Pegylation – in search of balance and enhanced bioavailability

Authors

DOI:

https://doi.org/10.20883/medical.e761

Keywords:

polyethylene glycol, photodynamic therapy, anticancer therapy

Abstract

In the process of finding better therapeutics, thousands of new molecules are synthesised every day. Many of these can be poorly soluble in water, leading to a potentially promising drug being rejected during testing due to its poor solubility. Polyethylene glycol (PEG) has become known as an excellent modification to remedy this and was initially used to increase circulation time and reduce the immunogenicity of therapeutic proteins. Thus significantly increasing their safety and range of use. Another group of compounds in which significant benefits of pegylation have been seen are photosensitisers. Used in photodynamic therapy, they are often characterised by very high hydrophobicity. Pegylation of their structure significantly increases their affinity for cancer cells and facilitates their penetration through cell membranes. Classical small-molecule drugs can benefit from temporary combinations hydrolysed in the body or very short PEG chains. This approach allows a significant increase in the bioavailability of the drug while avoiding the disadvantages of small molecule pegylation. However, the most common motive for pegylation recently is the creation of drug carriers. Liposomes and nanoparticles make it possible to exploit the advantages of PEG to stabilise their structure and increase circulation time while not modifying the structure of the active compound. Unfortunately, PEGs also have their drawbacks. The first is their high molecular weight range, especially for longer chains, which poses difficulties in purification. Another is the emergence of antibodies directed against PEG. Nevertheless, pegylation is still an up-and-coming method for modifying pharmaceutically active molecules.

Downloads

Download data is not yet available.

References

Greenwald RB, Choe YH, McGuire J, Conover CD. Effective drug delivery by PEGylated drug conjugates. Adv Drug Deliv Rev. 2003;55(2):217–50.

D’souza AA, Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin Drug Deliv [Internet]. 2016;13(9):1257–75. Available from: http://dx.doi.org/10.1080/17425247.2016.1182485

Herndon TM, Demko SG, Jiang X, He K, Gootenberg JE, Cohen MH, et al. U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of Patients with Melanoma. Oncologist [Internet]. 2012 Oct 1;17(10):1323–8. Available from: https://academic.oup.com/oncolo/article/17/10/1323/6400884

Jevševar S, Kunstelj M, Porekar VG. PEGylation of therapeutic proteins. Biotechnol J. 2010;5(1):113–28.

Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178–84.

Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. FDA Drug Approval Summary: Pegaspargase (Oncaspar®) for the First-Line Treatment of Children with Acute Lymphoblastic Leukemia (ALL). Oncologist. 2007;12(8):991–8.

Mishra P, Nayak B, Dey RK. PEGylation in anti-cancer therapy: An overview. Asian J Pharm Sci [Internet]. 2016;11(3):337–48. Available from: http://dx.doi.org/10.1016/j.ajps.2015.08.011

FDA Approved PEGylated Drugs Up To 2022 | Biopharma PEG [Internet]. [cited 2022 Oct 18]. Available from: https://www.biochempeg.com/article/58.html

Park EJ, Choi J, Lee KC, Na DH. Emerging PEGylated non-biologic drugs. Expert Opin Emerg Drugs [Internet]. 2019;24(2):107–19. Available from: https://doi.org/10.1080/14728214.2019.1604684

Swierczewska M, Lee KC, Lee S. What is the future of PEGylated therapies? Expert Opin Emerg Drugs [Internet]. 2015;20(4):531–6. Available from: http://dx.doi.org/10.1517/14728214.2015.1113254

Yadav D, Dewangan HK. PEGYLATION: an important approach for novel drug delivery system. J Biomater Sci Polym Ed [Internet]. 2021;32(2):266–80. Available from: https://doi.org/10.1080/09205063.2020.1825304

Hoy SM. Pegcetacoplan: First Approval. Drugs [Internet]. 2021;81(12):1423–30. Available from: https://doi.org/10.1007/s40265-021-01560-8

Sravanthi S, Kumari MM, Sharma JVC, Peg R. A Critique View On Skytrofa. 2021;4(11):188–91.

