Drug Delivery and Translational Research

, Volume 4, Issue 2, pp 203–209 | Cite as

Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model

  • Ming Yang
  • Tao Yu
  • Joseph Wood
  • Ying-Ying Wang
  • Benjamin C. Tang
  • Qi Zeng
  • Brian W. Simons
  • Jie Fu
  • Chi-Mu Chuang
  • Samuel K. Lai
  • T.-C. Wu
  • Chien-Fu Hung
  • Justin Hanes
Short Communication

Abstract

Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (∼13 % w/w) and prolonged release (∼13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol® (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated with only minimal to mild inflammation. Our findings support PTX/PEG-PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer and potentially other metastatic peritoneal cancers.

Keywords

Drug delivery Controlled release Chemotherapy Biodegradable polymers 

Supplementary material

13346_2013_190_MOESM1_ESM.doc (78 kb)
ESM 1(DOC 78.0 kb)

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3(7):502–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol. 2003;4(5):277–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43.PubMedCrossRefGoogle Scholar
  5. 5.
    Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2006;100(1):27–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Tummala MK, Alagarsamy S, McGuire WP. Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer? Expert Rev Anticancer Ther. 2008;8(7):1135–47.PubMedCrossRefGoogle Scholar
  7. 7.
    Lu Z, Wang J, Wientjes MG, Au JLS. Intraperitoneal therapy for peritoneal cancer. Future Oncol. 2010;6(10):1625–41.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    De Souza R, Zahedi P, Allen CJ, Piquette-Miller M. Polymeric drug delivery systems for localized cancer chemotherapy. Drug Deliv. 2010;17(6):365–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Xiao K, Luo J, Fowler WL, Li Y, Lee JS, Xing L, et al. A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer. Biomaterials. 2009;30(30):6006–16.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Werner ME, Karve S, Sukumar R, Cummings ND, Copp JA, Chen RC, et al. Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis. Biomaterials. 2011;32(33):8548–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Lu Z, Tsai M, Lu D, Wang J, Wientjes MG, Au JL-S. Tumor-penetrating microparticles for intraperitoneal therapy of ovarian cancer. J Pharmacol Exp Ther. 2008;327(3):673–82.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Zahedi P, Stewart J, De Souza R, Piquette-Miller M, Allen C. An injectable depot system for sustained intraperitoneal chemotherapy of ovarian cancer results in favorable drug distribution at the whole body, peritoneal and intratumoral levels. J Control Release. 2012;158(3):379–85.PubMedCrossRefGoogle Scholar
  14. 14.
    Bajaj G, Kim MR, Mohammed SI, Yeo Y. Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors. J Control Release. 2012;158(3):386–92.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Armstrong DK, Fleming GF, Markman M, Bailey HH. A phase I trial of intraperitoneal sustained-release paclitaxel microspheres (Paclimer) in recurrent ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(2):391–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Kumar N, Langer RS, Domb AJ. Polyanhydrides: an overview. Adv Drug Deliv Rev. 2002;54(7):889–910.PubMedCrossRefGoogle Scholar
  17. 17.
    Pillai O, Panchagnula R. Polymers in drug delivery. Curr Opin Chem Biol. 2001;5(4):447–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99(11):3181–98.PubMedCrossRefGoogle Scholar
  19. 19.
    Gopferich A, Tessmar J. Polyanhydride degradation and erosion. Adv Drug Deliv Rev. 2002;54(7):911–31.PubMedCrossRefGoogle Scholar
  20. 20.
    Leong KW, Brott BC, Langer R. Bioerodible polyanhydrides as drug-carrier matrices. I: characterization, degradation, and release characteristics. J Biomed Mater Res. 1985;19(8):941–55.PubMedCrossRefGoogle Scholar
  21. 21.
    Jiang HL, Zhu KJ. Preparation, characterization and degradation characteristics of polyanhydrides containing poly(ethylene glycol). Polym Int. 1999;48(1):47–52.CrossRefGoogle Scholar
  22. 22.
    Fu J, Fiegel J, Krauland E, Hanes J. New polymeric carriers for controlled drug delivery following inhalation or injection. Biomaterials. 2002;23(22):4425–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Fu J, Fiegel J, Hanes J. Synthesis and characterization of PEG-based ether-anhydride terpolymers: novel polymers for controlled drug delivery. Macromolecules. 2004;37(19):7174–80.CrossRefGoogle Scholar
  24. 24.
    Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009;106(46):19268–73.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Tang BC, Fu J, Watkins DN, Hanes J. Enhanced efficacy of local etoposide delivery by poly(ether-anhydride) particles against small cell lung cancer in vivo. Biomaterials. 2010;31(2):339–44.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Erdmann L, Uhrich KE. Synthesis and degradation characteristics of salicylic acid-derived poly(anhydride-esters). Biomaterials. 2000;21(19):1941–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Slivniak R, Domb AJ. Stereocomplexes of enantiomeric lactic acid and sebacic acid ester-anhydride triblock copolymers. Biomacromolecules. 2002;3(4):754–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Shikanov A, Vaisman B, Krasko MY, Nyska A, Domb AJ. Poly(sebacic acid-co-ricinoleic acid) biodegradable carrier for paclitaxel: in vitro release and in vivo toxicity. J Biomed Mater Res A. 2004;69(1):47–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Pfeifer BA, Burdick JA, Langer R. Formulation and surface modification of poly(ester-anhydride) micro- and nanospheres. Biomaterials. 2005;26(2):117–24.PubMedCrossRefGoogle Scholar
  30. 30.
    Shikanov A, Domb AJ. Poly(sebacic acid-co-ricinoleic acid) biodegradable injectable in situ gelling polymer. Biomacromolecules. 2006;7(1):288–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Shikanov A, Vaisman B, Shikanov S, Domb AJ. Efficacy of poly(sebacic acid-co-ricinoleic acid) biodegradable delivery system for intratumoral delivery of paclitaxel. J Biomed Mater Res A. 2010;92(4):1283–91.PubMedGoogle Scholar
  32. 32.
    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 Engl. 2010;49(36):6288–308.PubMedCrossRefGoogle Scholar
  33. 33.
    Gref R, Domb A, Quellec P, Blunk T, Muller RH, Verbavatz JM, et al. The controlled intravenous delivery of drugs using peg-coated sterically stabilized nanospheres. Adv Drug Deliv Rev. 1995;16(2–3):215–33.CrossRefGoogle Scholar
  34. 34.
    Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R. Biodegradable long-circulating polymeric nanospheres. Science. 1994;263(5153):1600–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Owens 3rd DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.PubMedCrossRefGoogle Scholar
  36. 36.
    Innocenti F, Danesi R, Di Paolo A, Agen C, Nardini D, Bocci G, et al. Plasma and tissue disposition of paclitaxel (taxol) after intraperitoneal administration in mice. Drug Metab Dispos Biol Fate Chem. 1995;23(7):713–7.PubMedGoogle Scholar
  37. 37.
    Hung CF, Tsai YC, He L, Wu TC. Control of mesothelin-expressing ovarian cancer using adoptive transfer of mesothelin peptide-specific CD8+ T cells. Gene Ther. 2007;14(12):921–9.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Chang CL, Tsai YC, He L, Wu TC, Hung CF. Cancer immunotherapy using irradiated tumor cells secreting heat shock protein 70. Cancer Res. 2007;67(20):10047–57.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J: Off Publ Fed Am Soc Exp Biol. 2008;22(3):659–61.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2014

