Intraperitoneal chemotherapy for peritoneal metastases using sustained release formula of cisplatin-incorporated gelatin hydrogel granules

• Published in: Surgery today (Tokyo, Japan) Vol. 49; no. 9; pp. 785 - 794
• Main Authors: Yamashita, Kota, Tsunoda, Shigeru, Gunji, Shutaro, Murakami, Takahide, Suzuki, Takahisa, Tabata, Yasuhiko, Sakai, Yoshiharu
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.09.2019
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Cisplatin - administration & dosage; Cisplatin - metabolism; Cisplatin - pharmacology; Cisplatin - toxicity; Delayed-Action Preparations; Disease Models, Animal; Female; Gelatin; Humans; Hydrogels; Injections, Intraperitoneal; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Mice, Nude; Original Article; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - secondary; Peritoneum - metabolism; Stomach Neoplasms - pathology; Surgery; Surgical Oncology; Gelatin hydrogel; Peritoneal metastases; Gastric cancer; Intraperitoneal chemotherapy; Cisplatin
• ISSN: 0941-1291; 1436-2813
• DOI: 10.1007/s00595-019-01792-y

Purpose We previously reported the effectiveness of gelatin microspheres incorporating cisplatin in a mouse model of peritoneal metastases. In this study, we report our new complete sustained-release formula of gelatin hydrogel granules incorporating cisplatin (GHG–CDDP), which exerted a good anti-tumor effect with less toxicity. Methods GHG–CDDP was prepared without organic solvents to enable its future clinical use. The pharmaceutical characterization of GHG–CDDP was performed, and its in vivo degradability was evaluated. The anti-tumor effect was evaluated using a murine peritoneal metastasis model of the human gastric cancer MKN45-Luc cell line. Results Our new manufacturing process dramatically reduced the initial burst of CDDP release to approximately 2% (wt), while the previous product had a 25–30% initial burst. In intraperitoneal degradation tests, approximately 30% of GHG–CDDP remained in the murine abdominal cavity 7 days after intraperitoneal injection and disappeared within 3 weeks. GHG–CDDP significantly suppressed the in vivo tumor growth ( p  = 0.02) and prolonged the survival time ( p  = 0.0012) compared with the control. In contrast, free CDDP did not show a significant therapeutic effect at any dose. Weight loss and hematological toxicity were also significantly ameliorated. Conclusions GHG–CDDP is a promising treatment option for peritoneal metastases through the complete sustained-release of CDDP with less systemic toxicity.