Construction Of Multifunctional Photothermal Nanomaterials For MR-guided Laser Immunotherapy Of Breast Cancer

Breast cancer is one of the major diseases threatening women’s health.At present,there are obvious defects in conventional therapies,including radiotherapy、chemotherapy and surgery,which make the treatment of breast cancer still a difficult problem to be solved urgently in medical research.In recent years,due to its own advantages including high selectivity,non-invasive and multi-course treatment,etc.,photothermal therapy（PTT）may become a new alternative for cancer therapy.Therefore,the research and development of new and efficient photothermal conversion materials to kill tumor tissues efficiently has become a hot spot in the field of cancer therapy.At the same time,some studies have reported that PTT can not only induce apoptosis and necrosis of tumor cells in situ effectively,but also induce immunogenic death of tumor cells and release a large number of tumor antigens.However,the recognition and presentation functions of antigen presenting cells severely weakened by the tumor immunosuppressive microenvironment,leading to failure to induce an effective anti-tumor immune response.In view of this,two novel near infrared（NIR）responsive photothermal nanomaterials were designed and synthesized,their applications in PTT combined immunotherapy for tumors were explored based on Polypyrrole（PPy）and Carbon Quantum Dots（CDs）.（1）Inspired by mussel biomimetic materials,polypyrrole composite hydrogel（PPH）with high photothermal conversion efficiency was prepared by one-step oxidation polymerization and metal coordination of polyphenols.Specifically,catechol grafted polyethylenimine（Cate-PEI）was firstly synthesized by an amide reaction;Then,the PPH was synthesized by simultaneously triggering the metal-catechol coordination reaction and the oxidative polymerization of covalent cross-linked pyrrole（Py）by ferric trivalent iron.The results indicated that PPH has rapid gelation function（less than 10 s）,and exhibited a high photothermal conversion efficiency（49.3%）.In vivo experiments showed that PPH could gelation in situ in mouse tumors and kill tumor cells by photothermal ablation with 808 nm NIR mediation.In addition,the introduction of iron can be used as a T₂-weighted contrast agent for real-time MR imaging to trace the retention and biodegradation of PPH in the body.Therefore,this multifunctional injectable PPH has potential application value in the field of tumor photothermal ablation,and provides design inspiration and ideas for the research and development of new medical hydrogels.（2）Near infrared photoresponsive in situ tumor vaccine（i TV）was constructed based on Fe dopped CDs（Fe-CDs）for combined photothermal and immunotherapy of tumor.Firstly,Fe-CDs with high photothermal conversion efficiency were prepared by microwave method;Subsequently,i TV was successfully constructed via thermal hydrogel F127 combined with Fe-CDs,alkyl radical initiator（AIPH）and immune adjuvant（cyclophospamide,CTX）.The results showed that Fe-CDs not only has good biocompatibility and optical properties,but also has high photothermal conversion efficiency（up to 37.9%）.In addition,the introduction of iron endowed i TV with the function of a T₁-weighted contrast agent for MR imaging.Under the irradiation of 808 nm NIR,i TV could make the local temperature rise rapidly（the temperature can rise to 60℃in 5 minutes）,which mediateed the photothermal ablation of the tumor.At the same time,the degradation of AIPH could also be induced by the local high temperature to produce alkyl radicals rapidly,which can further kill tumor cells.After degradation of i TV,the released CTX synergized with tumor-associated antigen derived from apoptotic tumor cells to inhibit regulatory T cells and activate cytotoxic T lymphocytes.In conclusion,the tumor cells can be killed by i TV and release tumor antigens through photothermal ablation and alkyl radicals.Meanwhile,CTX was used to regulate tumor immune microenvironment and enhance the body’s anti-tumor immune response effectively.This paper mainly focuses on the preparation of multifunctional photothermal nanomaterials and the establishment of a new comprehensive treatment scheme combined with tumor immunotherapy.This study lays a foundation for exploring the application of laser combined immunotherapy in the field of tumor therapy.