RESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Reagentes de Ligações Cruzadas , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Ácido Hialurônico , Hidrogel de Polietilenoglicol-Dimetacrilato , Infusões Parenterais , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Cavidade Peritoneal , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/metabolismoRESUMO
Injectable hydrogels are useful in biomedical applications. We have synthesized hyaluronic acids chemically modified with azide groups (HA-A) and cyclooctyne groups (HA-C), respectively. Aqueous HA-A and HA-C solutions were mixed using a double-barreled syringe to form a hydrogel via strain-promoted [3 + 2] cycloaddition without any catalyst at physiological conditions. The hydrogel slowly degraded in PBS over 2 weeks, which was accelerated to 9 days by hyaluronidase, while it rapidly degraded in a cell culture media with fetal bovine serum within 4 days. Both HA-A and HA-C showed good biocompatibility with fibroblast cells in vitro. They were administered using the double-barreled syringe into mice subcutaneously and intraperitoneally. Residue of the hydrogel was cleared 21 days after subcutaneous administration, while it was cleared 7 days after intraperitoneal administration. This injectable HA hydrogel is expected to be useful for tissue engineering and drug delivery systems utilizing its orthogonality.