肿瘤微环境自适性纳米递药系统抗乳腺癌转移及其作用机制研究

Cancer metastasis is one of the major challenges for breast cancer therapy. It is highly desirable to develop novel nanodrug carriers for treating metastatic breast cancer. In this project, we will design and construct a novel tumoral acidic and enzymatic microenvironment adaptable nanosized drug delivery system (NDDS) for combination treatment of the metastatic breast tumor. First, a photosensitizer pyropheophorbide A (PPa)-conjugated poly(ethylene glycol)-block-poly (2-(hexamethyleneimino) ethyl methacrylate) (PEG-b-PHMA) diblock copolymer, and an polymeric prodrug of doxorubicin (DOX) with iRGD modification will be synthesized, respectively. Afterwards, iRGD-modified DOX prodrug and PPa-conjugated PEG-b-PHMA diblock copolymer will be used for preparation of the self-assembled nanoparticles (NPs) with core-shell structure. Upon intratumoral accumulation through the enhanced penetration and retention (“EPR”) effect, the NPs will be dissociated in the tumoral weakly acidic microenvironment to activate the fluorescence and photodynamic properties of PPa, which can be used for fluorescence imaging and photodynamic therapy. iRGD and DOX will be liberated from the polymeric chain via matrix metalloproteinase-2/9 (MMP-2/9)-mediated cleavage of the PLGLAG spacer. iRGD can facilitate tumor penetration and cellular uptake of DOX, thus improve the therapy effect of combination photodynamic (PDT) and chemotherapy. The NDDS proposed in this study is of high novelty and great significance. It might provide novel insights for developing novel nanosized drug delivery systems for highly efficient treatment of the metastatic breast cancer.

肿瘤转移是乳腺癌治疗最大挑战。发展转移性肿瘤特异性药物载体是乳腺癌治疗领域极具挑战性和紧迫性的重要研究课题。本项目将在前期基础上，设计、构建具有肿瘤微环境自适应功能的新型纳米载药系统抗乳腺癌转移。拟合成焦脱镁叶绿酸A（PPa）修饰聚乙二醇-聚甲基丙烯酸六亚甲二胺基乙酯（PEG-b-PHMA）两嵌段共聚物和寡肽连接的iRGD-阿霉素大分子前药，并构建自组装纳米粒。该纳米粒具有肿瘤微酸性和MMP酶环境双重响应特性，可在转移性肿瘤间隙发生快速构型转变，释放化疗药物，延长药物瘤体滞留时间并克服肿瘤生理屏障，发挥主动瘤体渗透功能。将采用多种表征手段评价其理化特性，利用乳腺癌细胞、原位及转移瘤模型明确自组装纳米粒的化学构成与其抑制肿瘤细胞增殖，抗肿瘤生长和转移等生物活性间的构效关系，并从分子、细胞及组织水平揭示其抗肿瘤转移作用机制。该研究有望为发展高效抗乳腺癌转移纳米载体系统奠定基础。

本项目主要发展了转移性肿瘤特异性药物载体，借助肿瘤微环境微酸性和基质金属蛋白酶2的存在条件，设计并构建了具有肿瘤微环境自适应功能的新型纳米载药系统，克服肿瘤生理屏障以延长药物在瘤内的滞留时间，增加肿瘤细胞对抗肿瘤药物的摄取，以对抗乳腺癌转移。受项目资助，我们筛选出由光敏剂Ce6修饰的聚乙二醇-聚甲基丙烯酸六亚甲二胺基乙酯（PEG-b-PHMA-Ce6）与iRGD靶向肽所修饰阿霉素大分子前药自组装所形成的纳米粒，确定了其对肿瘤微环境中微酸性环境与MMP2的响应能力，及肿瘤细胞对药物摄取的增加，有效改善了光动力与化疗等对转移性肿瘤的联合治疗效果。项目负责人共发表标注基金号期刊论文22篇，其中SCI论文20篇，影响因子>10的论文12篇，包括SCI Immunol，Nat Commun, Adv Mater, Adv Funct Mater, Nano Lett和Small等免疫学和纳米生物学领域权威期刊，并申请中国发明专利8件。项目执行期间，项目负责人入选科技部中青年科技创新领军人才（2017），中科院青年创新人才促进会优秀会员（2018），获中国药学会-赛诺菲青年生物药物奖（2017）。共培养硕士研究生3名，博士研究生4名，其中4人获得研究生国家奖学金。超额完成项目规定的各项考核指标。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。