEG in nanoformulations for cancer therapy.
Current drug research on PEGylation with small molecular agents
Progress in Polymer Science, 2013
PEGylation, covalent attaching polyethylene glycol (PEG) polymers to therapeutic agents, is one of the most promising techniques to improve the therapeutic effect of drugs. Initially, this technology is mainly applied with macromolecular drugs, such as proteins, enzymes, with ten PEGylated biomacromolecules approved by the FDA for the treatment of related diseases. The clinical successful use of PEGylated macromolecular drug has promoted the application of this technology with small molecules drugs to overcome shortcomings associated with therapy, such as possible low solubility, high toxicity, undesirable pharmaceutical characteristics and nonspecific biodistribution profiles. So far, four PEGylated small drugs have been taken into clinical trials. This review mainly focuses on the recent advances of PEGylated small molecules, including their general configuration, and the current merits and limits of PEG modification. Herein PEG delivery systems are distinguished by therapeutic application (anti-tumor, anti-inflammatory, etc.) and their corresponding PEGylated small molecules are described in detail.
Pegylation: Concept and Applications in Cancer Therapeutics
INDIAN DRUGS, 2014
Polyethylene glycol-ylation (PEGylation) is a phenomenon of modification of a protein, peptide, or non-peptide molecule by linking of one or more polyethylene glycol chains. These synthetic polymers have received FDA approval for internal use. It is an effective method of delivering therapeutic proteins as it modifies their pharmacokinetic properties. The PEG-drug conjugates have several advantages - prolonged residence in body, decreased degradation by metabolic enzymes and reduction or elimination of protein immunogenicity. The delivery of several classes of protein drugs (including protein scaffolds, enzymes, cytokines and antibodies) is significantly improved by PEG-drug conjugate and they are useful in treating chronic diseases such as hepatitis C, leukemia, acromegaly, severe combined immunodeficiency disease (SCID), chronic gout, rheumatoid arthritis, and Crohn’s disease. This review envisages an overview of PEGylation and its applications in cancer therapeutics. PEGylation t...
PEGylation: An Approach for Drug Delivery. A Review
Critical Reviews in Therapeutic Drug Carrier Systems, 2008
The current review presents an update on polyethylene glycol (PEG), which is widely used as a covalent modifier of macromolecules. This review discusses the polymers suitable for conjugation, their conjugation methods, and their properties. Proteins and bioactive substances can be chemically modified by binding synthetic macromolecules of PEG to the surface of these biomolecules. Protein and peptide PEGylation improves the biopharmaceutical properties of drugs-that is, increased stability, increased resistance to proteolytic inactivation, decreased to nonexistent immunogenicity, increased circulatory lives, and low toxicity. These altered properties improve the delivery and efficacy of proteins.
pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery
Biomaterials, 2013
To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG 2000), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG 3400 (DSPE-PEG 3400-2C5), and poly(ethylene glycol)-coupled poly(Lhistidine) (PHIS-PEG 2000). The structure of PHIS-PEG 2000 was confirmed by 1 H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50wt% of PHIS-PEG 2000 showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG 2000. At pH around 5.5, about 75-95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome-specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG 2000 /DSPE-PEG 3400-2C5/PHIS-PEG 2000) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy.
PEGylated nanoparticles for biological and pharmaceutical applications
Advanced Drug Delivery Reviews, 2012
The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core-shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptormediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.
Review on Impact of Pegylation on Biopharmaceuticals
International Journal of Health Sciences (IJHS), 2022
Covalent conjugation of polyethylene glycol (PEG) molecules to biopharmaceutical molecules is known to increase the pharmacological and medicinal characteristics of proteins and other big molecules and has been utilized effectively in 12 authorized medications. PEG reagents with straight and branched chains up to 40 kDa were utilized with a variety of PEG derivatives with varied linker chemistries. This article discusses the characteristics of PEG, the history and evolution of PEGylation chemistry, and examples of PEGylated pharmaceuticals with a proven track record. They prefer to employ bigger PEG polymers and complicated PEG structures, although they use extremely pure and well-characterized PEG reagents. The preclinical toxicity data for PEG in PEGylated biologics 6623 that have been authorized are summarised. Microscopically detected cell vacuolization in phagocytes, which is connected to the biological function of absorption and elimination of particles and macromolecules from blood and tissues. It's possible. Side effects in toxicity tests typically relate to the active moiety of the medicine, not the PEG moiety, according to experience with commercially available PEGylated pharmaceuticals.
Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers
Biomaterials, 2015
A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (~80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.
PEGylation, successful approach to drug delivery
Drug Discovery Today, 2005
PEGylation defines the modification of a protein, peptide or non-peptide molecule by the linking of one or more polyethylene glycol (PEG) chains. This polymer is nontoxic, non-immunogenic, non-antigenic, highly soluble in water and FDA approved. The PEG-drug conjugates have several advantages: a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. Thanks to these favorable properties, PEGylation now plays an important role in drug delivery, enhancing the potentials of peptides and proteins as therapeutic agents.
Nanomedicine
Aim: pH-sensitive liposomes (pSL) have emerged as promising nanocarriers due to their endo/lysosome-escape abilities, however, their pH sensitivity is compromised by poly(ethylene glycol) (PEG) coating. This study investigates whether an intracellular PEG-detachment strategy can overcome this PEG dilemma. Materials & methods: First, PEG2000 was conjugated with a phospholipid via an acid-labile hydrazide–hydrazone bond (–CO–NH–N = CH–), which was postinserted into pSL, forming PEG-cleavable pSL (CL-PEG-pSL). Their endo/lysosomal-escape abilities in MIA PaCa-2 cells, pharmacokinetics and tumor accumulation abilities were studied using PEG-pSL as reference. Results: CL-PEG-pSL showed rapid endo/lysosome-escape abilities in the cancer cells and higher tumor accumulation in MIA PaCa-2 xenograft model in contrast to PEG-pSL. Conclusion: Cleavable PEGylation is an efficient strategy to ameliorate the PEG dilemma of pSL for cancer drug delivery.