Key words: polyethylene glycol; PEGylation; biomedicine; pharmaceutics; proteins.
- Abstract
- References
- How to cite
Polyethylene glycol (PEG) is one of the most versatile tools in pharmaceutics and biomedicine, combining high biocompatibility with a wide range of functional capabilities. The demand for PEG and its derivatives is steadily increasing due to the dynamic expansion of the biotechnology drug market and the development of personalized and targeted therapies.
The paper considers the physicochemical properties of PEG and presents the systemized derivatives of the polymer. Particular attention is paid to the technology of protein PEGylation: the modification methods are analyzed, and the study demonstrates how this process alters the therapeutic and pharmacodynamic profiles of biopharmaceuticals.
The review highlights the key areas of PEG application: fr om traditional use as a solvent and an excipient to cutting-edge solutions in targeted drug delivery and polymer matrices for regenerative medicine. An important part of the work is the analysis of the regulatory aspects governing the distribution of PEG-modified drugs, both within the international legal framework and within the Russian Federation.
PEG is a revolutionary medical tool of the XXI century. In the modern paradigm, it is viewed not as a mere excipient but as a multifunctional, high-tech agent with proven clinical efficacy that provides an innovative approach to solving medical challenges.
1. Hornsby B.D., Lee C.H., Steele C.A., Tuekpe J.K.K., Lim C.S. Therapeutic peptides and proteins: status and developments in drug delivery. J Control Release 2026; 394: 114895, https://doi.org/10.1016/j.jconrel.2026.114895.
2. Polyethylene glycol market (2026–2033). URL: https://www.grandviewresearch.com/industry-analysis/polyethylene-glycol-peg-market.
3. Polyethylene glycol market report. URL: https://www.marketsandmarkets.com/Market-Reports/polyethylene-glycol-market-83158233.html.
4. Christoforou I., Kalatzis A., Siamidi A., Vlachou M., Pispas S., Pippa N. The ubiquitous use of polyethylene glycol in pharmaceutical design and development: technological aspects and future perspectives. Nanomaterials (Basel) 2025; 15(23): 1762, https://doi.org/10.3390/nano15231762.
5. Santhanakrishnan K.R., Koilpillai J., Narayanasamy D. PEGylation in pharmaceutical development: current status and emerging trends in macromolecular and immunotherapeutic drugs. Cureus 2024; 16(8): e66669, https://doi.org/10.7759/cureus.66669.
6. Wang Z., Ye Q., Yu S., Akhavan B. Poly ethylene glycol (PEG)-based hydrogels for drug delivery in cancer therapy: a comprehensive review. Adv Healthc Mater 2023; 12(18): e2300105, https://doi.org/10.1002/adhm.202300105.
7. Moayedi S., Xia W., Lundergan L., Yuan H., Xu J. Zwitterionic polymers for biomedical applications: antimicrobial and antifouling strategies toward implantable medical devices and drug delivery. Langmuir 2024; 40(44): 23125–23145, https://doi.org/10.1021/acs.langmuir.4c02664.
8. Bento C., Katz M., Santos M.M.M., Afonso C.A.M. Striving for uniformity: a review on advances and challenges to achieve uniform polyethylene glycol. Org Process Res Dev 2024; 28(4): 860–890, https://doi.org/10.1021/acs.oprd.3c00428.
9. Gabizon A.A., Gabizon-Peretz S., Modaresahmadi S., La-Beck N.M. Thirty years from FDA approval of PEGylated liposomal doxorubicin (Doxil/Caelyx): an updated analysis and future perspective. BMJ Oncol 2025; 4(1): e000573, https://doi.org/10.1136/bmjonc-2024-000573.
10. Gao Y., Joshi M., Zhao Z., Mitragotri S. PEGylated therapeutics in the clinic. Bioeng Transl Med 2024; 9(1): e10600, https://doi.org/10.1002/btm2.10600.
11. Padín-González E., Lancaster P., Bottini M., Gasco P., Tran L., Fadeel B., Wilkins T., Monopoli M.P. Understanding the role and impact of poly (ethylene glycol) (PEG) on nanoparticle formulation: implications for COVID-19 vaccines. Front Bioeng Biotechnol 2022; 10: 882363, https://doi.org/10.3389/fbioe.2022.882363.
