Drug Delivery and Translational Research

, Volume 3, Issue 6, pp 499–503 | Cite as

Questioning the use of PEGylation for drug delivery

Invited Review Article

Abstract

Polyethylene glycol (PEG) is widely utilized in drug delivery and nanotechnology due to its reported “stealth” properties and biocompatibility. It is generally thought that PEGylation allows particulate delivery systems and biomaterials to evade the immune system and thereby prolong circulation lifetimes. However, numerous studies over the past decade have demonstrated that PEGylation causes significant reductions in drug delivery, including enhanced serum protein binding, reduced uptake by target cells, and the elicitation of an immune response that facilitates clearance in vivo. This report reviews some of the extensive literature documenting the detrimental effects of PEGylation, and thereby questions the wisdom behind employing this strategy in drug development.

Keywords

Polyethylene glycol PEG Transfection DNA RNA Drug delivery Immunogenicity Stealth 

Notes

Acknowledgments

Some of the work discussed here was supported by grant no. 1 RO1EB016378 and no. 1 RO1GM093287 to TJA.

Conflict of interest

The authors are academic researchers with no financial interest in any of the work described in this manuscript.

References

  1. 1.
    Knop K, Hoogenboom R, Fischer D, Schubert US. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed. 2010;49:6288–308.CrossRefGoogle Scholar
  2. 2.
    Xu L, Anchordoquy TJ. Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics. J Pharm Sci. 2011;100:38–52.CrossRefPubMedGoogle Scholar
  3. 3.
    Yan X, Scherphof GL, Kamps JAAM. Liposome opsonization. J Liposome Res. 2005;15:109–39.PubMedGoogle Scholar
  4. 4.
    Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A. 1991;88:11460–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R. Biodegradable long-circulating polymeric nanospheres. Science. 1994;263:1600–3.CrossRefPubMedGoogle Scholar
  6. 6.
    Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, et al. “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;18:301–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Leroux J-C, De Jaeghere F, Anner B, Doelker E, Gurny R. An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D, L-lactic acid) nanoparticles by human monocytes. Life Sci. 1995;57(7):695–703.CrossRefPubMedGoogle Scholar
  8. 8.
    Fang C, Shi B, Pei Y-Y, Hong M-H, Wu J, Chen H-Z. In vivo targeting of tumor necrosis factor-α-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size. Eur J Pharm Sci. 2006;27:27–36.CrossRefPubMedGoogle Scholar
  9. 9.
    Semple SC, Chonn A, Cullis PR. Interactions of liposomes and lipid-based carrier systems with blood proteins: relation to clearance behavior in vivo. Adv Drug Deliv Rev. 1998;32:3–17.CrossRefPubMedGoogle Scholar
  10. 10.
    Allen TM. In: Lopez-Berestein G, Fidler I, editors. Liposomes in the therapy of infectious diseases and cancer. New York: Liss; 1989. p. 405–15.Google Scholar
  11. 11.
    Johnstone SA, Masin D, Mayer L, Bally MB. Surface-associated serum proteins inhibit the uptake of phosphatidylserine and poly(ethylene glycol) liposomes by mouse macrophages. Biochim Biophys Acta. 2001;1513:25–37.CrossRefPubMedGoogle Scholar
  12. 12.
    Dos Santos N, Allen C, Doppen A-M, Anantha M, Cox KAK, Gallagher RC, et al. Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: relating plasma circulation lifetimes to protein binding. Biochim Biophys Acta. 2007;1768:1367–77.CrossRefPubMedGoogle Scholar
  13. 13.
    Sroda K, Rydlewski J, Langner M, Kozubek A, Grzybek M, Sikorski AF. Repeated injections of PEG-PE liposomes generate anti-PEG antibodies. Cell Mol Biol Lett. 2005;10:37–47.PubMedGoogle Scholar
  14. 14.
    Betker JL, Gomez J, Anchordoquy TJ. The effects of lipoplex formulation variables on the protein corona and comparisons with in vitro transfection efficiency. J Cont Rel. 2013; in press. doi: 10.1016/j.jconrel.2013.07.024
  15. 15.
    Hamad I, Al-Hanbali O, Hunter AC, Rutt KJ, Andresen TL, Moghimi SM. Distinct polymer architecture mediates switching of complement-activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering. ACS Nano. 2010;4(11):6629–38.CrossRefPubMedGoogle Scholar
  16. 16.
