In situ gelatinase-responsive and thermosensitive nanocomplex for local therapy of gastric cancer with peritoneal metastasis.

Abstract

Intraperitoneal chemotherapy (IPC) has been considered as an effective therapy for advanced gastric cancer (GC) especially those with peritoneal metastasis, while limited effectiveness, complications caused by chemotherapeutics and repeated infusion procedures restrict the application of IPC. In this study, to enhance the efficacy and safety of IPC, we intended to establish a biocompatible and biodegradable nanocomplex composed of intelligent gelatinase-responsive nanoparticles (NPs) and thermosensitive gel, which were prepared from different compositions of poly (ethyleneglycol)–poly (3-caprolactone) (PEG–PCL). Cancer stem cells (CSCs) inhibitor Salinomycin (SAL) and non-CSC inhibitor Docetaxel (DOC) were co-loaded in the NPs and delivered by liquid PEG-PCL-PEG gel (PECE) at room temperature, which was able to target tumor and formed a gel in situ at body temperature. Compared with free SAL-DOC solution administered at the same dose, PECE NP group inhibited intraperitoneal disseminated gastric cancer growth more remarkably, some of which even achieved complete response (CR) and continued for more than 2 weeks. Cytometric analysis of cellular suspension from abdominal tumor tissues showed that the proportion of CSCs (CD44+CD133+) and the expression of PD-L1 on the tumor cells in the PECE NP group were the lowest. In the allograft mouse models of GC, PECE NP significantly improved the infiltration of M1 macrophages into the tumor bed in vivo. This design may provide biodegradable smart drug-delivery system for potential application in IPC.