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EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment

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ABSTRACT

Purpose

To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against Saos-2 osteosarcoma cells.

Methods

PEGylated liposomes were prepared by thin film method using Dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearylphosphatidylethanolamine-polyethyleneglycol conjugate (DSPE-mPEG) in 67.9:29.1:3 M ratios, and loaded with DOX (L-DOX) by pH-gradient method. Targeted liposomes (YSA-L-DOX), were prepared by conjugating YSA-peptide to DSPE-mPEG. Liposomes were physicochemically characterized and tested in cellular toxicity assays.

Results

YSA conjugation efficiency was >98%. Size and polydispersity index of both L-DOX and YSA-L-DOX were around 88 nm and 0.188, respectively. Both had similar zeta potential, and 85% DOX loading efficiencies. DOX release kinetics followed the Korsmeyer-Peppa model, and showed comparable release for both formulations from 1–8 h, and a plateau of 29% after 48 h. Both formulations could be stably stored for ≥6 months at 4°C in the dark. Toxicity assays showed a significant 1.91-fold higher cytotoxicity compared to free DOX in the Saos-2 cells, and 2-fold lesser toxicity in primary bone cells compared to the Saos-2 cells. Cellular uptake studies showed higher and more nuclear uptake in YSA-L-DOX compared to L-DOX treated cells.

Conclusions

YSA-L-DOX vesicles might be effective for targeted treatment of osteosarcoma.

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Abbreviations

DOX-HCl:

Doxorubicin hydrochloride

Eph:

Ephrin receptors

EphA2:

Ephrin Alpha 2 receptor

exp:

Experimental

L:

Liposome

PDI:

Polydispersity index

pre:

Predicted

YSA-L:

Targeted liposome with YSA peptide

REFERENCES

  1. De Boer JP. Towards targeted treatment for osteosarcoma. VU University Medical Center; 2014.

  2. Ta HT, Dass CR, Choong PFM, Dunstan DE. Osteosarcoma treatment: state of the art. Cancer Metastasis Rev. 2009;28(1-2):247–63. Springer

    Article  Google Scholar 

  3. Machak GN, Tkachev SI, Solovyev YN, Sinyukov PA, Ivanov SM, Kochergina NV, et al. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc [Internet]. 2003;78(2):147–55. Elsevier. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0025619611625469

    Article  Google Scholar 

  4. Smeland S, Wiebe T, Böhling T, Brosjö O, Jonsson K, Alvegård T. Chemotherapy in osteosarcoma: the Scandinavian Sarcoma group experience. Acta Orthop Scand. 2004;75(Supplement 311):92–8. Taylor & Francis Group

    Article  CAS  Google Scholar 

  5. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219–34. Nature Publishing Group

    Article  Google Scholar 

  6. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013;65(2):157–70. Wiley Online Library

    Article  CAS  Google Scholar 

  7. Du C, Deng D, Shan L, Wan S, Cao J, Tian J, et al. A pH-sensitive doxorubicin prodrug based on folate-conjugated BSA for tumor-targeted drug delivery. Biomaterials. 2013;34(12):3087–97. Elsevier

    Article  CAS  Google Scholar 

  8. Elbialy NS, Fathy MM, Khalil WM. Doxorubicin loaded magnetic gold nanoparticles for in vivo targeted drug delivery. Int J Pharm. 2015;490(1):190–9. Elsevier

    Article  CAS  Google Scholar 

  9. Ahmed M, Moussa M, Goldberg SN. Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation. Chem Phys Lipids [Internet]. 2012;165(4):424–37. Elsevier. Available from: http://linkinghub.elsevier.com/retrieve/pii/S000930841100363X

    Article  CAS  Google Scholar 

  10. Varelias A, Koblar SA, Cowled PA, Carter CD, Clayer M. Human osteosarcoma expresses specific ephrin profiles. Cancer. 2002;95(4):862–9. Wiley Online Library

    Article  Google Scholar 

  11. Lindberg RA, Hunter T. cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases. Mol Cell Biol Am Soc Microbiol. 1990;10(12):6316–24.

    Article  CAS  Google Scholar 

  12. Bartley TD, Hunt RW, Welcher AA, Boyle WJ, Parker VP, Lindberg RA, Lu HS, Colombero AM, Elliott RL, Guthrie BA, Holst PL. B61 is a ligand for the ECK receptor protein-tyrosine kinase. Nature. 1994;368(6471):558–60.

    Article  CAS  Google Scholar 

  13. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10(3):165–80. Nature Publishing Group

    Article  CAS  Google Scholar 

  14. Posthumadeboer J, Piersma SR, Pham TV, van Egmond PW, Knol JC, Cleton-Jansen AM, et al. Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. Br J Cancer. 2013;109(8):2142–54. Nature Publishing Group

    Article  CAS  Google Scholar 

  15. Wang J, Liu Y, Li Y, Dai W, Guo Z, Wang Z, et al. EphA2 Targeted Doxorubicin Stealth Liposomes as a Therapy System for Choroidal Neovascularization in RatsYSA-SSL-DOX Improving DOX Efficacy in CNV Rat. Invest Ophthalmol Vis Sci. 2012;53(11):7348–57. The Association for Research in Vision and Ophthalmology

    Article  CAS  Google Scholar 

  16. Shahin M, Soudy R, El-Sikhry H, Seubert JM, Kaur K, Lavasanifar A. Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin. Cancer Lett. 2013;334(2):284–92. Elsevier

    Article  CAS  Google Scholar 

  17. Haghiralsadat F, Amoabediny G, Sheikhha MH, Zandieh-doulabi B, Naderinezhad S, Helder MN, Forouzanfar T. New liposomal doxorubicin nanoformulation for osteosarcoma: drug release kinetic study based on thermo and pH sensitivity. Chem Biol Drug Des. 2017. http://onlinelibrary.wiley.com/doi/10.1111/cbdd.12953/full.

