EGFR-targeted pemetrexed therapy of malignant pleural mesothelioma

Drug Deliv Transl Res. 2021 Nov 20. doi: 10.1007/s13346-021-01094-2. Online ahead of print.

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy with poor prognosis, for which chemotherapy with pemetrexed (PEM) is among the few clinical treatments. PEM suffers, however, fast clearance, moderate drug exposure, and dose-limiting toxicities. Here, we report on epidermal growth factor receptor (EGFR)-targeted disulfide-crosslinked biodegradable chimaeric polymersomes (EGFR-CPs) to firmly load PEM and boost chemotherapy of MPM. EGFR-CPs encapsulating 8.7-16.4 wt.% PEM (EGFR-CPs-PEM) showed diameters of 62-65 nm and reduction-responsive drug release property. EGFR-CPs-PEM was more efficiently taken up by EGFR-overexpressed MSTO-211H cells, inducing about 4.7-fold enhanced anticancer activity compared with non-targeted CPs-PEM control. Intriguingly, the in vivo experiments in MSTO-211H xenograft mouse model revealed that EGFR-CPs-PEM brought about superior tumor deposition and penetration to CPs-PEM, and significantly more potent tumor repression than CPs-PEM and free PEM. This polymersome-enabled EGFR-targeted delivery of PEM offers an appealing therapeutic strategy for MPM.

Keywords: Chemotherapy; Epidermal growth factor receptor; Malignant pleural mesothelioma; Polymersomes; Targeted delivery.