Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer

• Published in: Scientific reports Vol. 9; no. 1; pp. 14881 - 19
• Main Authors: De Clercq, Kaat, Xie, Feifan, De Wever, Olivier, Descamps, Benedicte, Hoorens, Anne, Vermeulen, An, Ceelen, Wim, Vervaet, Chris
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2019; Nature Publishing Group
• Subjects: 13/51; 59/5; 64/60; 692/308/153; 692/308/2778; 692/308/575; Abdomen - pathology; Animals; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; Ascites; Carcinoma, Ovarian Epithelial - mortality; Carcinoma, Ovarian Epithelial - pathology; Carcinoma, Ovarian Epithelial - therapy; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Controlled release; Drug Carriers; Drug Compounding - methods; Drug delivery; Drug Evaluation, Preclinical; Drug Liberation; Female; Gastric cancer; Gelatin; Gelatin - chemistry; Genipin; Humanities and Social Sciences; Humans; Intestines - drug effects; Intestines - pathology; Intravenous administration; Mice; Mice, Nude; Microspheres; multidisciplinary; Ovarian cancer; Ovary - drug effects; Ovary - pathology; Paclitaxel; Paclitaxel - pharmacokinetics; Paclitaxel - pharmacology; Peritoneal Neoplasms - mortality; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - prevention & control; Peritoneum; Science; Science (multidisciplinary); Sodium chloride; Surgery; Survival; Survival Analysis; Toxicity; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51419-y

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 µg PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTX nano -GP-MS) instead of ethanolic PTX solution (PTX EtOH -GP-MS). PTX release from PTX-GP-MS was prolonged. PTX nano -GP-MS displayed a more controlled release compared to a biphasic release from PTX EtOH -GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTX EtOH -GP-MS, D = 7.5 mg PTX/kg; PTX nano -GP-MS D = 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTX nano -GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTX nano -GP-MS caused drug-related toxicity in 27% of high-dosed PTX nano -GP-MS-treated mice. Dose simulations for PTX nano -GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5–15 mg PTX/kg. Low-dosed PTX nano -GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.