Authors and Affiliations

  • Ming Yang
    • 1
    • 9
  • Tao Yu
    • 1
    • 9
  • Joseph Wood
    • 1
  • Ying-Ying Wang
    • 1
    • 9
  • Benjamin C. Tang
    • 2
    • 9
    • 10
  • Qi Zeng
    • 4
  • Brian W. Simons
    • 7
  • Jie Fu
    • 3
    • 9
  • Chi-Mu Chuang
    • 4
  • Samuel K. Lai
    • 2
    • 11
  • T.-C. Wu
    • 4
    • 5
    • 6
  • Chien-Fu Hung
    • 4
    • 5
    • 6
  • Justin Hanes
    • 6
    • 8
    • 9
  1. 1.Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of Ophthalmology, The Wilmer Eye InstituteJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of Obstetrics and GynecologyJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Department of Oncology, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  7. 7.Department of Molecular and Comparative PathobiologyJohns Hopkins University School of MedicineBaltimoreUSA
  8. 8.Center for Cancer Nanotechnology Excellence, Institute for NanoBioTechnologyJohns Hopkins UniversityBaltimoreUSA
  9. 9.The Center for NanomedicineJohns Hopkins University School of MedicineBaltimoreUSA
  10. 10.Koch Institute for Integrated Cancer ResearchMassachusetts Institute of TechnologyCambridgeUSA
  11. 11.Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations