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Polysialic acid-polyethylene glycol conjugate-modified liposomes as a targeted drug delivery system for epirubicin to enhance anticancer efficiency

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Abstract

Polysialic acid (PSA) is a nonimmunogenic and biodegradable polysaccharide. In recent years, PSA has shown its potential applications to cancer treatment. In this study, PSA-polyethylene glycol (PEG) conjugate was synthesized for the decoration of epirubicin (EPI)-loaded liposomes. The study aimed to evaluate the PSA-PEG conjugated modified liposomes (EPI-PSL) in vitro and in vivo to investigate the role of PSA on physicochemical characteristics and antitumor activity in PEGylated liposomes. EPI-PSL showed a particle size of 116.9 ± 5.2 nm, zeta potential of − 40.3 ± 3.5 mV, and encapsulation efficiency of 99.1 ± 1.5%. The results of in vitro release experiments showed a delayed release of EPI from EPI-PSL. Greater cellular uptake of EPI-PSL was observed compared with PEGylated liposomes (EPI-PL) in B16 cells. Cytotoxicity studies suggested that EPI-PSL exhibited stronger cytotoxic activity than EPI-PL. Though EPI-PSL exhibited comparable blood plasma profiles with EPI-PL, biodistribution studies proved that the distribution of EPI-PSL in tumors was more than that of EPI-PL. The superior antitumor efficacy of EPI-PSL was also verified in the B16 xenograft mouse model with a reduction in systemic toxicity. In conclusion, these results therefore indicated that PSA-modified PEGylated liposomes may represent an excellent anticancer drug delivery system for targeted cancer therapy.

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Abbreviations

EPI:

Epirubicin

PSA:

Polysialic acid

DSPE-PEG2000-COOH:

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (ammonium salt)

EPI-S:

EPI solution

EPI-PL:

PEGylated liposomal EPI

EPI-PSL:

PSA-PEG2000-DSPE-modified liposomal EPI

EPR effect:

Enhanced permeation and retention effect

EE:

Encapsulation efficiency

AUC(0–t) :

Area under the drug concentration-time curve values

C max :

Maximum concentration

MRT(0–t) :

Mean residence time

CLz:

Total clearance

References

  1. Kwon IK, Lee SC, Han B, Park K. Analysis on the current status of targeted drug delivery to tumors. J Control Release. 2012;164:108–14.

    Article  CAS  PubMed  Google Scholar 

  2. Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30:592–9.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang L, Gu F, Chan J, Wang A, Langer R, Farokhzad O. Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther. 2008;83:761–9.

    Article  CAS  PubMed  Google Scholar 

  4. Ma Y, Yang Q, Wang L, Zhou X, Zhao Y, Deng Y. Repeated injections of PEGylated liposomal topotecan induces accelerated blood clearance phenomenon in rats. Eur J Pharm Sci. 2012;45:539–45.

    Article  CAS  PubMed  Google Scholar 

  5. Park J-H, Cho H-J, Yoon HY, Yoon I-S, Ko S-H, Shim J-S, et al. Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery. J Control Release. 2014;174:98–108.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang T, Zhou S, Kang L, Luo X, Liu Y, Song Y, et al. The effect of monosialylganglioside mix modifying the PEGylated liposomal epirubicin on the accelerated blood clearance phenomenon. Asian J Pharm Sci. 2017;12:134–42.

    Article  Google Scholar 

  7. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013;65:36–48.

    Article  CAS  PubMed  Google Scholar 

  8. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153:198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Taurin S, Nehoff H, Greish K. Anticancer nanomedicine and tumor vascular permeability; where is the missing link? J Control Release. 2012;164:265–75.

    Article  CAS  PubMed  Google Scholar 

  10. Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451–8.

    Article  CAS  PubMed  Google Scholar 

  11. Hoffman AS. The origins and evolution of “controlled” drug delivery systems. J Control Release. 2008;132:153–63.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang T, She Z, Huang Z, Li J, Luo X, Deng Y. Application of sialic acid/polysialic acid in the drug delivery systems. Asian J Pharm Sci. 2014;9:75–81.

    Article  Google Scholar 

  13. Hatakeyama H, Akita H, Harashima H. A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. Adv Drug Deliv Rev. 2011;63:152–60.

    Article  CAS  PubMed  Google Scholar 

  14. Deepagan V, Thambi T, Ko H, Kang YM, Park JH. Amphiphilic polysialic acid derivatives: synthesis, characterization, and in-vitro cytotoxicity. J Nanosci Nanotechnol. 2013;13:7312–8.

