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Intraperitoneal administration of cisplatin via an in situ cross-linkable hyaluronic acid-based hydrogel for peritoneal dissemination of gastric cancer

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Abstract

Purpose

To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively.

Methods

CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer.

Results

The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group.

Conclusions

In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.

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References

  1. Isobe Y, Nashimoto A, Akazawa K, Oda I, Hayashi K, Miyashiro I, Katai H, Tsujitani S, Kodera Y, Seto Y, Kaminishi M. Gastric cancer treatment in Japan: 2008 annual report of the JGCA nationwide registry. Gastric Cancer. 2011;14(4):301–16.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9(3):215–21.

    Article  PubMed  CAS  Google Scholar 

  3. Ikeguchi M, Miyake T, Matsunaga T, Yamamoto M, Fukumoto Y, Yamada Y, Fukuda K, Saito H, Tatebe S, Tsujitani S. Recent results of therapy for scirrhous gastric cancer. Surg Today. 2009;39(4):290–4.

    Article  PubMed  CAS  Google Scholar 

  4. Brigand C, Arvieux C, Gilly FN, Glehen O. Treatment of peritoneal carcinomatosis in gastric cancers. Dig Dis. 2004;22(4):366–73.

    Article  PubMed  CAS  Google Scholar 

  5. Kodera Y, Ito Y, Ito S, Ohashi N, Mochizuki Y, Yamamura Y, Koike M, Fujiwara M, Nakanishi H, Nakao A. Intraperitoneal paclitaxel: a possible impact of regional delivery for prevention of peritoneal carcinomatosis in patients with gastric carcinoma. Hepatogastroenterology. 2007;54(75):960–3.

    PubMed  CAS  Google Scholar 

  6. Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, Kamei T, Soma D, Miyato H, Yamashita H, Nagawa H. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010;21(1):67–70.

    Article  PubMed  CAS  Google Scholar 

  7. Alberts DS, Liu PY, Hannigan EV, O’Toole R, Williams SD, Young JA, Franklin EW, Clarke-Pearson DL, Malviya VK, DuBeshter B. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335(26):1950–5.

    Article  PubMed  CAS  Google Scholar 

  8. Francis P, Rowinsky E, Schneider J, Hakes T, Hoskins W, Markman M. Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: a Gynecologic Oncology Group pilot Study. J Clin Oncol. 1995;13(12):2961–7.

    PubMed  CAS  Google Scholar 

  9. Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis JL Jr, Rubin S, Curtin J, Barakat R, Phillips M, et al. Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study. J Clin Oncol. 1992;10(9):1485–91.

    PubMed  CAS  Google Scholar 

  10. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43.

    Article  PubMed  CAS  Google Scholar 

  11. Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D. Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist. 2005;10(2):112–22.

    Article  PubMed  CAS  Google Scholar 

  12. Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst. 1997;89(7):480–7.

    Article  PubMed  CAS  Google Scholar 

  13. Echarri Gonzalez MJ, Green R, Muggia FM. Intraperitoneal drug delivery for ovarian cancer: why, how, who, what, and when? Oncology (Williston Park). 2011;25(2):156–165, 170.

  14. Markman M, Walker JL. Intraperitoneal chemotherapy of ovarian cancer: a review, with a focus on practical aspects of treatment. J Clin Oncol. 2006;24(6):988–94.

    Article  PubMed  CAS  Google Scholar 

  15. Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Kondo A, Maeta M, Oka A, Tsujitani S, Ikeguchi M, Kaibara N. Hypotonic intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in mice. Br J Cancer. 1996;73(10):1166–70.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Tsujitani S, Oka A, Kondo A, Katano K, Oka S, Saito H, Ikeguchi M, Maeta M, Kaibara N. Administration in a hypotonic solution is preferable to dose escalation in intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in rats. Oncology. 1999;57(1):77–82.

    Article  PubMed  CAS  Google Scholar 

  18. Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol. 2003;4(5):277–83.

    Article  PubMed  CAS  Google Scholar 

  19. Howell SB. Pharmacologic principles of intraperitoneal chemotherapy for the treatment of ovarian cancer. Int J Gynecol Cancer. 2008;18(Suppl 1):20–5.

    Article  PubMed  Google Scholar 

  20. Luo Y, Kirker KR, Prestwich GD. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. J Control Release. 2000;69(1):169–84.

