Skip to main content

Advertisement

Log in

Antiangiogenic Activity of Sterically Stabilized Liposomes Containing Paclitaxel (SSL-PTX): In Vitro and In Vivo

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The purpose of this present study was to evaluate the antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX). The SSL-PTX was prepared by the thin-film method. The release of paclitaxel from SSL-PTX was analyzed using a dialysis method. The effect of SSL-PTX on endothelial cell proliferation and migration was investigated in vitro. The antitumor and antiangiogenic activity of SSL-PTX was evaluated in MDA-MB-231 tumor xenograft growth in BALB/c nude mice. The release of paclitaxel from SSL-PTX was 22% within 24 h. Our in vitro results indicated that SSL-PTX could effectively inhibit the endothelial cell proliferation and migration at a concentration-dependent manner. We also observed that metronomic SSL-PTX induced marked tumor growth inhibition in MDA-MB-231 xenograft model via the antiangiogenic mechanism, unlike that in paclitaxel injection (Taxol) formulated in Cremophor EL (CrEL). Overall, our results suggested that metronomic chemotherapy with low-dose, CrEL-free SSL-PTX should be feasible and effective.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Frei 3rd E, Elias A, Wheeler C, Richardson P, Hryniuk W. The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity. Clin Cancer Res. 1998;4:2027–37.

    CAS  PubMed  Google Scholar 

  2. Nieto Y. The verdict is not in yet. Analysis of the randomized trials of high-dose chemotherapy for breast cancer. Haematologica. 2003;88:201–11.

    CAS  PubMed  Google Scholar 

  3. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–36.

    Article  CAS  PubMed  Google Scholar 

  4. Laquente B, Viñals F, Germà JR. Metronomic chemotherapy: an antiangiogenic scheduling. Clin Transl Oncol. 2007;9:93–8.

    Article  CAS  PubMed  Google Scholar 

  5. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O’Reilly MS et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.

    CAS  PubMed  Google Scholar 

  6. Kamat AA, Kim TJ, Landen Jr CN, Lu C, Han LY, Lin YG et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res. 2007;67:281–8.

    Article  CAS  PubMed  Google Scholar 

  7. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 1996;2:1843–9.

    CAS  PubMed  Google Scholar 

  8. Ng SS, Figg WD, Sparreboom A. Taxane-mediated antiangiogenesis in vitro: influence of formulation vehicles and binding proteins. Cancer Res. 2004;64:821–4.

    Article  CAS  PubMed  Google Scholar 

  9. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60:1615–26.

    Article  CAS  PubMed  Google Scholar 

  10. Straubinger RM, Arnold RD, Zhou R, Mazurchuk R, Slack JE. Antivascular and antitumor activities of liposome-associated drugs. Anticancer Res. 2004;24:397–404.

    CAS  PubMed  Google Scholar 

  11. Sharma A, Sharma US, Straubinger RM. Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. Cancer Lett. 1996;107:265–72.

    Article  CAS  PubMed  Google Scholar 

  12. Huwyler J, Drewe J, Krähenbuhl S. Tumor targeting using liposomal antineoplastic drugs. Int J Nanomedicine. 2008;3:21–9.

    Article  CAS  PubMed  Google Scholar 

  13. Moghimi SM, Patel HM. Opsonophagocytosis of liposomes by peritoneal macrophages and bone marrow reticuloendothelial cells. Biochim Biophys Acta. 1992;1135:269–74.

    Article  CAS  PubMed  Google Scholar 

  14. Lasic DD. Doxorubicin in sterically stabilized liposomes. Nature. 1996;11(380):561–2.

    Article  Google Scholar 

  15. 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 

  16. Yang T, Cui FD, Choi MK, Cho JW, Chung SJ, Shim CK et al. Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation. Int J Pharm. 2007;338:317–26.

    Article  CAS  PubMed  Google Scholar 

  17. Yang T, Choi MK, Cui FD, Lee SJ, Chung SJ, Shim CK et al. Antitumor effect of paclitaxel-loaded PEGylated immunoliposomes against human breast cancer cells. Pharm Res. 2007;24:2402–11.

    Article  CAS  PubMed  Google Scholar 

  18. Crosasso P, Ceruti M, Brusa P, Arpicco S, Dosio F, Cattel L. Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. J Control Release. 2000;63:19–30.

    Article  CAS  PubMed  Google Scholar 

  19. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int J Nanomedicine. 2009;4:99–105.

