Investigational New Drugs

, Volume 30, Issue 1, pp 1–7 | Cite as

The antitumor effect of a thermosensitive polymeric hydrogel containing paclitaxel in a peritoneal carcinomatosis model

  • Jieun Yu
  • Hyuk-Joon Lee
  • Keun Hur
  • Mi Kyung Kwak
  • Tae Su Han
  • Woo Ho Kim
  • Soo-Chang Song
  • Kazuyoshi Yanagihara
  • Han-Kwang Yang
PRECLINICAL STUDIES

Summary

The prognosis of peritoneal carcinomatosis is regarded as poor because safe, effective therapeutic modalities are lacking. Intraperitoneal chemotherapy is one treatment option, involving the delivery of a high concentration of chemotherapeutic drugs into the abdominal cavity, but the severe side effects associated with such treatment are a major obstacle in clinical application. We evaluated the anti-cancer effects of intraperitoneal delivery of a thermosensitive polymeric hydrogel containing chemotherapeutics in an animal model of carcinomatosis. The progress of peritoneal carcinomatosis, introduced by injecting a luciferase-transfected human gastric cancer cell line (HSC44Luc) into the peritoneal cavity of nude mice, was quantitatively evaluated by in vivo bioluminescence imaging. Three days after intraperitoneal (IP) injection of HSC44Luc cells, treatment solutions were injected into the peritoneal cavity. Mice were categorized into four groups depending on treatment method; these were (1) a control PBS group (n = 5), (2) a hydrogel-only group (n = 5), (3) a paclitaxel solution (30 mg/kg) group (n = 3), and (4) a hydrogel-with-paclitaxel (15 mg/kg) group (n = 5). Quantitative photon counting was performed weekly in each animal. Mice were sacrificed on the 5th or 28th day after treatment, for pathologic evaluation. In vivo bioluminescence imaging showed that photon counts in the hydrogel-with-paclitaxel and paclitaxel solution groups were significantly lower than in the PBS group over the entire experimental period. Although neither group of responding mice showed any peritoneal nodules on the 28th day after treatment, only the paclitaxel solution group exhibited dilated edematous changes in the intestine; these side effects were absent in animals treated with hydrogel-with-paclitaxel group. In conclusion, a thermosensitive hydrogel containing paclitaxel may be a safe and effective treatment option for peritoneal carcinomatosis.

Keywords

Thermosensitive polymeric hydrogel Bioluminescence imaging Peritoneal dissemination Gastric cancer Paclitaxel 