  18. Haghiralsadat F, Amoabediny G, Sheikhha MH, Forouzanfar T, Helder MN, Zandieh-doulabi B. A novel approach on drug delivery: investigation of a new nano-formulation of liposomal doxorubicin andbiological evaluation of entrapped doxorubicin on various osteosarcoma cell lines. Cell J (Yakhteh). 2017;19 Suppl 1:55.

  19. Narsimhan B, Mallapragada SK, Peppas NA. Release Kinetics, Data Interpretation. In: Mathiowitz E, editor. Encyclopedia of Controlled Drug Delivery. New York: Wiley; 1999. p. 921.

    Google Scholar 

  20. Bourne DW. Pharmacokinetics In: Modern pharmaceutics. New York: Marcel Dekker Inc; 2002.

    Book  Google Scholar 

  21. Thawatchai P, Tamotsu K, Garnpimol CR. Chitosan citrate as film former: compatibility with water-soluble anionic dyes and drug dissolution from coated tablet. Int J Pharm. 2000;198:97–111.

    Article  Google Scholar 

  22. Hixson AW, Crowell JH. Dependence of reaction velocity upon surface and agitation. Ind Eng Chem. 1931;23(10):1160–8. ACS Publications

    Article  CAS  Google Scholar 

  23. Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci. 1961;50(10):874–5. Wiley Online Library

    Article  CAS  Google Scholar 

  24. Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9. Wiley Online Library

    Article  CAS  Google Scholar 

  25. Ritger PL, Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release. 1987;5(1):37–42. Elsevier

    Article  CAS  Google Scholar 

  26. Barzegar-Jalali M, Adibkia K, Valizadeh H, Shadbad MRS, Nokhodchi A, Omidi Y, et al. Kinetic analysis of drug release from nanoparticles. J Pharm Pharm Sci. 2008;11(1):167–77. Canadian Society for Pharmaceutical Sciences

    Article  CAS  Google Scholar 

  27. Naderinezhad S, Ghasem Amoabediny FH, Naderinezhad S, Amoabediny G, Haghiralsadat F. Co-delivery of hydrophilic and hydrophobic anticancer drugs using biocompatible pH-sensitive lipid-based nano-carrier for multidrug-resistant cancers. RSC Adv [Internet]. 2017;7(48):30008–19. The Royal Society of Chemistry. Available from: https://doi.org/10.1039/C7RA01736G

    Article  CAS  Google Scholar 

  28. Yang T, Li B, Qi S, Liu Y, Gai Y, Ye P, et al. Co-delivery of doxorubicin and Bmi1 siRNA by folate receptor targeted liposomes exhibits enhanced anti-tumor effects in vitro and in vivo. Theranostics. 2014;4(11):1096–111. Ivyspring International Publisher

    Article  CAS  Google Scholar 

  29. Kibria G, Hatakeyama H, Ohga N, Hida K, Harashima H. Dual-ligand modification of PEGylated liposomes shows better cell selectivity and efficient gene delivery. J Control Release. 2011;153(2):141–8. Elsevier

    Article  CAS  Google Scholar 

  30. Mourtas S, Fotopoulou S, Duraj S, Sfika V, Tsakiroglou C, Antimisiaris SG. Liposomal drugs dispersed in hydrogels: effect of liposome, drug and gel properties on drug release kinetics. Colloids Surf B Biointerfaces. 2007;(2):55, 212–221. Elsevier

  31. Sanson C, Schatz C, Le Meins J-F, Soum A, Thévenot J, Garanger E, et al. A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Control Release. 2010;147(3):428–35. Elsevier

    Article  CAS  Google Scholar 

  32. Haghiralsadat F, Amoabediny G, Helder MN, Naderinezhad S, Sheikhha MH, Forouzanfar T, et al. A comprehensive mathematical model of drug release kinetics from nano-liposomes, derived from optimization studies of cationic PEGylated liposomal doxorubicin formulations for drug-gene delivery. Artif Cells, Nanomedicine, Biotechnol [Internet]. 2017:1–9. Available from: https://doi.org/10.1080/21691401.2017.1304403. Taylor & Francis

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran

    Fateme Haghiralsadat

  2. Department of Oral & Maxillofacial Surgery, VU University Medical Center, MOVE Research Institute Amsterdam, Amsterdam, The Netherlands

    Fateme Haghiralsadat, Tymour Forouzanfar & Marco N. Helder

  3. Department of Biotechnology and Pharmaceutical Engineering, Faculty of Chemical Engineering, School of Engineering, University of Tehran, Tehran, Iran

    Ghasem Amoabediny & Samira Naderinezhad

  4. Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Univrsiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands

    Kamran Nazmi

  5. Department of Orthopedic Surgery, VU University Medical Center, Amsterdam Movement Sciences, Amsterdam, Netherlands

    Jantine Posthuma De Boer

  6. Oral Cell Biology and Functional Anatomy, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Behrouz Zandieh-Doulabi

Authors
  1. Fateme Haghiralsadat
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  2. Ghasem Amoabediny
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  3. Samira Naderinezhad
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  4. Kamran Nazmi
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  5. Jantine Posthuma De Boer
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  6. Behrouz Zandieh-Doulabi
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  7. Tymour Forouzanfar
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  8. Marco N. Helder
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Corresponding author

Correspondence to Ghasem Amoabediny.

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Haghiralsadat, F., Amoabediny, G., Naderinezhad, S. et al. EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment. Pharm Res 34, 2891–2900 (2017). https://doi.org/10.1007/s11095-017-2272-6

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  • DOI: https://doi.org/10.1007/s11095-017-2272-6

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