Aschenbrenner DS. New Treatment for Polycythemia Vera. AJN, Am J Nurs [Internet]. 2022 Mar;122(3):18–9. Available from: https://journals.lww.com/10.1097/01.NAJ.0000822968.37066.5c

Jadach B. From the carrier of active substance to drug delivery systems. J Med Sci. 2017;86(3):231–6.

Ghosh S, Carter KA, Lovell JF. Liposomal formulations of photosensitizers. Biomaterials [Internet]. 2019;218(April):119341. Available from: https://doi.org/10.1016/j.biomaterials.2019.119341

Allen TM. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharmacol Sci. 1994;15(7):215–20.

Nawalany K, Rusin A, Kepczyński M, Mikhailov A, Kramer-Marek G, Śnietura M, et al. Comparison of photodynamic efficacy of tetraarylporphyrin pegylated or encapsulated in liposomes: In vitro studies. J Photochem Photobiol B Biol. 2009;97(1):8–17.

Duggan ST, Keating GM. Pegylated Liposomal Doxorubicin. Drugs [Internet]. 2011 Dec;71(18):2531–58. Available from: http://link.springer.com/10.2165/11207510-000000000-00000

Knudsen NØ, Rønholt S, Salte RD, Jorgensen L, Thormann T, Basse LH, et al. Calcipotriol delivery into the skin with PEGylated liposomes. Eur J Pharm Biopharm. 2012;81(3):532–9.

Wang X, Song Y, Su Y, Tian Q, Li B, Quan J, et al. Are PEGylated liposomes better than conventional liposomes? A special case for vincristine. Drug Deliv [Internet]. 2016;23(4):1092–100. Available from: http://dx.doi.org/10.3109/10717544.2015.1027015

Amoozgar Z, Yeo Y. Recent advances in stealth coating of nanoparticle drug delivery systems. Wiley Interdiscip Rev Nanomedicine Nanobiotechnology. 2012;4(2):219–33.

Jokerst J V., Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine. 2011;6(4):715–28.

Locatelli E, Franchini MC. Biodegradable PLGA-b-PEG polymeric nanoparticles: Synthesis, properties, and nanomedical applications as drug delivery system. J Nanoparticle Res. 2012;14(12):1–17.

Zhu Y, Fang Y, Borchardt L, Kaskel S. PEGylated hollow mesoporous silica nanoparticles as potential drug delivery vehicles. Microporous Mesoporous Mater [Internet]. 2011;141(1–3):199–206. Available from: http://dx.doi.org/10.1016/j.micromeso.2010.11.013

Kübler AC. Photodynamic therapy. Med Laser Appl. 2005;20(1):37–45.

MACDONALD IJ, DOUGHERTY TJ. Basic principles of photodynamic therapy. J Porphyrins Phthalocyanines [Internet]. 2001 Feb;05(02):105–29. Available from: http://www.worldscientific.com/doi/abs/10.1002/jpp.328

Baskaran R, Lee J, Yang SG. Clinical development of photodynamic agents and therapeutic applications. Biomater Res. 2018;22:1–8.

Luciano M, Bruckner C. Modifications of porphyrins and hydroporphyrins for their solubilization in aqueous media. Vol. 22, Molecules. 2017.

Milton Harris J, Martin NE, Modi M. Pegylation: A novel process for modifying pharmacokinetics. Clin Pharmacokinet. 2001;40(7):539–51.

Gunaydin G, Gedik ME, Ayan S. Photodynamic Therapy for the Treatment and Diagnosis of Cancer–A Review of the Current Clinical Status. Front Chem. 2021;9(August):1–26.

Pavlíčková V, Rimpelová S, Jurášek M, Záruba K, Fähnrich J, Křížová I, et al. PEGylated purpurin 18 with improved solubility: Potent compounds for photodynamic therapy of cancer. Molecules. 2019;24(24):1–25.

Zhdanova KA, Cherepanova KS, Bragina NA, Mironov AF. New pegylated unsymmetrical meso-arylporphyrins as potential photosensitizers. Macroheterocycles. 2016;9(2):169–74.