Reference

  1. 1.
    Glehen O, Mithieux F, Osinsky D, Beaujard AC, Freyer G, Guertsch P, Francois Y, Peyrat P, Panteix G, Vignal J, Gilly FN (2003) Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: A Phase II Study. J Clin Oncol 21(5):799–806PubMedCrossRefGoogle Scholar
  2. 2.
    Yonemura Y, Kawamura T, Bandou E, Takahashi S, Sawa T, Matsuki N (2005) Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion. Br J Surg 92(3):370–375PubMedCrossRefGoogle Scholar
  3. 3.
    Fujimoto S, Shrestha RD, Kokubun M, Kobayashi K, Kiuchi S, Konno C, Ohta M, Takahashi M, Kitsukawa Y, Mizutani M, Chikenji T, Okui K (1990) Positive results of combined therapy of surgery and intraperitoneal hyperthermic perfusion for far-advanced gastric cancer. Ann Surg 212(5):592–6PubMedCrossRefGoogle Scholar
  4. 4.
    Sugarbaker PH, Yonemura Y (2000) Clinical pathway for the management of resectable gastric cancer with peritoneal seeding: best palliation with a ray of hope for cure. Oncology 58(2):96–107PubMedCrossRefGoogle Scholar
  5. 5.
    Chua TC, Yan TD, Saxena A, Morris DL (2009) Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann Surg 249(6):900–907PubMedCrossRefGoogle Scholar
  6. 6.
    Farb A, Heller PF, Shroff S, Cheng L, Kolodgie FD, Carter AJ, Scott DS, Froehlich J, Virmani R (2001) Pathological analysis of local delivery of paclitaxel via a polymer-Coated Stent. Circulation 104(4):473–479PubMedCrossRefGoogle Scholar
  7. 7.
    Moses MA, Brem H, Langer R (2003) Advancing the field of drug delivery taking aim at cancer. Cancer Cell 4(5):337–341PubMedCrossRefGoogle Scholar
  8. 8.
    Oh YK, Senter PD, Song SC (2009) Intelligent drug delivery systems. Bioconjug Chem 20(10):1813–1815PubMedCrossRefGoogle Scholar
  9. 9.
    Chun C, Lee SM, Kim SY, Yang HK, Song SC (2009) Thermosensitive poly(organophosphazene)-paclitaxel conjugate gels for antitumor applications. Biomaterials 30(12):2349–2360PubMedCrossRefGoogle Scholar
  10. 10.
    Han HD, Song CK, Park YS, Noh KH, Kim JH, Taewon Hwang T, Kim TW, Shin BC (2008) A chitosan hydrogel-based cancer drug delivery system exhibits synergistic antitumor effects. Int J Pharm 350(1–2):27–34PubMedCrossRefGoogle Scholar
  11. 11.
    Chen G, Hoffman AS (1995) Graft copolymers that exhibit temperature induced phase transitions over a wide range of pH. Nature 373(6509):49–52PubMedCrossRefGoogle Scholar
  12. 12.
    Jeong B, Bae YH, Lee DS, Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery systems. Nature 388(6645):860–862PubMedCrossRefGoogle Scholar
  13. 13.
    Lee BH, Lee YM, Sohn YS, Song SC (2002) A thermosensitive poly(organophosphazene) gel. Macromolecules 35(10):3876–3879CrossRefGoogle Scholar
  14. 14.
    Lee BH, Song SC (2004) Synthesis and characterization of biodegradable thermosensitive poly(organophosphazene) gels. Macromolecules 37(12):4533–4537CrossRefGoogle Scholar
  15. 15.
    Spencer CM, Faulds D (1994) Paclitaxel—a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer. Drugs 48(5):794–847PubMedCrossRefGoogle Scholar
  16. 16.
    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354(1):34–43PubMedCrossRefGoogle Scholar
  17. 17.
    Wang TH, Wang HS, Soong YK (2000) Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 88(11):2619–2628PubMedCrossRefGoogle Scholar
  18. 18.
    Crown J, O’Leary M (2000) The taxanes: an update. Lancet 355(9210):1176–1178PubMedCrossRefGoogle Scholar
  19. 19.
    Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N (1995) Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95(4):1789–1797PubMedCrossRefGoogle Scholar
  20. 20.
    Dong Z, Greene G, Pettaway C, Dinney CP, Eue I, Weixin Lu, Bucana CD (1999) Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-ß1. Cancer Res 59(4):872–879PubMedGoogle Scholar
  21. 21.
    Rehemtulla A, Stegman LD, Cardozo SJ, Gupta S, Hall DE, Contag CH, Ross BD (2000) Rapid and quantitative assessment of cancer treatment response using In Vivo Bioluminescence Imaging. Neoplasia 2(6):491–495PubMedCrossRefGoogle Scholar
  22. 22.
    Edinger M, Cao Y, Hornig YS, Jenkins DE (2002) Advancing animal models of neoplasia through in vivo bioluminescence imaging. Eur J Cancer 38(16):2128–2136PubMedCrossRefGoogle Scholar
  23. 23.
    Kwak MK, Hur K, Yu JE, Han TS, Yanagihara K, Kim WH, Lee SM, Song SC, Yang HK (2009) Suppression of in vivo tumor growth by using a biodegradable thermosensitive hydrogel polymer containing chemotherapeutic agent. Invest New Drugs 28(3):284–290PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jieun Yu
    • 1
  • Hyuk-Joon Lee
    • 1
    • 2
    • 6
  • Keun Hur
    • 1
  • Mi Kyung Kwak
    • 1
  • Tae Su Han
    • 1
  • Woo Ho Kim
    • 1
    • 3
  • Soo-Chang Song
    • 4
  • Kazuyoshi Yanagihara
    • 5
  • Han-Kwang Yang
    • 1
    • 2
  1. 1.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  2. 2.Department of SurgerySeoul National University College of MedicineSeoulKorea
  3. 3.Department of PathologySeoul National University College of MedicineSeoulKorea
  4. 4.Korea Institute of Science and TechnologySeoulKorea
  5. 5.National Cancer Center Research InstituteTokyoJapan
  6. 6.Department of Surgery and Cancer Research InstituteSeoul National University College of MedicineSeoulKorea

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