12. Li C., Li T., Tian X., An W., Wang Z., Han B., Tao H., Wang J., Wang X. Research progress on the PEGylation of therapeutic proteins and peptides (TPPs). Front Pharmacol 2024; 15: 1353626, https://doi.org/10.3389/fphar.2024.1353626.
13. Herzberger J., Niederer K., Pohlit H., Seiwert J., Worm M., Wurm F.R., Frey H. Polymerization of ethylene oxide, propylene oxide, and other alkylene oxides: synthesis, novel polymer architectures, and bioconjugation. Chem Rev 2016; 116(4): 2170–2243, https://doi.org/10.1021/acs.chemrev.5b00441.
14. Burggraef M.J., Oxley A., Zaidi N.A., Cutillas P.R., Gaffney P.R.J., Livingston A.G. Exactly defined molecular weight poly(ethylene glycol) allows for facile identification of PEGylation sites on proteins. Nat Commun 2024; 15(1): 9814, https://doi.org/10.1038/s41467-024-54076-6.
15. Shi D., Beasock D., Fessler A., Szebeni J., Ljubimova J.Y., Afonin K.A., Dobrovolskaia M.A. To PEGylate or not to PEGylate: immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives. Adv Drug Deliv Rev 2022; 180: 114079, https://doi.org/10.1016/j.addr.2021.114079.
16. Banerjee S.S., Aher N., Patil R., Khandare J. Poly(ethylene glycol)-prodrug conjugates: concept, design, and applications. J Drug Deliv 2012; 2012: 103973, https://doi.org/10.1155/2012/103973.
17. Belén L.H., Rangel-Yagui C.O., Beltrán Lissabet J.F., Effer B., Lee-Estevez M., Pessoa A., Castillo R.L., Farías J.G. From synthesis to characterization of site-selective PEGylated proteins. Front Pharmacol 2019; 10: 1450, https://doi.org/10.3389/fphar.2019.01450.
18. Makharadze D., Del Valle L.J., Katsarava R., Puiggalí J. The art of PEGylation: from simple polymer to sophisticated drug delivery system. Int J Mol Sci 2025; 26(7), https://doi.org/10.3390/ijms26073102.
19. Turecek P.L., Bossard M.J., Schoetens F., Ivens I.A. PEGylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs. J Pharm Sci 2016; 105(2): 460–475, https://doi.org/10.1016/j.xphs.2015.11.015.
20. Zuma L.K., Gasa N.L., Makhoba X.H., Pooe O.J. Protein PEGylation: navigating recombinant protein stability, aggregation, and bioactivity. Biomed Res Int 2022; 2022: 8929715, https://doi.org/10.1155/2022/8929715.
21. Milla P., Dosio F., Cattel L. PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery. Curr Drug Metab 2012; 13(1): 105–119, https://doi.org/10.2174/138920012798356934.
22. Patel M., Park J.K., Jeong B. Rediscovery of poly(ethylene glycol)s as a cryoprotectant for mesenchymal stem cells. Biomater Res 2023; 27(1): 17, https://doi.org/10.1186/s40824-023-00356-z.
23. Roberts M.J., Bentley M.D., Harris J.M. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 2002; 54(4): 459–476, https://doi.org/10.1016/s0169-409x(02)00022-4.
24. Ibrahim M., Ramadan E., Elsadek N.E., Emam S.E., Shimizu T., Ando H., Ishima Y., Elgarhy O.H., Sarhan H.A., Hussein A.K., Ishida T. Polyethylene glycol (PEG): the nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J Control Release 2022; 351: 215–230, https://doi.org/10.1016/j.jconrel.2022.09.031.
25. Ivens I.A., Achanzar W., Baumann A., Brändli-Baiocco A., Cavagnaro J., Dempster M., Depelchin B.O., Rovira A.R., Dill-Morton L., Lane J.H., Reipert B.M., Salcedo T., Schweighardt B., Tsuruda L.S., Turecek P.L., Sims J. PEGylated biopharmaceuticals: current experience and considerations for nonclinical development. Toxicol Pathol 2015; 43(7): 959–983, https://doi.org/10.1177/0192623315591171.
