Mesenchymal stem cell-delivered paclitaxel nanoparticles exhibit enhanced efficacy against a syngeneic orthotopic mouse model of pancreatic cancer.

ABSTRACT

Pancreatic cancer is considered the deadliest among various solid tumors, with a five-year survival rate of 13 %. One of the major challenges in the management of advanced pancreatic cancer is the inefficient delivery of chemotherapeutics to the tumor site. Even though nanocarriers have been developed to improve tumoral delivery of chemotherapeutics, less than 1 % of the drugs reach tumors, rendering inadequate concentration for effective inhibition of tumors. As a potential alternative, mesenchymal stem cells (MSCs) can effectively deliver their cargo to tumor sites because of their resistance to chemotherapeutics and inherent tumor tropism. In this study, we used MSCs for the delivery of dibenzocyclooctyne (DBCO)-functionalized paclitaxel (PTX)-loaded poly(lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA) nanoparticles. MSCs were modified to generate artificial azide groups on their surface, allowing nanoparticle loading via endocytosis and surface conjugation via click chemistry. This dual drug loading strategy significantly improves the PTX-loading capacity of azide-expressed MSCs (MSC-Az, 55.4 pg/cell) compared to unmodified MSCs (28.1 pg/cell). The in vitro studies revealed that PTX-loaded MSC-Az, nano-MSCs, exhibited cytotoxic effects against pancreatic cancer without altering their inherent phenotype, differentiation abilities, and tumor tropism. In an orthotopic pancreatic tumor model, nano-MSCs demonstrated significant inhibition of tumor growth (p < 0.05) and improved survival (p < 0.0001) compared to PTX solution, PTX nanocarriers, and Abraxane. Thus, nano-MSCs could be an effective delivery system for targeted pancreatic cancer chemotherapy and other solid tumors.