Engineering Unsaturated Fatty Acids-Based All-Active Anticancer Micelles

There has been a growing interest in redox homeostasis regulation nanomedicine for cancer management,including photodynamic therapy,sonodynamic therapy,chemodynamic therapy and ferroptotic therapy.Nanocarriers can enhance the delivery of anticancer agents in several aspects,but they also suffer from poor accumulation in solid tumor and uncontrolled cargo release therein.It was hypothesized that engineering all-active,polyunsaturated fatty acids(PUFAs)-conjugated polymer micelles could not only realize on-demand drug release,but also produce toxic side-products for efficacy enhancement to compromise the low tumor targeting efficiency of nanomedicines.In this thesis,such concept was validated in both photodynamic and ferroptotic anticancer therapy.In terms of“all-active antitumor micelles for photodynamic efficacy enhancement”,a photosensitizer was encapsulated within polymeric micelles.Upon light irradiation,the photosensitizer-produced singlet oxygen(¹O₂)could induce lipid peroxidation,resulting in the generation of both active free radicals and aldehydes.These supplementary radicals could exert cytotoxic effect for direct killing tumor cells.The aldehyde end-products induced significant cell cycle arrest in 4T1 cells.The peroxidation process also facilitated the on-demand disassembly of micelles and rapid release of photosensitizer to maximize the therapeutic effect of ¹O₂.These all-active micelles showed a significantly enhanced cytotoxicity with the half maximal inhibitory concentration(IC₅₀)of 0.6±0.2?g/m L in contrast to the control group at3.4±0.5?g/m L.In the 4T1 tumor-bearing mice model,the all-active micelles improved antitumor efficacy and extended animal survival rate.Regarding the“triggered ferroptotic micelles for reversing MDR to chemotherapy”,a potent ferroptotic inducer was encapsulated in the unsaturated fatty acid micelles to target the glutathione peroxidase 4(GPX4)and induce ferroptosis.The micelles can enable rapid cargo release upon free radical-triggering in the tumor microenvironment followed by cancer stem cells(CSCs)removal and multidrug resistance(MDR)reversal.In the drug resistant human ovarian adenocarcinoma cells,the triggered ferroptotic micelles were 30-fold more toxic than the controls due to the ferroptotic machinery.The lipid peroxidation-induced intracellular glutathione depletion also made a contribution,which enhanced the potency of ferroptosis and enabled the drug-loaded micelles all-active.The population of CSCs biomarkers was significantly lower for the ferroptotic micelles in contrast to the control.The potency of ferroptotic micelles regarding CSCs reduction was also proved by the in vitro soft agar colony forming assay.The in vivo anti-tumor efficacy of triggered micelles was further demonstrated in xenograft mouse model in terms of CSCs biomarkers,tumor growth inhibition,mice survival,and GPX4 inhibition.In summary,this thesis provided a facile approach to enhance the antitumor efficacy of PDT and ferroptosis by using the biocompatible,PUFAs-laden micelles.The“all-active”drug delivery strategy can be extended to a broad variety of cancer therapies with the mechanisms of action by regulating intracellular redox homeostasis.