    Article  PubMed  CAS  Google Scholar 

  21. Wang Y, Gong C, Yang L, Wu Q, Shi S, Shi H, Qian Z, Wei Y. 5-FU-hydrogel inhibits colorectal peritoneal carcinomatosis and tumor growth in mice. BMC Cancer. 2010;10:402.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Yu J, Lee HJ, Hur K, Kwak MK, Han TS, Kim WH, Song SC, Yanagihara K, Yang HK. The antitumor effect of a thermosensitive polymeric hydrogel containing paclitaxel in a peritoneal carcinomatosis model. Invest New Drugs. 2012;30(1):1–7.

    Article  PubMed  Google Scholar 

  23. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev. 2001;53(3):321–39.

    Article  PubMed  CAS  Google Scholar 

  24. Kwak MK, Hur K, Yu JE, Han TS, Yanagihara K, Kim WH, Lee SM, Song SC, Yang HK. Suppression of in vivo tumor growth by using a biodegradable thermosensitive hydrogel polymer containing chemotherapeutic agent. Invest New Drugs. 2010;28(3):284–90.

    Article  PubMed  CAS  Google Scholar 

  25. Wu W, Liu J, Cao S, Tan H, Li J, Xu F, Zhang X. Drug release behaviors of a pH sensitive semi-interpenetrating polymer network hydrogel composed of poly(vinyl alcohol) and star poly[2-(dimethylamino)ethyl methacrylate]. Int J Pharm. 2011;416(1):104–9.

    Article  PubMed  CAS  Google Scholar 

  26. He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Control Release. 2008;127(3):189–207.

    Article  PubMed  CAS  Google Scholar 

  27. Liao YH, Jones SA, Forbes B, Martin GP, Brown MB. Hyaluronan: pharmaceutical characterization and drug delivery. Drug Deliv. 2005;12(6):327–42.

    Article  PubMed  CAS  Google Scholar 

  28. Yamada J, Kitayama J, Tsuno NH, Yamashita H, Miyato H, Soma D, Otani K, Kamei T, Ishigami H, Hidemura A, Kaisaki S, Takahashi K, Nagawa H. Intra-peritoneal administration of paclitaxel with non-animal stabilized hyaluronic acid as a vehicle—a new strategy against peritoneal dissemination of gastric cancer. Cancer Lett. 2008;272(2):307–15.

    Article  PubMed  CAS  Google Scholar 

  29. Luo Y, Prestwich GD. Synthesis and selective cytotoxicity of a hyaluronic acid-antitumor bioconjugate. Bioconjug Chem. 1999;10(5):755–63.

    Article  PubMed  CAS  Google Scholar 

  30. Hahn SK, Kim JS, Shimobouji T. Injectable hyaluronic acid microhydrogels for controlled release formulation of erythropoietin. J Biomed Mater Res A. 2007;80(4):916–24.

    Article  PubMed  Google Scholar 

  31. Isayeva I, Sarkar Das S, Chang A, Defoe J, Luu HM, Vorvolakos K, Patwardhan D, Whang J, Pollack S. pH effect on the synthesis, shear properties, and homogeneity of iron-crosslinked hyaluronic acid-based gel/adhesion barrier. J Biomed Mater Res B Appl Biomater. 2010;95(1):9–18.

    Article  PubMed  Google Scholar 

  32. Yeo Y, Highley CB, Bellas E, Ito T, Marini R, Langer R, Kohane DS. In situ cross-linkable hyaluronic acid hydrogels prevent post-operative abdominal adhesions in a rabbit model. Biomaterials. 2006;27(27):4698–705.

    Article  PubMed  CAS  Google Scholar 

  33. Ito T, Yeo Y, Highley CB, Bellas E, Benitez CA, Kohane DS. The prevention of peritoneal adhesions by in situ cross-linking hydrogels of hyaluronic acid and cellulose derivatives. Biomaterials. 2007;28(6):975–83.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Sako A, Kitayama J, Koyama H, Ueno H, Uchida H, Hamada H, Nagawa H. Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer. Cancer Res. 2004;64(10):3624–8.

    Article  PubMed  CAS  Google Scholar 

  35. Bulpitt P, Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res. 1999;47(2):152–69.

    Article  PubMed  CAS  Google Scholar 

  36. Jia X, Colombo G, Padera R, Langer R, Kohane DS. Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid. Biomaterials. 2004;25(19):4797–804.