26. López-Estevez A.M., Gref R., Alonso M.J. A journey through the history of PEGylated drug delivery nanocarriers. Drug Deliv Transl Res 2024; 14(8): 2026–2031, https://doi.org/10.1007/s13346-024-01608-8.
27. Gonçalves J., Caliceti P. Optimizing pharmacological and immunological properties of therapeutic proteins through PEGylation: investigating key parameters and their impact. Drug Des Devel Ther 2024; 18: 5041–5062, https://doi.org/10.2147/DDDT.S481420.
28. Jiang K., Tian K., Yu Y., Wu E., Yang M., Pan F., Qian J., Zhan C. Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin. Nat Commun 2024; 15(1): 6136, https://doi.org/10.1038/s41467-024-50568-7.
29. Fornasari D.M.M. PEGylated proteins: how much does molecular weight matter? Clin Pharmacokinet 2025; 64(11): 1587–1597, https://doi.org/10.1007/s40262-025-01568-3.
30. Chen B.M., Cheng T.L., Roffler S.R. Polyethylene glycol immunogenicity: theoretical, clinical, and practical aspects of anti-polyethylene glycol antibodies. ACS Nano 2021; 15(9): 14022–14048, https://doi.org/10.1021/acsnano.1c05922.
31. Lu X., Zhang K. PEGylation of therapeutic oligonucletides: from linear to highly branched PEG architectures. Nano Res 2018; 11(10): 5519–5534, https://doi.org/10.1007/s12274-018-2131-8.
32. Santos J.H.P.M., Torres-Obreque K.M., Meneguetti G.P., Amaro B.P., Rangel-Yagui C.O. Protein PEGylation for the design of biobetters: from reaction to purification processes. Braz J Pharm Sci 2018; 54(Special): e01009, https://doi.org/10.1590/s2175-97902018000001009.
33. Kim J., Kong Y.P., Niedzielski S.M., Singh R.K., Putnam A.J., Shikanov A. Characterization of the crosslinking kinetics of multi-arm poly(ethylene glycol) hydrogels formed via Michael-type addition. Soft Matter 2016; 12(7): 2076–2085, https://doi.org/10.1039/c5sm02668g.
34. Adkins C.E., Nounou M.I., Hye T., Mohammad A.S., Terrell-Hall T., Mohan N.K., Eldon M.A., Hoch U., Lockman P.R. NKTR-102 efficacy versus irinotecan in a mouse model of brain metastases of breast cancer. BMC Cancer 2015; 15: 685, https://doi.org/10.1186/s12885-015-1672-4.
35. Garrett C.R., Bekaii-Saab T.S., Ryan T., Fisher G.A., Clive S., Kavan P., Shacham-Shmueli E., Buchbinder A., Goldberg R.M. Randomized phase 2 study of PEGylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer 2013; 119(24): 4223–4230, https://doi.org/10.1002/cncr.28358.
36. Charych D.H., Hoch U., Langowski J.L., Lee S.R., Addepalli M.K., Kirk P.B., Sheng D., Liu X., Sims P.W., VanderVeen L.A., Ali C.F., Chang T.K., Konakova M., Pena R.L., Kanhere R.S., Kirksey Y.M., Ji C., Wang Y., Huang J., Sweeney T.D., Kantak S.S., Doberstein S.K. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res 2016; 22(3): 680–690, https://doi.org/10.1158/1078-0432.CCR-15-1631.
37. Munasinghe A., Mathavan A., Mathavan A., Lin P., Colina C.M. Atomistic insight towards the impact of polymer architecture and grafting density on structure-dynamics of PEGylated bovine serum albumin and their applications. J Chem Phys 2021; 154(7): 075101, https://doi.org/10.1063/5.0038306.
38. Dozier J.K., Distefano M.D. Site-specific PEGylation of therapeutic proteins. Int J Mol Sci 2015; 16(10): 25831–25864, https://doi.org/10.3390/ijms161025831.
39. Pfister D., Morbidelli M. Process for protein PEGylation. J Control Release 2014; 180: 134–149, https://doi.org/10.1016/j.jconrel.2014.02.002.