    Article  CAS  PubMed  Google Scholar 

  15. Wang B, Chen Y, Ren H, Zhang N, Troy I, Arthur F. Biochemical characterization and analyses of polysialic acid-associated carrier proteins and genes in piglets during neonatal development. Chembiochem. 2017;

  16. Hildebrandt H, Dityatev A. Polysialic acid in brain development and synaptic plasticity. Top Curr Chem. 2013;366:55–96.

    Article  Google Scholar 

  17. Barry GT, Goebel WF. Colominic acid, a substance of bacterial origin related to sialic acid. Nature. 1957;179:206.

    Article  CAS  PubMed  Google Scholar 

  18. Manzi AE, Higa HH, Diaz S, Varki A. Intramolecular self-cleavage of polysialic acid. J Biol Chem. 1994;269:23617–24.

    CAS  PubMed  Google Scholar 

  19. Lee HJ, Rakić B, Gilbert M, Wakarchuk WW, Withers SG, Strynadka NC. Structural and kinetic characterizations of the polysialic acid O-acetyltransferase OatWY from Neisseria meningitidis. J Biol Chem. 2009;284:24501–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robbins JB, Schneerson R, Xie G, Hanson LÅ, Miller MA. Capsular polysaccharide vaccine for group B Neisseria meningitidis, Escherichia coli K1, and Pasteurella haemolytica A2. Proc Natl Acad Sci. 2011;108:17871–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Greco F, Arif I, Botting R, Fante C, Quintieri L, Clementi C, et al. Polysialic acid as a drug carrier: evaluation of a new polysialic acid–epirubicin conjugate and its comparison against established drug carriers. Polym Chem. 2013;4:1600–9.

    Article  CAS  Google Scholar 

  22. Jung B, Shim M-K, Park M-J, Jang EH, Yoon HY, Kim K, et al. Hydrophobically modified polysaccharide-based on polysialic acid nanoparticles as carriers for anticancer drugs. Int J Pharm. 2017;520:111–8.

    Article  CAS  PubMed  Google Scholar 

  23. Wu J, Lu S, Zheng Z, Zhu L, Zhan X. Modification with polysialic acid–PEG copolymer as a new method for improving the therapeutic efficacy of proteins. Prep Biochem Biotechnol. 2016;46:788–97.

    Article  CAS  PubMed  Google Scholar 

  24. Sato C, Kitajima K. Disialic, oligosialic and polysialic acids: distribution, functions and related disease. J Biochem. 2013;154:115–36.

    Article  CAS  PubMed  Google Scholar 

  25. Itoh N. The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull. 2007;30:1819–25.

    Article  CAS  PubMed  Google Scholar 

  26. Ono S, Hane M, Kitajima K, Sato C. Novel regulation of fibroblast growth factor 2 (FGF2)-mediated cell growth by polysialic acid. J Biol Chem. 2012;287:3710–22.

    Article  CAS  PubMed  Google Scholar 

  27. Zheng Z-Y, Wang S-Z, Li G-S, Zhan X-B, Lin C-C, Wu J-R, et al. A new polysialic acid production process based on dual-stage pH control and fed-batch fermentation for higher yield and resulting high molecular weight product. Appl Microbiol Biotechnol. 2013;97:2405–12.

    Article  CAS  PubMed  Google Scholar 

  28. Rode B, Endres C, Ran C, Stahl F, Beutel S, Kasper C, et al. Large-scale production and homogenous purification of long chain polysialic acids from E. coli K1. J Biotechnol. 2008;135:202–9.

    Article  CAS  PubMed  Google Scholar 

  29. Gregoriadis G, Fernandes A, Mital M, McCormack B. Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cell Mol Life Sci. 2000;57:1964–9.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang W, Dong D, Li P, Wang D, Mu H, Niu H, et al. Novel pH-sensitive polysialic acid based polymeric micelles for triggered intracellular release of hydrophobic drug. Carbohydr Polym. 2016;139:75–81.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang T, Zhou S, Hu L, Peng B, Liu Y, Luo X, et al. Polysialic acid-modifying liposomes for efficient delivery of epirubicin, in-vitro characterization and in-vivo evaluation. Int J Pharm. 2016;515:449–59.

    Article  CAS  PubMed  Google Scholar 

  32. Care IoLARCo, Animals UoL, Resources NIoHDoR. Guide for the care and use of laboratory animals. Washington: The National Academies Press; 1985.

    Google Scholar 

  33. Zhou S, Zhang T, Peng B, Luo X, Liu X, Hu L, et al. Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity. Int J Pharm. 2017;523:203–16.