    Article  PubMed  CAS  Google Scholar 

  37. Cai S, Xie Y, Davies NM, Cohen MS, Forrest ML. Pharmacokinetics and disposition of a localized lymphatic polymeric hyaluronan conjugate of cisplatin in rodents. J Pharm Sci. 2010;99(6):2664–71.

    PubMed Central  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Lessan K, Aguiar DJ, Oegema T, Siebenson L, Skubitz AP. CD44 and beta1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. Am J Pathol. 1999;154(5):1525–37.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Oertl A, Castein J, Engl T, Beecken WD, Jonas D, Melamed R, Blaheta RA. Endothelial adhesion of synchronized gastric tumor cells changes during cell cycle transit and correlates with the expression level of CD44 splice variants. World J Gastroenterol. 2005;11(40):6243–8.

    PubMed  CAS  Google Scholar 

  41. De Stefano I, Battaglia A, Zannoni GF, Prisco MG, Fattorossi A, Travaglia D, Baroni S, Renier D, Scambia G, Ferlini C, Gallo D. Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. Cancer Chemother Pharmacol. 2011;68(1):107–16.

    Article  PubMed  CAS  Google Scholar 

  42. Zoller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11(4):254–67.

    Article  PubMed  Google Scholar 

  43. Auzenne E, Ghosh SC, Khodadadian M, Rivera B, Farquhar D, Price RE, Ravoori M, Kundra V, Freedman RS, Klostergaard J. Hyaluronic acid-paclitaxel: antitumor efficacy against CD44(+) human ovarian carcinoma xenografts. Neoplasia. 2007;9(6):479–86.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Takahashi K, Seki T, Nishikawa K, Minamide S, Iwabuchi M, Ono M, Nagamine S, Horinishi H. Antitumor activity and toxicity of serum protein-bound platinum formed from cisplatin. Jpn J Cancer Res. 1985;76(1):68–74.

    PubMed  CAS  Google Scholar 

  45. Yeo Y, Bellas E, Highley CB, Langer R, Kohane DS. Peritoneal adhesion prevention with an in situ cross-linkable hyaluronan gel containing tissue-type plasminogen activator in a rabbit repeated-injury model. Biomaterials. 2007;28(25):3704–13.

    Article  PubMed  CAS  Google Scholar 

  46. Jeong YI, Kim ST, Jin SG, Ryu HH, Jin YH, Jung TY, Kim IY, Jung S. Cisplatin-incorporated hyaluronic acid nanoparticles based on ion-complex formation. J Pharm Sci. 2008;97(3):1268–76.

    Article  PubMed  CAS  Google Scholar 

  47. Kamei T, Kitayama J, Yamaguchi H, Soma D, Emoto S, Konno T, Ishihara K, Ishigami H, Kaisaki S, Nagawa H. Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) in peritoneal metastatic nodules. Cancer Sci. 2010;102(1):200–5.

    Article  PubMed  Google Scholar 

  48. Luo Y, Ziebell MR, Prestwich GD. A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells. Biomacromolecules. 2000;1(2):208–18.

    Article  PubMed  CAS  Google Scholar 

  49. Cai S, Xie Y, Bagby TR, Cohen MS, Forrest ML. Intralymphatic chemotherapy using a hyaluronan–cisplatin conjugate. J Surg Res. 2008;147(2):247–52.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Ministry of Health, Labor and Welfare of Japan. We thank Kikkoman for providing HA. We thank Nippon Kayaku for providing CDDP. We thank Baxter for providing the dual syringes.

Conflict of interest

We declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Shigenobu Emoto, Hironori Yamaguchi, Takao Kamei, Hironori Ishigami, Joji Kitayama & Toshiaki Watanabe

  2. Department of Chemical System Engineering, The University of Tokyo, Tokyo, Japan

    Takashi Suhara, Yukimitsu Suzuki & Taichi Ito

  3. Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo, Japan

    Taichi Ito

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  1. Shigenobu Emoto
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  2. Hironori Yamaguchi
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Correspondence to Shigenobu Emoto.

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Emoto, S., Yamaguchi, H., Kamei, T. et al. Intraperitoneal administration of cisplatin via an in situ cross-linkable hyaluronic acid-based hydrogel for peritoneal dissemination of gastric cancer. Surg Today 44, 919–926 (2014). https://doi.org/10.1007/s00595-013-0674-6

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