Responsive Core-shell Tecto Dendrimers For Mri-guided Chemotherapy And Chemodynamics Therapy

As a common malignant tumor,breast cancer has been a serious threat to the health of women all over the world.Chemotherapy,as a routine clinical treatment,has some defects such as high toxicity to normal tissue and easy-to-produce drug resistance,so it is difficult to completely eliminate tumors and inhibit tumor metastasis.Chemodynamic therapy has attracted more and more attention due to its unique characteristics of tumor microenvironment reaction and low side effects.Therefore,the construction of a tumor-specific integrated nanoplatform for tumor imaging and the combined treatment of chemotherapy and chemodynamic therapy will achieve an accurate diagnosis and efficient treatment of tumors.Copper ion（Cu）is an essential trace metal element of the human body.Recent studies have shown that copper ions can not only be used as catalytic ions in chemodynamic therapy and magnetic resonance imaging contrast agent but also induce a new death mechanism of tumor cells,“cuproptosis”,showing great advantages in the field of tumor diagnosis and treatment.Therefore,in view of the characteristics of the tumor microenvironment,we designed a responsive core-shell teco dendrimer delivery platform（CSTD）containing phenylborate ester bonds to load Cu（II）and chemotherapy drug disulfiram（DSF）with high efficiency for magnetic resonance image-guided targeted chemotherapy and chemodynamic combination therapy.We modified phenylboric acid（as core of CSTD）and mannose（as shell of CSTD）on the surface of fifth-generation polyamides and amines dendrimer respectively,and constructed CSTD with mannose surface by phenylborate ester bond.Finally,the p H/H₂O₂responsive CSTD nanoplatform was obtained after acetylation modification.Our results have shown that the CSTD nanoplatform has good colloidal stability,can efficiently load Cu and DSF,and has responsive decomposition behavior in the tumor microenvironment,thus achieving rapid drug release and a significant increase in r₁ relaxation rate.In vitro cell experiments demonstrated that CSTD-Cu（II）@DSF nanoplatform could be specifically endocytosed by human breast cancer cells（MCF-7）with rich galactolectin,showing a better tumor inhibition effect than free DSF.The mechanism of synergistic therapy between Cu and DSF was analyzed by means of molecular biology.DSF could be used as Cu chelating agent to promote the uptake of Cu by cells and play the function of chemotherapy to induce cell apoptosis and block the cell cycle at the G2/M phase.Cu ions can not only cause protein stress and induce cuproptosis of tumor cells,but also generate toxic hydroxyl radicals in Fenton-like reaction in tumor cells to destroy redox homeostasis and achieve chemodynamic therapy of tumor cells.In vivo experiments have proved that the CSTD-Cu（II）@DSF nanoplatform has good biosafety and long circulation time in the body and can actively enrich tumor sites,thereby showing enhanced magnetic resonance imaging performance and effective tumor growth inhibition.In conclusion,we have prepared a responsive core-shell tecto dendrimers nanoplatform for targeted tumor imaging and combined chemotherapy and chemodynamic therapy to maximize the early diagnosis and precision treatment of breast cancer,providing ideas for the development of a new nano platform for integrated diagnosis and treatment.