免疫检查点靶向纳米载药系统用于转移性肿瘤免疫协同治疗的研究

Metastasis is the major challenges for cancer therapy. This project is aimed to develop programmed death ligand 1 (PD-L1)-targeting and multi-stimuli responsive nanovectors for combination immunotherapy of metastatic cancer. The nanovectors were constructed by self-assembly of chemotherapeutic- and IDO inhibitor-modified poly(ethylene glycol)-block-poly(di-isopropyl amine ethyl methacrylate) (PEG-b-PDPA) diblock copolymer. The resultant micellar nanoparticles were further modified by anti-PD-L1 nanobody (PD-L1-Nb). The chemotherapeutics and IDO inhibitors are encapsulated inside the hydrophobic core of the micellar nanoparticles, which can minimize the reverse effects of anticancer drugs and IDO inhibitors. The nanovectors can actively target the primary and metastatic tumors through the specific interaction between PD-L1 and PD-L1-Nb. The hydrophilic PEG shell of nanovectors can be quickly cleaved in the MMP-2/-9 enzymatic microenvironment of tumor, which facilitating the tumor accumulation and deep penetration of the nanoparticles at the tumor site. Upon intracellular uptake, the drug payloads were then activated and released in the acidity and reductive microenvironment of tumor cells. The anti-PD-L1 nanobody can block the PD-L1 immune checkpoint on the surface of the tumor cells and inhibit immune evasion. The chemotherapeutics (i.e., Oxaliplatin, OXA) can induce immunogenic cell death (ICD) and facilitate the infiltration of cytotoxic T cells in the tumor tissue. Meanwhile, the IDO inhibitors can modulate the immunosuppressive tumor microenvironment (ITM). PD-L1 blockade, ICD effect and ITM modulation by the versatile nanovectors can synergistically inhibit tumor growth and distant metastasis.

转移是肿瘤治疗最大挑战。本项目拟在前期研究基础上，合成化疗药和IDO抑制剂修饰聚乙二醇-聚甲基丙烯酸二异丙基胺基乙酯（PEG-b-PDPA）两嵌段共聚物，利用自组装和表面抗体修饰技术构建免疫检查点靶向智能纳米载药系统，用于转移性乳腺癌免疫治疗。共价包载的化疗药物和IDO抑制剂处于纳米粒疏水内核，可避免对正常组织毒副作用。纳米粒的PEG亲水外壳可在肿瘤MMP-2/-9酶环境中快速脱除，增加药物在肿瘤部位蓄积和深部渗透。该纳米载药系统具有长循环特性，可主动靶向肿瘤组织和细胞。经细胞摄取后，在细胞酸性和还原环境中解离并释放药物分子。纳米粒表面抗PD-L1纳米抗体可结合肿瘤细胞表面PD-L1免疫检查点，阻断免疫逃避。化疗药可诱导免疫性细胞死亡，激活保护性免疫效应。IDO抑制剂可改善免疫抑制微环境，实现免疫协同治疗。本项目创新性强，有望为发展新型免疫治疗用纳米载药系统奠定基础。

本项目主要构建具有肿瘤主动靶向和药物还原响应释放的智能纳米载药系统，通过特异性靶向肿瘤细胞并激活肿瘤局部原性细胞死亡（ICD）免疫反应，促进抗肿瘤药物的释放与摄取，实现免疫协同治疗以抑制肿瘤转移及复发。受项目资助，我们利用分子共组装和可控自由基聚合技术设计并构建具有肿瘤主动靶向和药物还原响应释放的智能纳米载药系统，特异性靶向肿瘤细胞并激活肿瘤局部ICD免疫反应，以改善肿瘤细胞对抗肿瘤药物的摄取和肿瘤免疫抑制微环境，实现免疫协同治疗，抑制肿瘤转移及复发。项目负责人共发表标注基金号期刊论文34篇，通讯作者发表SCI论文34篇，其中影响因子>10的论文24篇，包括SCI Immunol、Nat Commun、Adv Mater、Adv Funct Mater、Nano Lett和Small Methods等免疫学和纳米生物学领域权威期刊。申请中国发明专利7件，授权中国发明专利4件。项目执行期间，项目负责人在多个纳米生物学和生物材料相关的国内外重要学术会议进行邀请报告 4次。获得国家自然科学奖（新型纳米载药系统克服肿瘤化疗耐药的应用基础研究）二等奖（2021），《中国化学快报》优秀青年学者奖（2020）。共培养博士后3名，博士研究生1名，硕士研究生5名。博士后1人获得人社部“博新计划”支持，3人获得上海市超级博士后支持，研究生2人获得研究生国家奖学金。本项目的研究成果有望对提升我国转移性肿瘤治疗领域的研究水平和和国际竞争力起到一定推动作用。

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