    Allen TM, Austin GA, Chonn A, Lin L, Lee KC. Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size. Biochim Biophys Acta. 1991;1061:56–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Moghimi SM, Andersen AJ, Hashemi SH, Lettiero B, Ahmadvand D, Hunter AC, et al. Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. J Control Release. 2010;146:175–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Molino NM, Bilotkach K, Fraser DA, Ren D, Wang S-W. Complement activation and cell uptake responses toward polymer-functionalized protein nanocapsules. Biomacromolecules. 2012;13:974–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent Smancs. Cancer Res. 1986;46:6387–92.PubMedGoogle Scholar
  20. 20.
    Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzym Regul. 2001;41:189–207.CrossRefGoogle Scholar
  21. 21.
    Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63:136–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Harvie P, Wong FMP, Bally MB. Use of poly(ethylene glycol)-lipid conjugates to regulate the surface attributes and transfection activity of lipid-DNA particles. J Pharm Sci. 2000;89(5):652–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Mishra S, Webster P, Davis ME. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol. 2004;83:97–111.CrossRefPubMedGoogle Scholar
  24. 24.
    Xu L, Anchordoquy TJ. Effect of cholesterol nanodomains on the targeting of lipid-based gene delivery in cultured cells. Mol Pharm. 2010;7(4):1311–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Xu L, Wempe MF, Anchordoquy TJ. The effect of cholesterol domains on PEGylated liposomal gene delivery in vitro. Ther Deliv. 2011;2:451–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Bao Y, Jin Y, Chivukula P, Zhang J, Liu Y, Liu J, et al. Effect of PEGylation on biodistribution and gene silencing of siRNA/lipid nanoparticle complexes. Pharm Res. 2013;30:342–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Hong K, Zheng W, Baker A, Papahadjopoulos D. Stabilization of cationic liposome-plasmid DNA complexes by polyamines and poly(ethylene glycol)-phospholipid conjugates for efficient in vivo gene delivery. FEBS Lett. 1997;400:233–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Ambegia E, Ansell S, Cullis P, Heyes J, Palmer L, MacLachlan I. Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression. Biochim Biophys Acta. 2005;1669:155–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Hatakeyama H, Akita J, Kogure K, Oishi M, Nagasaki Y, Kihira Y, et al. Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene Ther. 2007;14:68–77.CrossRefPubMedGoogle Scholar
  30. 30.
    Moghimi SM, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 2003;42:463–78.CrossRefPubMedGoogle Scholar
  31. 31.
    Garay RP, El-Gewely R, Armstrong JK, Garratty G, Richette P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Hamad I, Hunter AC, Rutt KJ, Liu Z, Dai H, Moghimi SM. Complement activation by PEGylated single-walled carbon nanotubes is independent of C1q and alternative pathway turnover. Mol Immunol. 2008;45:3797–803.CrossRefPubMedGoogle Scholar
  33. 33.
    Ishida T, Kiwada H. Anti-polyethyleneglycol antibody response to PEGylated substances. Biol Pharm Bull. 2013;36:889–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Ishida T, Atobe K, Wang X, Kiwada H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J Control Release. 2006;115:251–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Ishida T, Kashima S, Kiwada H. The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release. 2008;126:162–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Shimizu T, Ichihara M, Yoshioka Y, Ishida T, Nakagawa S, Kiwada H. Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response. Biol Pharm Bull. 2012;35:1336–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H. PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release. 2007;122:349–55.CrossRefPubMedGoogle Scholar
  38. 38.
    Koide H, Asai T, Hatanaka K, Akai S, Ishii T, Kenjo E, et al. T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes. Int J Pharm. 2010;392:218–23.CrossRefPubMedGoogle Scholar
  39. 39.
    Wang X, Ishida T, Kiwada H. Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release. 2007;119:236–44.CrossRefPubMedGoogle Scholar
  40. 40.
    Ishida T, Ichihara M, Wang X, Kiwada H. Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J Control Release. 2006;115:243–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, et al. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release. 2006;112:15–25.CrossRefPubMedGoogle Scholar
