Scheme 1.

Preclinical development of carrier-free prodrug nanoparticles (F68-FDOX) for enhanced antitumor therapeutic potential with less toxicity. a The cancer-specific prodrug was simply prepared by conjugating cathepsin B-specific cleavable tetrapeptide (Phe-Arg-Arg-Gly; FRRG) to doxorubicin (DOX). The resulting FRRG-DOX spontaneously self-assembled into nanoparticles via intermolecular hydrophobic interactions without any additional carrier materials and further stabilized with FDA-approved excipient, Pluronic F68. b The preclinical development process of F68-FDOX, such as mass production, characterization, and in vitro and in vivo evaluation is studied. c F68-FDOX efficiently accumulates within tumor tissues by enhanced permeability and retention (EPR) effect and subsequently release the DOX by cathepsin B-specific cleavage mechanism, showing a potent antitumor activity in colon, breast and pancreatic cancers. d The F68-FDOX greatly minimize the DOX-related systemic toxicity by maintaining inactive state in normal tissues with innately low cathepsin B