    CAS  PubMed  Google Scholar 

  20. Stinchcombe TE. Nanoparticle albumin-bound paclitaxel: a novel Cremophor-EL free formulation of paclitaxel. Nanomedicine (Lond). 2007;2:415–23.

    Article  CAS  Google Scholar 

  21. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317–24.

    Article  CAS  PubMed  Google Scholar 

  22. Ng SS, Sparreboom A, Shaked Y, Lee C, Man S, Desai N et al. Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus Cremophor EL-based paclitaxel. Clin Cancer Res. 2006;12:4331–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ashton AW, Yokota R, John G, Zhao S, Suadicani SO, Spray DC et al. Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A(2). J Biol Chem. 1999;274:35562–70.

    Article  CAS  PubMed  Google Scholar 

  24. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–6.

    Article  CAS  PubMed  Google Scholar 

  25. Bijman MN, Van Nieuw Amerongen GP, Laurens N, van Hinsbergh VW, Boven E. Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol Cancer Ther. 2006;5:2348–57.

    Article  CAS  PubMed  Google Scholar 

  26. Liu XR, Wu KC, Huang Y, Sun JB, Ke XY, Wang JC et al. In vitro and in vivo studies on plasma-to-blood ratio of paclitaxel in human, rabbit and rat blood fractions. Biol Pharm Bull. 2008;31:1215–20.

    Article  CAS  PubMed  Google Scholar 

  27. Aapro MS, Von Minckwitzb G. Molecular basis for the development of novel taxanes in the treatment of metastatic breast cancer. EJC Supplements. 2008;6:3–11.

    CAS  Google Scholar 

  28. Kunstfeld R, Wickenhauser G, Michaelis U, Teifel M, Umek W, Naujoks K et al. Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a “humanized” SCID mouse model. J Invest Dermatol. 2003;120:476–82.

    Article  CAS  PubMed  Google Scholar 

  29. Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M et al. Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res. 2003;9:2335–41.

    CAS  PubMed  Google Scholar 

  30. Strieth S, Eichhorn ME, Sauer B, Schulze B, Teifel M, Michaelis U et al. Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature. Int J Cancer. 2004;110:117–24.

    Article  CAS  PubMed  Google Scholar 

  31. Strieth S, Nussbaum CF, Eichhorn ME, Fuhrmann M, Teifel M, Michaelis U et al. Tumor-selective vessel occlusions by platelets after vascular targeting chemotherapy using paclitaxel encapsulated in cationic liposomes. Int J Cancer. 2008;122:452–60.

    Article  CAS  PubMed  Google Scholar 

  32. Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U et al. Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res. 2008;14:4603–11.

    Article  CAS  PubMed  Google Scholar 

  33. Bode C, Trojan L, Weiss C, Kraenzlin B, Michaelis U, Teifel M et al. Paclitaxel encapsulated in cationic liposomes: a new option for neovascular targeting for the treatment of prostate cancer. Oncol Rep. 2009;22:321–6.

    CAS  PubMed  Google Scholar 

  34. Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res. 1999;59:1454–7.

    CAS  PubMed  Google Scholar 

  35. Ellis AG, Webster LK. Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL. Cancer Chemother Pharmacol. 1999;43:13–8.

    Article  CAS  PubMed  Google Scholar 

  36. Marcel Musteata F, Pawliszyn J. Determination of free concentration of paclitaxel in liposome formulation. J Pharm Pharm Sci. 2006;9:231–7.

    PubMed  Google Scholar 

  37. Fielding RM. Liposomal drug delivery. Advantages and limitations from a clinical pharmacokinetic and therapeutic perspective. Clin Pharmacokinet. 1991;21:155–64.

    Article  CAS  PubMed  Google Scholar 

  38. Campbell RB, Ying B, Kuesters GM, Hemphill R. Fighting cancer: from the bench to bedside using second generation cationic liposomal therapeutics. J Pharm Sci. 2009;98:411–29.

    Article  CAS  PubMed  Google Scholar 

  39. Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment. Urol Oncol. 2008;26:57–64.

    CAS  PubMed  Google Scholar 

  40. Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 1994;54:3352–6.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 30873170) and the National Basic Research Program of China (973 Program 2007CB935800 and 2009CB930300).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xuan Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, Y., Chen, XM., Zhao, BX. et al. Antiangiogenic Activity of Sterically Stabilized Liposomes Containing Paclitaxel (SSL-PTX): In Vitro and In Vivo . AAPS PharmSciTech 11, 752–759 (2010). https://doi.org/10.1208/s12249-010-9430-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-010-9430-z

Key words

Navigation