40. Swierczewska M., Lee K.C., Lee S. What is the future of PEGylated therapies? Expert Opin Emerg Drugs 2015; 20(4): 531–536, https://doi.org/10.1517/14728214.2015.1113254.
41. Sharma A.R., Kundu S.K., Nam J.S., Sharma G., Priya Doss C.G., Lee S.S., Chakraborty C. Next generation delivery system for proteins and genes of therapeutic purpose: why and how? Biomed Res Int 2014; 2014: 327950, https://doi.org/10.1155/2014/327950.
42. Kumar V., Barwal A., Sharma N., Mir D.S., Kumar P., Kumar V. Therapeutic proteins: developments, progress, challenges, and future perspectives. 3 Biotech 2024; 14(4): 112, https://doi.org/10.1007/s13205-024-03958-z.
43. Veronese F.M., Mero A., Pasut G. Protein PEGylation, basic science and biological applications. In: Veronese F.M. (eds). PEGylated protein drugs: basic science and clinical applications. Birkhäuser Basel; 2009; p. 11–31, https://doi.org/10.1007/978-3-7643-8679-5_2.
44. Bonora G.M., Drioli S. Reactive PEGs for protein conjugation. In: Veronese F.M. (eds). PEGylated protein drugs: basic science and clinical applications. Milestones in drug therapy. Birkhäuser Basel; 2009; p. 33–45, https://doi.org/10.1007/978-3-7643-8679-5_3.
45. Kolate A., Baradia D., Patil S., Vhora I., Kore G., Misra A. PEG — a versatile conjugating ligand for drugs and drug delivery systems. J Control Release 2014; 192: 67–81, https://doi.org/10.1016/j.jconrel.2014.06.046.
46. Gundecha S., Shirolkar S., Deshkar S., Chitlange S., Shewale S., Jagtap R.A. A review on impact of PEGylation on biopharmaceuticals. International Journal of Health Sciences 2022; 6(S3): 6622–6634, https://doi.org/10.53730/ijhs.v6ns3.7477.
47. Gupta V., Bhavanasi S., Quadir M., Singh K., Ghosh G., Vasamreddy K., Ghosh A., Siahaan T.J., Banerjee S., Banerjee S.K. Protein PEGylation for cancer therapy: bench to bedside. J Cell Commun Signal 2019; 13(3): 319–330, https://doi.org/10.1007/s12079-018-0492-0.
48. Fee C.J., Van Alstine J.M. Purification of PEGylated proteins. In: Janson J.-C. (eds). Protein purification. 2011; p. 339–362, https://doi.org/10.1002/9780470939932.ch14.
49. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65(1–2): 55–63, https://doi.org/10.1016/0022-1759(83)90303-4.
50. Zhang C., Desai R., Perez-Luna V., Karuri N. PEGylation of lysine residues improves the proteolytic stability of fibronectin while retaining biological activity. Biotechnol J 2014; 9(8): 1033–1043, https://doi.org/10.1002/biot.201400115.
51. Rajender Reddy K., Modi M.W., Pedder S. Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C. Adv Drug Deliv Rev 2002; 54(4): 571–586, https://doi.org/10.1016/s0169-409x(02)00028-5.
52. Dunne M., Zheng J., Rosenblat J., Jaffray D.A., Allen C. APN/CD13-targeting as a strategy to alter the tumor accumulation of liposomes. J Control Release 2011; 154(3): 298–305, https://doi.org/10.1016/j.jconrel.2011.05.022.
53. Zhu L., Kate P., Torchilin V.P. Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. ACS Nano 2012; 6(4): 3491–3498, https://doi.org/10.1021/nn300524f.
54. Kumari M., Sahni G., Datta S. Development of site-specific PEGylated granulocyte colony stimulating factor with prolonged biological activity. Front Bioeng Biotechnol 2020; 8: 572077, https://doi.org/10.3389/fbioe.2020.572077.
55. Doherty D.H., Rosendahl M.S., Smith D.J., Hughes J.M., Chlipala E.A., Cox G.N. Site-specific PEGylation of engineered cysteine analogues of recombinant human granulocyte-macrophage colony-stimulating factor. Bioconjug Chem 2005; 16(5): 1291–1298, https://doi.org/10.1021/bc050172r.