    Article  CAS  PubMed  Google Scholar 

  34. Dos Santos N, Cox KA, McKenzie CA, van Baarda F, Gallagher RC, Karlsson G, et al. pH gradient loading of anthracyclines into cholesterol-free liposomes: enhancing drug loading rates through use of ethanol. Biochim Biophys Acta. 2004;1661:47–60.

    Article  CAS  PubMed  Google Scholar 

  35. She Z, Zhang T, Wang X, Li X, Song Y, Cheng X, et al. The anticancer efficacy of pixantrone-loaded liposomes decorated with sialic acid–octadecylamine conjugate. Biomaterials. 2014;35:5216–25.

    Article  CAS  PubMed  Google Scholar 

  36. Yang Q, Zhang T, Wang C, Jiao J, Li J, Deng Y. Coencapsulation of epirubicin and metformin in PEGylated liposomes inhibits the recurrence of murine sarcoma S180 existing CD133+ cancer stem-like cells. Eur J Pharm Biopharm. 2014;88:737–45.

    Article  CAS  PubMed  Google Scholar 

  37. Cui J, Li C, Guo W, Li Y, Wang C, Zhang L, et al. Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? J Control Release. 2007;118:204–15.

    Article  CAS  PubMed  Google Scholar 

  38. Mühlenhoff M, Eckhardt M, Gerardy-Schahn R. Polysialic acid: three-dimensional structure, biosynthesis and function. Curr Opin Struct Biol. 1998;8:558–64.

    Article  PubMed  Google Scholar 

  39. Nowotarski K, Sapoń K, Kowalska M, Janas T, Janas T. Membrane potential-dependent binding of polysialic acid to lipid monolayers and bilayers. Cell Mol Biol Lett. 2013;18:579–94.

    Article  CAS  PubMed  Google Scholar 

  40. Bader RA, Silvers AL, Zhang N. Polysialic acid-based micelles for encapsulation of hydrophobic drugs. Biomacromolecules. 2011;12:314–20.

    Article  CAS  PubMed  Google Scholar 

  41. H-z Z, F-p G, L-r L, Li X-m, Z-m Z, X-d Y, et al. Pullulan acetate nanoparticles prepared by solvent diffusion method for epirubicin chemotherapy. Colloids Surf B Biointerfaces. 2009;71:19–26.

    Article  Google Scholar 

  42. Li D, Wang H, Xiang J-J, Deng N, Wang P-P, Kang Y-L, et al. Monoclonal antibodies targeting basic fibroblast growth factor inhibit the growth of B16 melanoma in vivo and in vitro. Oncol Rep. 2010;24:457–63.

    CAS  PubMed  Google Scholar 

  43. Löffek S, Zigrino P, Angel P, Anwald B, Krieg T, Mauch C. High invasive melanoma cells induce matrix metalloproteinase-1 synthesis in fibroblasts by interleukin-1α and basic fibroblast growth factor-mediated mechanisms. J Investig Dermatol. 2005;124:638–43.

    Article  PubMed  Google Scholar 

  44. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 1999;51:691–744.

    CAS  PubMed  Google Scholar 

  45. Xiao K, Li Y, Luo J, Lee JS, Xiao W, Gonik AM, et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011;32:3435–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657–66.

    Article  CAS  PubMed  Google Scholar 

  47. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102.

    Article  CAS  PubMed  Google Scholar 

  48. Song S, Liu D, Peng J, Sun Y, Li Z, Gu J-R, et al. Peptide ligand-mediated liposome distribution and targeting to EGFR expressing tumor in vivo. Int J Pharm. 2008;363:155–61.

    Article  CAS  PubMed  Google Scholar 

  49. Song X, Wan Z, Chen T, Fu Y, Jiang K, Yi X, et al. Development of a multi-target peptide for potentiating chemotherapy by modulating tumor microenvironment. Biomaterials. 2016;108:44–56.

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 81373334).

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Author notes

  1. Ting Zhang and Songlei Zhou contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China

    Ting Zhang, Songlei Zhou, Ling Hu, Bo Peng, Yang Liu, Xiang Luo, Xinrong Liu, Yanzhi Song & Yihui Deng

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  1. Ting Zhang
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Correspondence to Yihui Deng.

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Zhang, T., Zhou, S., Hu, L. et al. Polysialic acid-polyethylene glycol conjugate-modified liposomes as a targeted drug delivery system for epirubicin to enhance anticancer efficiency. Drug Deliv. and Transl. Res. 8, 602–616 (2018). https://doi.org/10.1007/s13346-018-0496-6

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