Abstract
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 (PTXnano-GP-MS) instead of ethanolic PTX solution (PTXEtOH-GP-MS). PTX release from PTX-GP-MS was prolonged. PTXnano-GP-MS displayed a more controlled release compared to a biphasic release from PTXEtOH-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTXEtOH-GP-MS, D = 7.5 mg PTX/kg; PTXnano-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. PTXnano-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 PTXnano-GP-MS caused drug-related toxicity in 27% of high-dosed PTXnano-GP-MS-treated mice. Dose simulations for PTXnano-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5–15 mg PTX/kg. Low-dosed PTXnano-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.
Highlights
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
GP-MS were developed for IP administration, and their applicability to prevent post-operative peritoneal adhesions was demonstrated[32]
Since a hydrophilic environment is preferred for this drug loading step to allow GP-MS swelling and to maximize PTX penetration into GP-MS, PTX was dissolved in a 75/25 v/v ethanol/water mixture to allow partial swelling of the microspheres and to provide sufficient solubility of PTX in the loading medium
Summary
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. Prospective randomized phase III clinical trials showed that adjuvant IP chemotherapy significantly improved overall survival of patients with advanced ovarian cancer[2,15,16,17]. The risk of recurrent peritoneal disease remains high[18,19] This can be partly attributed to a short residence time of the chemotherapeutics in the abdominal cavity and the single administration of HIPEC18,20. Current IP therapy is based on off-label use of IV chemotherapeutics These conventional low molecular weight drugs are rapidly absorbed from the peritoneal cavity and lack tumor specificity[8,20,21]. Two nanoparticulate formulations have been applied in phase I clinical trials for IP use, NanoTax , a 600–700 nm rod shaped
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