56. Ramirez-Paz J., Saxena M., Delinois L.J., Joaquín-Ovalle F.M., Lin S., Chen Z., Rojas-Nieves V.A., Griebenow K. Thiol-maleimide poly(ethylene glycol) crosslinking of L-asparaginase subunits at recombinant cysteine residues introduced by mutagenesis. PLoS One 2018; 13(7): e0197643, https://doi.org/10.1371/journal.pone.0197643.
57. Luo S., Lu X., Liu C., Zhong J., Zhou L., Chen T. Site specific PEGylation of β-lactoglobulin at glutamine residues and its influence on conformation and antigenicity. Food Res Int 2019; 123: 623–630, https://doi.org/10.1016/j.foodres.2019.05.038.
58. Sakane T., Pardridge W.M. Carboxyl-directed PEGylation of brain-derived neurotrophic factor markedly reduces systemic clearance with minimal loss of biologic activity. Pharm Res 1997; 14(8): 1085–1091, https://doi.org/10.1023/a:1012117815460.
59. Zaghmi A., Mendez-Villuendas E., Greschner A.A., Liu J.Y., de Haan H.W., Gauthier M.A. Mechanisms of activity loss for a multi-PEGylated protein by experiment and simulation. Mater Today Chem 2019; 12: 121–131, https://doi.org/10.1016/j.mtchem.2018.12.007.
60. Wang B., Cao Y., Chi S., Lou D. A PEGylation technology of L-asparaginase with monomethoxy polyethylene glycol-propionaldehyde. Zeitschrift für Naturforschung C 2012; 67(5–6): 312-318, https://doi.org/10.1515/znc-2012-5-611.
61. Benet L.Z. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci 2013; 102(1): 34–42, https://doi.org/10.1002/jps.23359.
62. D’souza A.A., Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin Drug Deliv 2016; 13(9): 1257–1275, https://doi.org/10.1080/17425247.2016.1182485.
63. Werner M.E., Cummings N.D., Sethi M., Wang E.C., Sukumar R., Moore D.T., Wang A.Z. Preclinical evaluation of Genexol-PM, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2013; 86(3): 463–468, https://doi.org/10.1016/j.ijrobp.2013.02.009.
64. Krasnyuk (Jr.) I.I., Naryshkin S.R., Krasnyuk I.I., Belyatskaya A.V., Stepanova O.I., Bobrov I.S., Yankova V.G., Rau J.V., Vorobiev A.N. Effect of solid dispersions on the solubility of metronidazole. Pharmacy & Pharmacology 2021; 9(3): 195–204, https://doi.org/10.19163/2307-9266-2021-9-3-195-204.
65. Tambosi G., Coelho P.F., Luciano S., Lenschow I.C.S., Zétola M., Stulzer H.K., Pezzini B.R. Challenges to improve the biopharmaceutical properties of poorly water-soluble drugs and the application of the solid dispersion technology. Matéria (Rio de Janeiro) 2018; 23(4). https://doi.org/10.1590/s1517-707620180004.0558.
66. Le Khanh H.P., Haimhoffer Á., Nemes D., Józsa L., Vasvári G., Budai I., Bényei A., Ujhelyi Z., Fehér P., Bácskay I. Effect of molecular weight on the dissolution profiles of peg solid dispersions containing ketoprofen. Polymers (Basel) 2023; 15(7), https://doi.org/10.3390/polym15071758.
67. Silva Freitas D.d., Abrahão-Neto J. Batch purification of high-purity lysozyme from egg white and characterization of the enzyme modified by PEGylation. Pharm Biol 2010; 48(5): 554–562, https://doi.org/10.3109/13880200903196859.
68. Porfiryeva N.N., Moustafine R.I., Khutoryanskiy V.V. PEGylated systems in pharmaceutics. Polym Sci Ser 2020; 61(1): 62–74, https://doi.org/10.1134/S181123822001004X.
