Coordination-driven Self-assembly Of Metal-celastrol Nanostructures For Efficient Tumor Therapy

Celastrol（Cel）is a natural drug active ingredient and has attracted much attention due to its extensive antitumor activities.However,the clinical application of Cel is limited by its low bioavailability and potential toxicity.To solve the above problems,this paper adopts innovative coordination assembly technology.Using Cel and metal ion coordination as the core（Cel-Metal）,two novel multi-functional Cel-Metal nanoparticles（NPs）have been constructed to achieve efficient drug delivery and tumor therapy.In Chapter 2,a strategy for constructing Metal-Drug-Organic-Frameworks using the coordination of zinc ion(Zn²⁺)with Cel is developed.Cel-ZIF-8 NPs were formed by combining deprotonated Cel as an organic ligand with zeolite imidazolate frame-8（ZIF-8）.This strategy greatly improves the assembly efficiency and water solubility of Cel.Cel-ZIF-8remains stable at the physiological condition while dissociating and releasing Cel at an acidic tumor microenvironment,realizing the tumor-specific killer.In conclusion,a novel Cel-ZIF-8 NPs was constructed by using the coordination strategy of Cel deprotonation for the first time,which is expected to promote the application of Cel in cancer treatment.In Chapters 3 and 4,a carrier-free metallic drug NPs that combines chemotherapy and chemo-dynamic therapy（CDT）is further synthesized.Copper ion(Cu²⁺)is coordinated with Cel to construct Cel-Cu-TA-Cu（CCTC）NPs under the complexation of tannic acid（TA）,which successfully realizes the ultra-high load and co-delivery of Cel and Cu²⁺.CCTC can be effectively taken up by tumor cells,and Cu²⁺catalyzes the production of highly toxic hydroxyl radical（·OH）to achieve the CDT effect.At the same time,released Cel can reduce the expression of antioxidant bcl-2 protein and activate the caspase 3 pathway,reduce the antioxidant capacity of the tumor,induce tumor cell apoptosis,and further enhance the efficacy of CDT.In conclusion,CCTC not only improves the water solubility and stability of Cel through coordination but also exerts a highly effective anti-tumor effect under the synergistic treatment of Cel and Cu²⁺.