肿瘤靶向和双硫交联的多功能高分子纳米药物

Biodegradable polymeric nanocarriers are one of the most promising systems for targeted tumor therapy. The therapeutic efficacy of current polymeric nanomedicines is, however, not optimal, due to problems of low in vivo stability, poor tumor targetability, and inadequate control over drug release. In this project, we will design and develop a series of proprietary tumor-targeting and disulfide-crosslinked multifunctional polymeric nanocarriers including micelles and polymersomes. These multifunctional nanocarriers are mainly based on novel biodegradable poly(dithiolane trimethylene carbonate) and copolymers, which are simple and easy to scale up in a GMP facility. The micelles can be used to load and deliver lipophilic chemotherapeutics (e.g. doxorubicin and docetaxel) while polymersomes can be used to deliver not only lipophilic chemotherapeutics but also hydrophilic chemotherapeutics (e.g. doxorubicin hydrochloride and methotrexate disodium) and protein drugs (e.g. granzyme B and apoptin). Interestingly, these micelles and polymersomes are self-crosslinked following self-assembly, exhibiting a high drug loading, high in vivo stability and low drug leakage, while are prone to rapid auto-decrosslinking and fast drug release under the cytoplasmic reductive environment inside the tumor cells, leading to a superior antitumor effect. Moreover, the surface of these multifunctional nanomedicines is easy to decorate with tumor specific molecules like peptides and antibodies, which might bring about precisely targeted tumor therapy (including lung tumor, melanoma, breast cancer and ovarian cancer).

生物可降解高分子纳米载体是实现肿瘤靶向治疗最具前景的体系之一。然而，现有高分子纳米药物存在体内稳定性低、肿瘤靶向性差、药物释放难于控制等问题，临床肿瘤疗效并不理想。本项目将研发一系列具独立知识产权的肿瘤靶向和双硫交联稳定的多功能高分子纳米药物载体包括胶束和囊泡。该多功能载体主要基于新型生物可降解聚二硫戊环三亚甲基碳酸酯及共聚物，非常简单，可在GMP净化间大量、重复制备。胶束可运载疏水化疗药物（如阿霉素、多西他赛等），而囊泡不但可包裹疏水药物而且可高效装载亲水化疗药物（如阿霉素盐酸盐、甲氨蝶呤二钠盐等）及蛋白质药物（如颗粒酶B、凋亡蛋白等）。该胶束和囊泡自组装形成后即发生自交联，载药量大，体内稳定性高，药物泄漏少，但在肿瘤细胞内还原环境下则自动解交联，快速释放药物，产生高抗癌活性。多功能纳米药物表面易修饰肿瘤特异性多肽和抗体等分子，可望实现肺癌、黑色素瘤、乳腺癌、卵巢癌等肿瘤的精准靶向治疗。

纳米药物为肿瘤的靶向治疗提供了一新策略，然而因其不够稳定、药物易泄露、靶向性不强、药物在肿瘤细胞内释放慢、制备复杂等问题，临床治疗效果欠佳。本项目创新研发一系列具独立知识产权的肿瘤靶向和双硫交联稳定的多功能高分子纳米载体和药物，包括（i）囊泡化疗药物和分子靶向药物，实现了恶性血液肿瘤和实体瘤的高效靶向化疗和分子药物治疗；（ii）不对称膜囊泡，实现了蛋白药物、溶瘤肽、siRNA、免疫佐剂等生物药物的高效装载和体内靶向递送，有力提升了恶性肿瘤的生物治疗和免疫治疗效果；（iii）胶束纳米化疗药物和分子靶向药物，实现了恶性肿瘤的高效化疗和分子靶向治疗。项目执行期间,在国际主流期刊已发表论文91篇，授权中国发明专利34件、PCT国际专利3件，8件专利转让给博瑞生物医药（苏州）股份有限公司（科创板上市企业），同时签订了400万元的横向合作开发合同;共培养博士7人、硕士13人，1人次获得江苏省普通高校研究生科研创新计划项目的资助，2人次获得百特中国青年研究者奖，1人现为南京中医药大学特聘教授，1人为复旦大学青年研究员。项目负责人应邀在重要国际学术会议上做邀请报告12次，作为大会主席组织了第五届新型高分子材料与控制释放国际会议（SIPCD 2018），于2018年入选美国医学与生物工程院会士， 2018-2021年连续4年入选全球高被引科学家，2015-2019年担任Biomacromolecules副主编，2019起担任药剂学重要期刊Journal of Controlled Release副主编，担任Mater. Today, Acta Pharmaceutica Sinica B, Biomacromolecules, Nanotechnology, PLoS One, Mater. Today Chem., J. Gene Med.等8本国际期刊及《药学学报》编委。

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