  42. 42.
    Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol. 2013;13:118–32.CrossRefPubMedGoogle Scholar
  43. 43.
    Porto APNA, Lammers AJJ, Bennink RJ, Berge IJM, Speelman P, Hoekstra JBL. Assessment of splenic function. Eur J Clin Microbiol Infect Dis. 2010;29:1465–73.CrossRefPubMedGoogle Scholar
  44. 44.
    Li C, Zhao X, Wang Y, Yang H, Li H, Li H, et al. Prolongation of time interval between doses could eliminate accelerated blood clearance phenomenon induced by pegylated liposomal topotecan. Int J Pharm. 2013;443:17–25.CrossRefPubMedGoogle Scholar
  45. 45.
    Ishihara T, Takeda M, Sakamoto H, Kimoto A, Kobayashi C, Takasaki N, et al. Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles. Pharm Res. 2009;26:2270–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, Kiwada H. Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes. J Control Release. 2005;105:305–17.CrossRefPubMedGoogle Scholar
  47. 47.
    Shimizu T, Ishida T, Kiwada H. Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon. Immunobiology. 2013;218:725–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Laverman P, Brouwers AH, Dams ET, Oyen WJ, Storm G, van Rooijen N, et al. Preclinical and clinical evidence for disappearance of long-circulating characteristics of polyethylene glycol liposomes at low lipid dose. J Pharmacol Exp Ther. 2000;293:996–1001.PubMedGoogle Scholar
  49. 49.
    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. 2007;110(1):103–11.CrossRefPubMedGoogle Scholar
  50. 50.
    Pidaparti M, Bostrom G. Comparison of allergic reactions to pegasparaginase given intravenously versus intramuscularly. Pediatr Blood Cancer. 2011. doi: 10.1002/pbc.23380.PubMedGoogle Scholar
  51. 51.
    Moghimi SM, Hamad I, Andresen TL, Jorgensen K, Szebeni J. Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production. FASEB J. 2006;20:E2057–67.CrossRefGoogle Scholar
  52. 52.
    Sherman MR, Williams LD, Sobczyk MA, Michaels SJ, Saifer MGP. Role of methoxy group in immune responses to mPEG-protein conjugates. Bioconjug Chem. 2012;23:485–99.CrossRefPubMedGoogle Scholar
  53. 53.
    Suzuki T, Ichihara M, Hyodo K, Yamamoto E, Ishida T, Kiwada H, et al. Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs. Int J Pharm. 2012;436:636–43.CrossRefPubMedGoogle Scholar
  54. 54.
    Abu Lila AS, Eldin NE, Ichihara M, Ishida T, Kiwada H. Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application. Int J Pharm. 2012;438:176–83.CrossRefPubMedGoogle Scholar
  55. 55.
    Hunter AC, Moghimi SM. Therapeutic synthetic polymers: a game of Russian roulette? Drug Discov Today. 2002;7:998–1001.CrossRefPubMedGoogle Scholar
  56. 56.
    Moghimi SM, Hunter AC, Andresen TL. Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Ann Rev Pharmacol Toxicol. 2012;52:481–503.CrossRefGoogle Scholar
  57. 57.
    Zhang ATJ. The role of lipid charge density in the serum stability of cationic lipid/DNA complexes. Biochim Biophys Acta Biomembr. 2004;1663:143–57.CrossRefGoogle Scholar
  58. 58.
    Zhang Y, Bradshaw-Pierce EL, DeLille A, Gustafson DL, Anchordoquy TJ. In vivo comparative study of lipid/DNA complexes with different in vitro serum stability: effects on biodistribution and tumor accumulation. J Pharm Sci. 2008;97:237–50.CrossRefPubMedGoogle Scholar
  59. 59.
    Xu L, Anchordoquy TJ. Cholesterol domains in cationic lipid/DNA complexes improve transfection. Biochim Biophys Acta Biomembr. 2008;1778(10):2177–81.CrossRefGoogle Scholar
  60. 60.
    Schellekens H, Hennink WE, Brinks V. The immunogenicity of polyethylene glycol: facts and fiction. Pharm Res. 2013;30:1729–34.CrossRefPubMedGoogle Scholar
  61. 61.
    Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153:198–205.CrossRefPubMedGoogle Scholar
  62. 62.
    Grainger DW. Connecting drug delivery reality to smart materials design. Int J Pharm. 2013. doi: 10.1016/j.ijpharm.2013.04.061.PubMedGoogle Scholar

Copyright information

© Controlled Release Society 2013

Authors and Affiliations

  1. 1.School of Pharmacy and Pharmaceutical SciencesUniversity of UtrechtUtrechtThe Netherlands
  2. 2.Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado DenverAuroraUSA

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