Skip to main content

Advertisement

SpringerLink
Log in

Influence of PEG coating on the biodistribution and tumor accumulation of pH-sensitive liposomes

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Liposomes are lipid vesicles widely used as nanocarriers in targeted drug delivery systems for therapeutic and/or diagnostic purposes. A strategy to prolong the blood circulation time of the liposomes includes the addition of a hydrophilic polymer polyethylene glycol (PEG) moiety onto the surface of the vesicle. Several studies claim that liposome PEGylation by a single chain length or a combination of PEG with different chain lengths may alter the liposomes’ pharmacokinetic properties. Therefore, the purpose of this study was to evaluate the influence of PEG on the biodistribution of pH-sensitive liposomes in a tumor-bearing animal model. Three liposomal formulations (PEGylated or not) were prepared and validated to have a similar mean diameter, monodisperse distribution, and neutral zeta potential. The pharmacokinetic properties of each liposome were evaluated in healthy animals, while the biodistribution and scintigraphic images were evaluated in tumor-bearing mice. High tumor-to-muscle ratios were not statistically different between the PEGylated and non-PEGylated liposomes. While PEGylation is a well-established strategy for increasing the blood circulation of nanostructures, in our study, the use of polymer coating did not result in a better in vivo profile. Further studies must be carried out to confirm the feasibility of the non-PEGylated pH-sensitive liposomes for tumor treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Nishioka Y, Yoshino H. Lymphatic targeting with nanoparticulate system. Adv Drug Deliv. 2001;47(1):55–64.

    Article  CAS  Google Scholar 

  2. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.

    Article  Google Scholar 

  3. Fenske DB, Cullis PR. Liposomal nanomedicines. Expert Opin Drug Deliv. 2008;5:25–44.

    Article  CAS  Google Scholar 

  4. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions the lamellae of swollen phospholipids. J Mol Biol. 1965;13:238–52.

    Article  CAS  Google Scholar 

  5. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–60.

    Article  CAS  Google Scholar 

  6. Allen TM. Liposomal drug formulations. Rationale for development and what we can expect for the future. Drugs. 1998;56(5):747–56.

    Article  CAS  Google Scholar 

  7. Allen TM, Hansen C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta. 1991;1068(2):133–41.

    Article  CAS  Google Scholar 

  8. Pastorino F, Stuart D, Ponzoni M, Allen TM. Targeted delivery of antisense oligonucleotides in cancer. J Control Release. 2001;74(1–3):69–75.

    Article  CAS  Google Scholar 

  9. Allen TM, Hansen C, Rutledge J. Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta. 1989;981(1):27–35.

    Article  CAS  Google Scholar 

  10. Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994;54(4):987–92.

    CAS  PubMed  Google Scholar 

  11. Parr MJ, Masin D, Cullis PR, Bally MB. Accumulation of liposomal lipid and encapsulated doxorubicin in murine Lewis lung carcinoma: the lack of beneficial effects by coating liposomes with poly(ethylene glycol). J Pharmacol Exp Ther. 1997;280:1319–27.

    CAS  PubMed  Google Scholar 

  12. Mayer LD, Cullis PR, Bally MB. Designing therapeutically optimized liposomal anticancer delivery systems: lessons from conventional liposomes. Medical Application Liposomes. 1998;1:231–57.

  13. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 1990;268:235–7.

    Article  CAS  Google Scholar 

  14. Sadzuka Y, Nakade A, Hirama R, Miyagishima A, Nozawa Y, Hirota S, et al. Effects of mixed polyethyleneglycol modification on fixed aqueous layer thickness and antitumor activity of doxorubicin containing liposome. Int J Pharm. 2002;238:171–80.

    Article  CAS  Google Scholar 

  15. Sadzuka Y, Tsuruda T, Sonobe T. Characterization and cytotoxicity of mixed PEG-DSG modified liposomes. Yakugaku Zasshi. 2005;125(1):149–57.

    Article  CAS  Google Scholar 

  16. Sadzuka Y, Sugiyama I, Tsuruda T, Sonobe T. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin. Int J Pharm. 2006;312(1):83–9.

    Article  CAS  Google Scholar 

  17. Sugiyama Y, Sadzuka Y. Characterization of novel mixed polyethyleneglycol modified liposomes. Biol Pharm Bul. 2007;30:208–11.

    Article  CAS  Google Scholar 

  18. Devine DV, Marjan JM. The role of immunoproteins in the survival of liposomes in the circulation. Crit Rev Ther Drug Carrier Syst. 1997;14:105–31.

    Article  CAS  Google Scholar 

  19. Yan X, Scherphof GL, Kamps JA. Liposome opsonization. J Liposome Res. 2005;15:109–39.

    Article  CAS  Google Scholar 

  20. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 1995;55:3752–6.

    CAS  PubMed  Google Scholar 

  21. de Barros ALB, Mota LG, Cardoso VN. Bombesin derivative radiolabeled with technetium-99m as agent for tumor identification. Bioorg Med Chem Let. 2010;30:6182–4.

    Article  Google Scholar 

  22. Bartlett GR. Phosphorus assay in column chromatography. J Biol Chem. 1959;234:466–8.

    CAS  PubMed  Google Scholar 

  23. Satterfield MB, Welch MJ. Comparison by LC-MS and MALDI-MS of prostate-specific antigen from five commercial sources with certified reference material 613. Clin Biochem. 2005;38(2):166–74.