69. Nsairat H., Khater D., Sayed U., Odeh F., Al Bawab A., Alshaer W. Liposomes: structure, composition, types, and clinical applications. Heliyon 2022; 8(5): e09394, https://doi.org/10.1016/j.heliyon.2022.e09394.
70. Raikov A.O., Hashem A., Baryshnikova M.A. Liposomes as target delivery of antitumor drugs. Russian Journal of Biotherapy 2016; 15(2): 90–96, https://doi.org/10.17650/1726-9784-2016-15-2-90-96.
71. Jyothirmayi P., Anusha A., Srinivasarao N., Nandini Y., Kavya A., Jayalakshmi K. A review of targetted drug delivery systems — a new era of drug carriers in cancer therapy. Indo Am J P Sci 2024; 11(12): 525–542.
72. Minamisakamoto T., Nishiguchi S., Hashimoto K., Ogawara K.I., Maruyama M., Higaki K. Sequential administration of PEG-Span 80 niosome enhances anti-tumor effect of doxorubicin-containing PEG liposome. Eur J Pharm Biopharm 2021; 169: 20–28, https://doi.org/10.1016/j.ejpb.2021.08.013.
73. Dunn S.E., Brindley A., Davis S.S., Davies M.C., Illum L. Polystyrene-poly (ethylene glycol) (PS-PEG2000) particles as model systems for site specific drug delivery. 2. The effect of PEG surface density on the in vitro cell interaction and in vivo biodistribution. Pharm Res 1994; 11(7): 1016–1022, https://doi.org/10.1023/a:1018939521589.
74. Gref R., Lück M., Quellec P., Marchand M., Dellacherie E., Harnisch S., Blunk T., Müller R.H. ‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B Biointerfaces 2000; 18(3-4): 301–313, https://doi.org/10.1016/s0927-7765(99)00156-3.
75. Muralidharan P., Mallory E., Malapit M., Hayes D., Mansour H.M. Inhalable PEGylated phospholipid nanocarriers and PEGylated therapeutics for respiratory delivery as aerosolized colloidal dispersions and dry powder inhalers. Pharmaceutics 2014; 6(2): 333–353, https://doi.org/10.3390/pharmaceutics6020333.
76. Definitions of biomaterials for the twenty-first century. Williams D., Zhang X. (eds). Elsevier; 2019, https://doi.org/10.1016/c2018-0-02529-3.
77. Moore E.M., West J.L. Bioactive poly(ethylene glycol) acrylate hydrogels for regenerative engineering. Regen Eng Transl Med 2018; 5(2): 167–179, https://doi.org/10.1007/s40883-018-0074-y.
78. De Vriendt S., Casares C.M., Rocha S., Vankelecom H. Matrix scaffolds for endometrium-derived organoid models. Front Endocrinol (Lausanne) 2023; 14: 1240064, https://doi.org/10.3389/fendo.2023.1240064.
79. Cheng H., Yang A., Lv G., Zheng H., Li H. Polyethylene glycol (PEG)-based wet-adhesive absorbable bone wax for osseous hemostasis and repair. Int J Mol Sci 2025; 27(1): 276, https://doi.org/10.3390/ijms27010276.
80. Betz M.W., Yeatts A.B., Richbourg W.J., Caccamese J.F., Coletti D.P., Falco E.E., Fisher J.P. Macroporous hydrogels upregulate osteogenic signal expression and promote bone regeneration. Biomacromolecules 2010; 11(5): 1160–1168, https://doi.org/10.1021/bm100061z.
81. Fu S., Guo G., Gong C., Zeng S., Liang H., Luo F., Zhang X., Zhao X., Wei Y., Qian Z. Injectable biodegradable thermosensitive hydrogel composite for orthopedic tissue engineering. 1. Preparation and characterization of nanohydroxyapatite/poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) hydrogel nanocomposites. J Phys Chem B 2009; 113(52): 16518–16525, https://doi.org/10.1021/jp907974d.
82. Huang J., Grater S.V., Corbellini F., Rinck S., Bock E., Kemkemer R., Kessler H., Ding J., Spatz J.P. Impact of order and disorder in RGD nanopatterns on cell adhesion. Nano Lett 2009; 9(3): 1111–1116, https://doi.org/10.1021/nl803548b.
