近红外响应双载药纳米载体用于乳腺癌化疗-免疫协同治疗的作用及机制研究

Breast cancer is the most common cancer in women. The treatment options for metastatic breast cancer are very limited and the mortality rate is very high. Tumor immunotherapy based on immuno-checkpoint inhibitors brings new hope for cancer treatment, but breast cancer is insensitive to immuno-checkpoint inhibitors because of its immuno-depleted tumor microenvironment. Based on previous studies, this project intends to construct a near-infrared-responsive drug delivery system by incorporation of black phosphorus quantum dots into liposomal bilayers, which co-loaded with immunogenic cell death drugs and IDO-pathway inhibitors. When the drug carrier is transported to breast cancer sites, light irradiation is carried out to induce rapid drug release and regional accumulation, so as to overcome the shortcomings of naked drugs in in vivo targeting, circulation time and drug concentration. The research includes as following: study the changes of tumor microenvironment and effector T cells viability caused by immunogenic cell death; explore the immune response of breast cancer to IDO pathway inhibitors; and study the inhibitory effect of combined chemotherapy and immunotherapy on the growth and metastasis of breast cancer. Successful implementation of this project can construct a nano-drug carrier with effective integration of chemotherapeutic drugs and immunosuppressive agents, targeted co-transport and light-controlled release drugs, realize the synergistic chemo-immunotherapy of breast cancer, and provide new ideas and theoretical basis for the development of new generation of malignant breast cancer treatment strategies.

乳腺癌是女性最常见的癌症，尤其是转移性乳腺癌的治疗选择十分有限，死亡率极高。基于免疫检查点抑制剂的肿瘤免疫疗法为癌症治疗带来了新希望，但乳腺癌由于其免疫耗竭的肿瘤微环境，对免疫检查点抑制剂不敏感。本项目基于前期开发的具有精准近红外响应释药功能的黑磷量子点脂质体，拟构建共载免疫原性细胞死亡化疗药物和IDO信号通路抑制剂的靶向纳米载体，将两种药物共运输到乳腺肿瘤部位，并利用近红外光刺激控制药物的释放和区域性大量积聚，以克服裸药在体内靶向差、循环时间短和药物浓度低的缺陷。从而研究免疫原性细胞死亡所导致的肿瘤微环境改变和效应T细胞活力变化；探讨乳腺癌对IDO抑制剂的免疫应答；研究化疗和免疫治疗联合抑制乳腺癌生长和转移的作用。本项目的成功实施，可构建一种化疗药物与免疫抑制剂有效整合、靶向共运输及光控释药一体化的纳米载药平台，为开发新一代恶性乳腺癌治疗策略，实现化疗和免疫协同治疗提供新思路和理论依据。

本项目拟制备一种基于二维黑磷的近红外响应双载药纳米载体，用于肿瘤的多模式治疗，并探讨相关的抗肿瘤机制。在项目开展初期，我们发现黑磷作为一种生物可降解纳米材料，具有选择性肿瘤细胞杀伤作用，在原位实体瘤（肝癌）动物模型和血液肿瘤（急性髓系白血病）动物模型中，系统评价了黑磷作为一种生物活性纳米材料的体内外化疗抑瘤作用机制。另外，构建了一种基于黑磷的光响应纳米囊泡，将超小尺寸的黑磷量子点载入脂质体内部水相，同时将肿瘤靶向肽-磷脂共聚物修饰到脂质体表面，利用黑磷自身的光热和化疗双重作用联合治疗多重耐药肿瘤。最后，本项目将免疫原性细胞死亡化疗药物，阿霉素（DOX），和IDO信号通路抑制剂，Indoximod，分别载入黑磷量子点脂质体的内部水相和脂质双分子层， 构建了一种新型的近红外响应性双载药纳米载体。在类似于人类三阴性乳腺癌的小鼠原位模型中，研究了该双载药纳米载体的药代动力学、药物组合靶向运输及近红外药物控释；阐明了肿瘤部位免疫原性细胞死亡及肿瘤微环境的改变及免疫抑制效应。最终，所构建的这种化疗药物与免疫抑制剂有效整合、靶向共运输及光控释药一体化的纳米载药平台，为开发新一代恶性乳腺癌治疗策略、实现化疗和免疫协同治疗提供新思路和理论依据。