Carrier-free nano-prodrugs for enhanced cancer therapy: stimuli-responsive design and applications

This review focuses on the development of carrier-free nano-prodrugs as an innovative approach to cancer therapy. We discuss the design strategies, synthesis methods, and characteristics of nano-prodrugs responsive to various stimuli, including enzymes, reactive oxygen species (ROS), and glutathione (GSH). This paper highlights recent advances in the development of a new class of stimulus-responsive nano-prodrugs without the use of carriers, thereby addressing the challenges faced by conventional nanocarrier-based drug delivery systems. The key aspects covered include (1) the design and synthesis of esterase-activated nano-prodrugs based on the anticancer agent SN-38, demonstrating the importance of substituent hydrophobicity for controlling hydrolysis resistance and drug release profiles; (2) the development of ROS-activated nano-prodrugs using camptothecin combined with trimethyl lock groups, demonstrating a novel molecular design principle for drugs with tertiary alcohol moieties; and (3) the GSH-responsive dimeric prodrugs of SN-38 linked by disulfide bonds, demonstrating enhanced antitumor effects and reduced side effects in vivo. These carrier-free nano-prodrugs exhibit high drug-loading capacity, excellent stimulus responsiveness, and improved therapeutic efficacy with reduced side effects. Finally, we discuss future research directions, including the optimization of nanoprodrug designs for enhanced cancer therapy. Carrier-free nano-prodrugs (NPDs) were developed for selective drug release in cancer cells using stimulus-responsive systems: esterases, reactive oxygen species (ROS), and glutathione (GSH). Esterase-activated NPDs showed hydrophobicity-dependent drug release through SN-38 modification. ROS-responsive NPDs with trimethyl lock groups demonstrated selective activation by intracellular H2O2. GSH-responsive dimeric SN-38 prodrugs exhibited enhanced antitumor effects with reduced side effects. These NPDs achieved high drug loading and excellent stimulus responsiveness without using carriers, providing a promising platform for safer and more effective cancer therapy.