Introduction: Malignant pleural mesothelioma (MPM) is an asbestos-induced refractory cancer. Although chemotherapy using cisplatin (CDDP) and pemetrexed has been attempted, the median survival post-diagnosis is less than 12 months. Therefore, more effective therapies are needed. Hyaluronan (HA) is a major component of the extra cellular matrix and particularly overexpressed in tumor tissues. MPM produces large amounts of HA, as well as its receptor, CD44. Therefore, we expected that HA could be used as a ligand for MPM-targeted therapy. We previously developed HA-based nanogels, composed of iminodiacetic acid (IDA)-conjugated HA (HA-IDA) and CDDP, for peritoneal dissemination of gastric cancer. In this study, we evaluated the antitumor effects of nanogels for MPM. Materials and Methods: We firstly synthesized HA-IDA of various molecular weights. Then nanogels were fabricated by mixing HA-IDA with CDDP. We evaluated CDDP release profile from nanogels and their in vitro antitumor efficacy to MPM cells (AB22) or normal mesothelial cells (MeT-5A). Finally, nanogels were administrated into BALB/c mouse model of MPM and survival time was evaluated. Results and discussion: The synthesis of nanogels with different molecular weight HA was confirmed by 1H NMR and AAS. The modification degree of IDA was 28 % and the loading amount of CDDP was 30 wt%. 850 kDa nanogels showed most sustained CDDP release. Release of CDDP plateaued around 2 days and almost 40% of loaded CDDP was retained in nanogels after 1 week. The cytotoxic effect of 850 kDa nanogels to AB22 cells was comparable to that of free CDDP, in contrast, that of 850 kDa nanogels to MeT-5A was lower than that of free CDDP. It was supposed that this selectivity was attributed to CD44 targeting of HA. Treatment of 850 kDa nanogels to MPM-bearing mice significantly prolonged survival time than that of free CDDP. These results suggested usefulness of HA-IDA nanogels for treating MPM.

Antitumor effects of cisplatin-incorporating hyaluronan nanogel for malignant pleural mesothelioma

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.