A biomimetic dual-targeting nanomedicine for pancreatic cancer therapy†

Abstract

The physiological characteristics of pancreatic cancer (PC) involve the interplay between tumor cells, cancer-associated fibroblasts (CAF) and the extracellular matrix (ECM). This intricate microenvironment contributes to the cancer's resistance to conventional chemoradiotherapy and its poor prognosis. Carbon monoxide (CO), a promising molecule in gas therapy, can effectively penetrate solid tumors and induce tumor cell apoptosis at high concentrations. However, precise dosing control remains a significant challenge in the administration of exogenous CO, and its inherent toxicity at elevated concentrations presents substantial barriers to clinical translation. In this study, we developed a novel biomimetic nanomedical drug delivery system capable of simultaneously targeting CAF and PC tumor cells, degrading the ECM, and inhibiting tumor growth. The strategy integrates iron carbonyl (FeCO), an anti-cancer agent, and losartan (Lo), a drug that degrades tumor matrix, into a biodegradable nanomaterial—mesoporous polydopamine (MPDA). The resulting nanoparticles are then coated with CAF cell membranes (CAFM) and functionalized with plectin-1 targeted peptide (PTP), a molecule that targets PC cells, to construct the (Lo + FeCO)@MPDA@CAFM-PTP nanomedicine. This system utilizes the homologous adhesion properties of CAF membranes to target CAFs, delivering Lo to degrade the ECM. Following ECM degradation, the nanomedicine penetrates further to bind to PC tumor cells via PTP. Then anti-cancer drug FeCO is released to react with the excessive reactive oxygen species (ROS) in PC tumor cells to produce high concentrations of CO, effectively inducing tumor cell apoptosis. The (Lo + FeCO)@MPDA@CAFM-PTP nanomedicine demonstrated significant cytotoxicity against Panc-1 cells in vitro and effectively inhibited PC tumor growth in vivo. This innovative approach holds great promise for advancing pancreatic cancer treatment.