Abstract
Most small molecule drugs, such as Monomethyl auristatin E (MMAE), Camptothecin (CPT), and Doxorubicin (DOX), face clinical limitations due to poor solubility and severe side effects. While delivery systems like polymeric micelles and nanoparticles (NPs) improve pharmacokinetics, challenges including low loading capacity and premature release persist. This dissertation focuses on developing stimuli-responsive systems with high drug loading and precise release to enhance efficacy and minimize toxicity. We engineered redox-sensitive CPT prodrugs using disulfide linkers and alkyl chains of varying lengths, significantly enhancing loading capacity and glutathione (GSH)-responsive release. To optimize carrier alignment, a responsive prodrug-initiated ring-opening polymerization (ROP) strategy was developed. By using a CPT-derived disulfide initiator for the ROP of lactide, we engineered a CPT-ss-PLA prodrug with a tunable hydrophobic chain. When co-assembled with PEG-b-PLA into uniform NPs, these systems demonstrated high payloads, precise GSH-triggered release, and potent antitumor efficacy in in vitro and in vivo models. Additionally, small molecule drug amphiphiles (SMDAs) were developed to achieve carrier-free self-assembly. We engineered a redox-responsive albumin-hitchhiking system (EB-ss-DM1) by conjugating the cytotoxin DM1 to Evans Blue. By modulating linker length, we achieved controlled NP assembly and albumin affinity. These NPs transform into stable albumin-binding complexes, prolonging circulation and enabling targeted drug release in the tumor microenvironment.