Excipient-free nanodispersion of 7-ethyl-10-hydroxycamptothecin exerts potent therapeutic effects against pancreatic cancer cell lines and patient-derived xenografts.

Irinotecan (CPT-11) is an anti-tumor drug and formulated as nanomedicines to reduce side effects and improve efficacy. In vivo, CPT-11 must be hydrolyzed by carboxylesterase to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) to exert anti-tumor activity, but the lack of this enzyme in humans causes inefficient generation of SN-38. Thus, direct delivery of SN-38, not relying on carboxylesterase, will potentially achieve higher efficacy. However, it is difficult to effectively formulate SN-38 using current excipients due to its hydrophobicity and tendency to crystallize. Herein, we report the nanodispersion of SN-38 with its amphiphilic prodrug, CPT-11, as an effective treatment for pancreatic cancer (PC). SN-38 and CPT-11 formed stable nanoparticles without any other excipients, and showed potent cytotoxicity against PC cells in vitro, slowed tumor growth in vivo, namely subcutaneously and orthotopically xenografted mice, with minimal adverse effects, and prolonged their overall survival. Even in clinically-relevant patient-derived xenograft (PDX) models, the nanodispersion showed greater anti-tumor efficacy than CPT-11. Importantly, the nanodispersion directly released SN-38, resulting in carboxylesterase-independent anti-tumor activity, in contrast to carboxylesterase-dependent CPT-11. These characteristics may enable the excipient-free nanodispersion to exert potent therapeutic effects in patients.