Darwish WM, Bayoumi NA, El-Shershaby HM, Allahloubi NM. Targeted photoimmunotherapy based on photosensitizer-antibody conjugates for multiple myeloma treatment. J Photochem Photobiol B Biol [Internet]. 2020;203(January):111777. Available from: https://doi.org/10.1016/j.jphotobiol.2020.111777

Purushothaman B, Choi J, Park S, Lee J, Samson AAS, Hong S, et al. Biotin-conjugated PEGylated porphyrin self-assembled nanoparticles co-targeting mitochondria and lysosomes for advanced chemo-photodynamic combination therapy. J Mater Chem B. 2019;7(1):65–79.

Wierzchowski M, Łażewski D, Tardowski T, Grochocka M, Czajkowski R, Sobiak S, et al. Nanomolar photodynamic activity of porphyrins bearing 1,4,7-trioxanonyl and 2-methyl-5-nitroimidazole moieties against cancer cells. J Photochem Photobiol B Biol [Internet]. 2020;202(October 2019):111703. Available from: https://doi.org/10.1016/j.jphotobiol.2019.111703

Mandal AK, Sahin T, Liu M, Lindsey JS, Bocian DF, Holten D. Photophysical comparisons of PEGylated porphyrins, chlorins and bacteriochlorins in water. New J Chem [Internet]. 2016;40(11):9648–56. Available from: http://dx.doi.org/10.1039/C6NJ02091G

Zhang N, Jiang J, Liu M, Taniguchi M, Mandal AK, Evans-Storms RB, et al. Bioconjugatable, PEGylated hydroporphyrins for photochemistry and photomedicine. Narrow-band, near-infrared-emitting bacteriochlorins. New J Chem [Internet]. 2016;40(9):7750–67. Available from: http://dx.doi.org/10.1039/C6NJ01155A

Liu M, Chen CY, Mandal AK, Chandrashaker V, Evans-Storms RB, Pitner JB, et al. Bioconjugatable, PEGylated hydroporphyrins for photochemistry and photomedicine. Narrow-band, red-emitting chlorins. New J Chem [Internet]. 2016;40(9):7721–40. Available from: http://dx.doi.org/10.1039/C6NJ01154C

Ding F, Li C, Xu Y, Li J, Li H, Yang G, et al. PEGylation Regulates Self-Assembled Small-Molecule Dye–Based Probes from Single Molecule to Nanoparticle Size for Multifunctional NIR-II Bioimaging. Adv Healthc Mater. 2018;7(23):1–9.

Hou W, Xia F, Alves CS, Qian X, Yang Y, Cui D. MMP2-Targeting and Redox-Responsive PEGylated Chlorin e6 Nanoparticles for Cancer Near-Infrared Imaging and Photodynamic Therapy. ACS Appl Mater Interfaces. 2016;8(2):1447–57.

Cheng L, Jiang D, Kamkaew A, Valdovinos HF, Im HJ, Feng L, et al. Renal-Clearable PEGylated Porphyrin Nanoparticles for Image-Guided Photodynamic Cancer Therapy. Adv Funct Mater. 2017;27(34):1–10.

Mewis RE, Savoie H, Archibald SJ, Boyle RW. Synthesis and phototoxicity of polyethylene glycol (PEG) substituted metal-free and metallo-porphyrins: Effect of PEG chain length, coordinated metal, and axial ligand. Photodiagnosis Photodyn Ther. 2009;6(3–4):200–6.

Kepczyński M, Nawalany K, Jachimska B, Romek M, Nowakowska M. Pegylated tetraarylporphyrin entrapped in liposomal membranes. A possible novel drug-carrier system for photodynamic therapy. Colloids Surfaces B Biointerfaces. 2006;49(1):22–30.

Nawalany K, Rusin A, Kepczynski M, Filipczak P, Kumorek M, Kozik B, et al. Novel nanostructural photosensitizers for photodynamic therapy: In vitro studies. Int J Pharm [Internet]. 2012;430(1–2):129–40. Available from: http://dx.doi.org/10.1016/j.ijpharm.2012.04.016

Lazewski D, Kucinska M, Potapskiy E, Kuzminska J, Tezyk A, Popenda L, et al. Novel Short PEG Chain-Substituted Porphyrins: Synthesis, Photochemistry, and In Vitro Photodynamic Activity against Cancer Cells. Int J Mol Sci. 2022;23(17).

