Tumor Microenvironment-Responsive Cu(?)-Porphyrin Nano-Delivery Systems For Tumor Chemodynamic-Photodynamic Therapy

Photodynamic therapy(PDT)is a novel method for cancer clinic treatment.However,the disadvantages such as poor solubility,limited penetration of light,lack of tumor targeting,and worse tumor hypoxia environment,result in a reduced curative effect finally.A combination of photosensitizers and Fenton-triggering metal ions has proved to be effective ways for solving problems of tumor cell hypoxia and improve the therapeutic effect.In this thesis,the amphiphilic macromolecule poly(enthylene glycol)-block-poly(_L-glutamate)(mPEG-b-PLG)was synthesized firstly as the matrix,after cross-linking with photosensitizer meso-tetra-(4-carboxyphenyl)porphine(TCPP)via the copper ions-triggered chelation,the nano-drug delivery systemP-Cu-T for chemodynamic and photodynamic therapy was constructed.Further,the tumor microenvironment responsive calcium carbonate(CaCO₃)was developed to stabilize P-Cu-T nanoparticles.It mainly includes:(1)Amphiphilic poly(ethylene glycol)-block-poly(glutamic acid)(mPEG-b-PLG)was used as a carrier to co-deliver Cu(?)ion and photosensitizer TCPP to prepare nano delivery system(P-Cu-T).For P-Cu-T,not only the?-?stacking effect between TCPP molecules can be reduced,but also the quenching effect caused by photosensitizer aggregation can be avoided.Moreover,Cu(?)ions can also produce Fenton-like reactions in tumor cells,which convert the over-expressed hydrogen peroxide in tumor cells into more toxic hydroxyl free radicals,thereby efficiently killing tumor cells and realizing chemical kinetics-photodynamics combination therapy.(2)Following,tumor microenvironment acid responsive nano delivery system CaCO₃@P-Cu-T was constructed by using CaCO₃ as cross linker to improve the stability of P-Cu-T nanoparticles.When CaCO₃@P-Cu-T was internalized into tumor tissue,the crosslinked CaCO₃ would decompose and release free TCPP and Cu(?)triggered by the weak acid microenvironment.The photosensitizer TCPP would generate ¹O₂ when being applied by the specific light irradiation.Meanwhile,Cu(?)could trigger GSH depletion and consume excessive H₂O₂ to increase oxidative stress of cells,realizing the combination of chemodynamic therapy with photodynamic therapy to enhance the therapeutic effect.