83. Quizon M.J., Deppen J.N., Barber G.F., Kalelkar P.P., Coronel M.M., Levit R.D., Garcia A.J. VEGF-delivering PEG hydrogels promote vascularization in the porcine subcutaneous space. J Biomed Mater Res A 2024; 112(6): 866–880, https://doi.org/10.1002/jbm.a.37666.
84. Kraehenbuehl T.P., Zammaretti P., Van der Vlies A.J., Schoenmakers R.G., Lutolf M.P., Jaconi M.E., Hubbell J.A. Three-dimensional extracellular matrix-directed cardioprogenitor differentiation: systematic modulation of a synthetic cell-responsive PEG-hydrogel. Biomaterials 2008; 29(18): 2757–2766, https://doi.org/10.1016/j.biomaterials.2008.03.016.
85. Zhu J. Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 2010; 31(17): 4639–4656, https://doi.org/10.1016/j.biomaterials.2010.02.044.
86. Lee H.J., Tomasini-Johansson B.R., Gupta N., Kwon G.S. Fibronectin-targeted FUD and PEGylated FUD peptides for fibrotic diseases. J Control Release 2023; 360: 69–81, https://doi.org/10.1016/j.jconrel.2023.06.008.
87. Dashti R., Safaei F., Sadeghian G., Hosseini S.A., Salimibani M. Peptide-functionalized nanomaterials for controlled drug delivery and regenerative therapies in retinal diseases. J Biomater Appl 2026; 40(10): 1235–1262, https://doi.org/10.1177/08853282251395196.
88. Chu J., Shi P., Yan W., Fu J., Yang Z., He C., Deng X., Liu H. PEGylated graphene oxide-mediated quercetin-modified collagen hybrid scaffold for enhancement of MSCs differentiation potential and diabetic wound healing. Nanoscale 2018; 10(20): 9547–9560, https://doi.org/10.1039/c8nr02538j.
89. Egorikhina M.N., Timofeeva L.B., Rubtsova Y.P., Farafontova E.A., Linkova D.D., Charykova I.N., Ryabkov M.G., Ezhevskaya A.A., Levicheva E.A., Aleynik D.Y. Study of the effectiveness of skin restoration using a biopolymer hydrogel scaffold with encapsulated mesenchymal stem cells. Int J Mol Sci 2025; 26(16): 7840, https://doi.org/10.3390/ijms26167840.
90. Jang H.J., Shin C.Y., Kim K.B. Safety evaluation of polyethylene glycol (PEG) compounds for cosmetic use. Toxicol Res 2015; 31(2): 105–136, https://doi.org/10.5487/TR.2015.31.2.105.
91. Davis G.R., Santa Ana C.A., Morawski S.G., Fordtran J.S. Development of a lavage solution associated with minimal water and electrolyte absorption or secretion. Gastroenterology 1980; 78(5): 991–995. https://doi.org/10.1016/0016-5085(80)90781-7.
92. Shekunova E.V., Mazukina E.V., Vavilova V.A., Kashkin V.V., Balabanyan V.Yu., Fazylov M.F., Makarova M.N., Makarov V.G. Experimental study of the efficacy and safety of a new PEG-based laxative. Safety and Risk of Pharmacotherapy 2022; 10(2): 176–195, https://doi.org/10.30895/2312-7821-2022-10-2-176-195.
93. Damiri F., Simińska-Stanny J., Rasoulian F., Pinal C., Kaczmarek-Szczepanska B., Patel C.D., Patel H.M., Papadimitirou S.A., Jaradat E., Paiva-Santos A.C., Okoro O.V., Shavandi A., Berrada M., Vora L.K., Fatimi A. Emerging trends in polysaccharide-based smart PEGylated hydrogels for biomedical applications. Carbohydr Polym 2026; 375: 124707, https://doi.org/10.1016/j.carbpol.2025.124707.