Sibrian-Vazquez M, Jensen TJ, Vicente MGH. Synthesis and cellular studies of PEG-functionalized meso-tetraphenylporphyrins. J Photochem Photobiol B Biol. 2007;86(1):9–21.

Sobotta L, Wierzchowski M, Mierzwicki M, Gdaniec Z, Mielcarek J, Persoons L, et al. Photochemical studies and nanomolar photodynamic activities of phthalocyanines functionalized with 1,4,7-trioxanonyl moieties at their non-peripheral positions. J Inorg Biochem [Internet]. 2016;155:76–81. Available from: http://www.sciencedirect.com/science/article/pii/S0162013415301112

Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv. 2006;13(6):399–409.

Greenwald RB, Pendri A, Bolikal D. Highly Water Soluble Taxol Derivatives: 7-Polyethylene Glycol Carbamates and Carbonates. J Org Chem [Internet]. 1995 Jan 1;60(2):331–6. Available from: https://pubs.acs.org/doi/abs/10.1021/jo00107a010

Parveen S, Arjmand F, Tabassum S. Clinical developments of antitumor polymer therapeutics. RSC Adv. 2019;9(43):24699–721.

Zhang X, Wang H, Ma Z, Wu B. Effects of pharmaceutical PEGylation on drug metabolism and its clinical concerns. Expert Opin Drug Metab Toxicol. 2014;10(12):1691–702.

Li W, Zhan P, De Clercq E, Lou H, Liu X. Current drug research on PEGylation with small molecular agents. Prog Polym Sci [Internet]. 2013;38(3–4):421–44. Available from: http://dx.doi.org/10.1016/j.progpolymsci.2012.07.006

Floettmann E, Bui K, Sostek M, Payza K, Eldon M. Pharmacologic profile of naloxegol, a peripherally acting μ-opioid receptor antagonist, for the treatment of opioid-induced constipation. J Pharmacol Exp Ther. 2017;361(2):280–91.

Chehardoli G, Bahmani A. The role of crown ethers in drug delivery. Supramol Chem [Internet]. 2019;31(4):221–38. Available from: https://doi.org/10.1080/10610278.2019.1568432

Verhoef JJF, Anchordoquy TJ. Questioning the use of PEGylation for drug delivery. Drug Deliv Transl Res. 2013;3(6):499–503.

Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer [Internet]. 2007 Jul 1;110(1):103–11. Available from: https://onlinelibrary.wiley.com/doi/10.1002/cncr.22739

Sebak AA. Limitations of pegylated nanocarriers: Unfavourable physicochemical properties, biodistribution patterns and cellular and subcellular fates. Int J Appl Pharm. 2018;10(5):6–12.

Xu J, Gattacceca F, Amiji M. Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice. Mol Pharm [Internet]. 2013 May 6;10(5):2031–44. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624763/pdf/nihms412728.pdf

Rafiei Pedram HA. IJN-121881-docetaxel-loaded-plga-and-plga-peg-nanoparticles-for-intrave. Int J Nanomedicine. 2017;12:935–47.

Zalipsky S, Harris JM. Introduction to Chemistry and Biological Applications of Poly(ethylene glycol). Vol. 680, ACS Symposium Series. 1997. 1–13 p.

Zhang F, Liu MR, Wan HT. Discussion about several potential drawbacks of PEGylated therapeutic proteins. Biol Pharm Bull. 2014;37(3):335–9.

Downloads

Published

2022-12-30

Issue

Section

Review Papers

How to Cite

1.
Łażewski D, Murias M, Wierzchowski M. Pegylation – in search of balance and enhanced bioavailability. JMS [Internet]. 2022 Dec. 30 [cited 2024 Nov. 13];91(4):e761. Available from: https://jmsnew.ump.edu.pl/index.php/JMS/article/view/761
Received 2022-10-25
Accepted 2022-11-18
Published 2022-12-30