    Article  CAS  Google Scholar 

  24. Dziubla TD, Karim A, Muzykantov VR. Polymer nanocarriers protecting active enzyme cargo against proteolysis. J Cont Rel. 2005;102(2):427–39.

    Article  CAS  Google Scholar 

  25. Maeda H, Fanga J, Inutsuka T, et al. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol. 2003;3:319–28.

    Article  CAS  Google Scholar 

  26. Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE. Tumor-derived endothelial cells exhibit aberrant Rho-madiated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad. 2008;105:11305–10.

    Article  CAS  Google Scholar 

  27. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer. 2005;5:161–71.

    Article  CAS  Google Scholar 

  28. de Barros ALB, Mota LG, Soares DCF, et al. Long-circulating, pH-sensitive liposomes versus long-circulating, non-pH-sensitive liposomes as a delivery system for tumor identification. J Biomed Nanotechnol. 2013;9:1636–43.

    Article  Google Scholar 

  29. Harasym TO, Tardi P, Longman SA, et al. Poly(ethy1ene glycol)-modified phospholipids prevent aggregation during covalent conjugation of proteins to liposomes. Bioconjug Chem. 1995;6(2):187–94.

    Article  Google Scholar 

  30. Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochim Biophys Acta. 1992;113(2):171–99.

    Article  Google Scholar 

  31. Hashizaki K, Taguchi H, Itoh C, Sakai H, Abe M, Saito Y, et al. Effects of poly(ethylene glycol) (PEG) concentration on the permeability of PEG-grafted liposomes. Chem Pharm Bull. 2005;53(1):27–31.

    Article  CAS  Google Scholar 

  32. de Barros ALB, Oliveira MC, Cardoso VN. Tumor bombesin analog loaded long-circulating and pH-sensitive liposomes as tool for tumor identification. Bioorg Med Chem Lett. 2011;21:7373–5.

    Article  Google Scholar 

  33. Evjen TJ, Nilssen EA, Fowler RA, Rognvaldsson S, Brandl M, Fossheim SL. Lipid membrane composition influences drug release from dioleoylphosphatidylethanolamine-based liposomes on exposure to ultrasound. Int J Pharm. 2011;406:114–6.

    Article  CAS  Google Scholar 

  34. Fugit KD, Xiang T-X, Choi DH, Kangarlou S, Csuhai E, Bummer PM, et al. Mechanistic model and analysis of doxorubicin release from liposomal formulations. J Control Release. 2015;217:82–91.

    Article  CAS  Google Scholar 

  35. Chow T-H, Lin Y-Y, Hwang JJ, Wang HE, Tseng YL, Wang SJ, et al. Improvement of biodistribution and therapeutic index via increase of polyethylene glycol on drug-carrying liposomes in an HT-29/luc xenografted mouse model. Anticancer Res. 2009;29:2111–20.

    CAS  PubMed  Google Scholar 

  36. Awasthi VD, Garcia D, Goins BA, Phillips WT. Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits. Int J Pharm. 2003;253:121–32.

    Article  CAS  Google Scholar 

  37. Carvalho-júnior AD, Mota LG, Oliveira MC. Tissue distribuition evaluation of stealth pH-sensitive liposomal cisplatin versus free cisplatin in ehrlich tumor-bearing mice. Life Sci. 2007;80:659–64.

    Article  Google Scholar 

  38. Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics. 2014;4:81–9.

    Article  CAS  Google Scholar 

  39. Elbialy NS, Mady MS. Ehrlich tumor inhibition using doxorubicin containing liposomes. Saudi Pharm J. 2015;23:182–7.

    Article  Google Scholar 

  40. Silva JO, Fernandes RS, Lopes SCA, Cardoso VN, Leite EA, Cassali GD, et al. pH-sensitive, long circulating liposomes as an alternative tool to deliver doxorubicin into tumors: a feasibility animal study. Mol Imaging Biol. 2016;18:898–904.

    Article  CAS  Google Scholar 

Download references

Funding

We wish to thank Pro-Reitoria de Pesquisa (UFMG), Comissão Nacional de Energia Nuclear (CNEN), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for their financial support and fellowships.

Author information

Authors and Affiliations

  1. Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31279-901, Brazil

    Shirleide Santos Nunes, Renata Salgado Fernandes, Carolina Henriques Cavalcante, Isabela da Costa César, Elaine Amaral Leite, Sávia Caldeira Araújo Lopes, Mônica Cristina de Oliveira, Valbert Nascimento Cardoso & André Luís Branco de Barros

  2. Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics, Clinical Laboratory, Microbiology, Pathology, Trasfusional Medicine, Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100, Rovigo, Italy

    Alice Ferretti & Domenico Rubello

  3. Department of Drug Discovery and Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA

    Danyelle M. Townsend

  4. Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    André Luís Branco de Barros

Authors
  1. Shirleide Santos Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renata Salgado Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carolina Henriques Cavalcante
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabela da Costa César
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elaine Amaral Leite
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sávia Caldeira Araújo Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alice Ferretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Domenico Rubello
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Danyelle M. Townsend
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mônica Cristina de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Valbert Nascimento Cardoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. André Luís Branco de Barros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Domenico Rubello or André Luís Branco de Barros.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nunes, S.S., Fernandes, R.S., Cavalcante, C.H. et al. Influence of PEG coating on the biodistribution and tumor accumulation of pH-sensitive liposomes. Drug Deliv. and Transl. Res. 9, 123–130 (2019). https://doi.org/10.1007/s13346-018-0583-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-018-0583-8

Keywords

Search

Navigation