94. Piñol-Cancer M., Fernández-Méndez L., Carrillo-Romero J., Urkola-Arsuaga A., Azkargorta M., Elortza F., Goñi-de-Cerio F., García-Mouton C., de Alejo C.M., Ismalaj E., Cañadas O., Pérez-Gil J., Ruíz-Cabello J., Carregal-Romero S. The role of PEGylation in the pulmonary delivery of antifibrotic liposomal therapies. J Control Release 2025; 386: 114134, https://doi.org/10.1016/j.jconrel.2025.114134.
95. PEGylated protein drugs: basic science and clinical applications. Francesco M. (eds). Springer Nature; 2009.
96. Bailon P., Won C.Y. PEG-modified biopharmaceuticals. Expert Opin Drug Deliv 2009; 6(1): 1–16, https://doi.org/10.1517/17425240802650568.
97. Stucchi F., Li M., Castellano G., Cellesi F. Regulatory framework for polymer-based nanotherapeutics in clinical translation. Front Bioeng Biotechnol 2026; 14: 1735885, https://doi.org/10.3389/fbioe.2026.1735885.
98. Chikara R., Chaudhary A., Goswami H., Rana D., Nagar T., Sachdeva M., Sharma S. Cancer nanomedicine: scientific advances, clinical translation, regulatory frameworks, and safety perspectives. Int J Pharm Chem Anal 2026; 13(1): 36–44, https://doi.org/10.18231/j.ijpca.16080.1773817035.
99. Jan N., Rejili M. Nature-inspired alternatives to PEG for next-generation long-circulating nanocarriers. Int J Nanomedicine 2026; 21: 618454, https://doi.org/10.2147/IJN.S618454.
100. Wong G.L., Yuen M.F., Lin B., Douglas M.W., Hu P., Xie Q., Lv F., Tak W.Y., Leerapun A., Kim D.J., Tangkijvanich P., Lim Y.S., Dai C.Y., O'Beirne J., Weltman M., Khemnark S., Piratvisuth T., Manasirisuk W., Chen X., Liu C.J., Heo J., Lee J., Niu J., Kumar R., Kumar R., Zhu C., Cao K., Tian A., Chen X., Zhu Q., Margolis D., Jia J., Hong Z. Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial. Nat Med 2026; 32(1): 151–159, https://doi.org/10.1038/s41591-025-04049-z.
101. Buti M., Heo J., Tanaka Y., Andreone P., Atsukawa M., Cabezas J., Chak E., Coffin C.S., Fujiwara K., Gankina N., Gordon S.C., Janczewska E., Komori A., Lampertico P., McPherson S., Morozov V., Plesniak R., Poulin S., Ryan P., Sagalova O., Sheng G., Voloshina N., Xie Q., Yim H.J., Dixon S., Paff M., Felton L., Lee M., Greene T., Lim J., Lakshminarayanan D., McGonagle G., Plein H., Youssef A.S., Elston R., Kendrick S., Theodore D. Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B. J Hepatol 2025; 82(2): 222–234, https://doi.org/10.1016/j.jhep.2024.08.010.
102. Lampertico P., Anolli M.P., Roulot D., Wedemeyer H. Antiviral therapy for chronic hepatitis delta: new insights from clinical trials and real-life studies. Gut 2025; 74(5): 853–862, https://doi.org/10.1136/gutjnl-2024-332597.
103. ClinicalTrials.gov. URL: https://clinicaltrials.gov/.
104. Decision of the Council of the Eurasian Economic Commission No.18 dated February 21, 2025, “On amending the requirements for the instructions for medical use of a medicinal product and the summary of product characteristics for a medicinal product for medical use”.
105. Dreier P., Matthes R., Fuß F., Schmidt J., Schulz D., Linden G.M., Barent R.D., Schüttner S., Neun B.W., Cedrone E., Dobrovolskaia M.A., Bros M., Frey H. Isomerization of poly(ethylene glycol): a strategy for the evasion of anti-PEG antibody recognition. J Am Chem Soc 2025; 147(25): 21538–21548, https://doi.org/10.1021/jacs.5c02716.
106. Schmidt J., Bockhard C., Simon L., Linden G.M., Scheiger J.M., Frey H. From PEG to randomized PEG: a macromolecular strategy tackling PEG immunogenicity. Adv Drug Deliv Rev 2026; 238: 115943, https://doi.org/10.1016/j.addr.2026.115943.