TME-responsive BSA Nanocarriers For Combined Chemo/chemodynamic Cancer Therapy

The tumor microenvironment（TME）is a low acidic environment that contains various cell types（such as tumor cells,immune and inflammatory cells and tumor-related fibroblasts,etc.）and extracellular matrix components with high glutathione（GSH）,high hydrogen peroxide（H₂O₂）and low oxygen（O₂）contents.The interaction between tumor cells and the complicated TME is responsible for drug resistance,limited therapeutic efficacy and invasion and metastasis after various treatments.It has been recognized that the modulation of the TME by promoting ROS（reactive oxygen species）and/or reducing ROS scavenging agents（e.g.,GSH）could effectively ablate cancer cells by elevating intracellular oxidative stress.Recently,copper-based fenton-like reactions with higher reaction rates in a broader p H range showed more possibilities for highly efficient CDT.However,because copper is present at low levels in the human body,it cannot produce sufficient CDT efficacy by itself.In contrast,high concentrations can cause toxicity to normal cells.Hence,for the sake of improving the anti-tumor efficacy and reduce its side effects on the body,it is extremely urgent to explore a new therapeutic strategy combining CDT with other treatments.In order to enhance the anticancer efficacy and meanwhile compromise the side effects,it is a great urgent to integrate CDT with other therapeutic modalities.Chemotherapy using toxic drugs（like DOX and DSF etc）has been one of the most pivotal methods to treat cancer over the past decades,while the clinical outcome is severely hindered by unsatisfactory antitumor efficacy and various side effects.Hence,it would be of great promise for efficient cancer treatment by developing a biocompatible nanocarrier to specifically deliver and release DOX and copper ions into the tumor site for combined chemo and chemodynamic therapy.Herein,we synthesize a novel nanoscale coordination polymers（GA-Cu@BSA-DOX,GCBD NPs）based on BSA nanocarriers for combined chemo and chemodynamic cancer therapy.GA-Cu nanodots（GC NDs）are formed by the in-situ coordination of GA and copper ions absorbed in BSA,which subsequently gather together by hydrophobic interactions upon the addition of doxorubicin（DOX）,forming GCBD NPs with larger sizes.Under acidic conditions,the GCBD NPs would simultaneously release copper ions(Cu²⁺)and DOX.The released Cu²⁺could consume GSH and produce Cu⁺,which subsequently induces a fenton-like reaction by catalyzing a high content of H₂O₂ in the TME to generate highly cytotoxic hydroxyl radicals（·OH）for cancer cell death.Meanwhile,the enhanced drug delivery and specific DOX release based on the BSA nanocarrier would further kill tumor cells by inhibiting their DNA replication and produce more H₂O₂ to fuel CDT.The residual chemical groups in GCBD NPs could be stably labeled with radionuclide ¹²⁵I to evaluate the blood circulation and biodistribution behavior in mice.Taking advantage of the efficient tumoral accumulation and specific release of DOX and Cu²⁺,GCBD NPs would strongly inhibit tumor growth by a synergistic effect.In addition,we also designed a novel nanomedicine based on BSA nanocarriers（GA-Cu@BSA-DSF,GCBF NPs）for Cu²⁺enhanced chemotherapy in response to tumor microenvironment.Moreover,it has been proved that it has a good killing effect on 4T1 cells at the cellular level.In conclusion,two biocompatible nanoplatforms（GCBD NPs and GCBF NPs）were designed in this work,which can utilize the characteristics of TME for combined chemotherapy and CDT,providing a new strategy for efficient and specific radical treatment of tumors.