CT可视和还原响应生物可降解碘化聚合物囊泡用于肺癌筛查和精准靶向治疗

Lung cancers with the highest morbidity and mortality have become the most lethal malignancy worldwide. The precision therapy may effectively improve lung cancer treatment efficacy. However, due to the intrinsic tumor heterogeneity, accurate screening is the key to precision therapy. After patient screening, how to achieve precision lung cancer therapy poses another challenge. In this project, we will design and develop a CT visible, lung cancer targeting, and disulfide crosslinked iodinated polymersome nanoplatform to simultaneously achieve lung cancer screening, precision therapy and response evaluation. The iodinated polymersomes are designed to have a small size (50 -100 nm), high iodine content and high stability. They allow facile modification with different lung cancer targeting peptides (e.g. GE11 and cRGD) and precisely controlled peptide surface densities, which potentiates targeted CT imaging and accurate CT screening of different lung cancers. After CT screening showing that targeted polymersomes can efficiently home and accumulate in a specific lung cancer, we will load the same polymersomes with anticancer drugs to achieve precision targeted therapy. The anticancer drugs can be clinically used hydrophobic drugs like docetaxel and hydrophilic drugs like DOXHCl. During or after the treatment, we can use the same targeted polymersomes (without drug) as CT contrast agent for response evaluation. These CT visible multifunctional iodinated polymersomes are simple and easy to fabricate, biodegradable and biocompatible, which render them interesting for clinical translation.

肺癌是当今发病率和死亡率最高的恶性肿瘤。精准治疗模式可望有效提高肺癌的疗效。然而，由于肿瘤固有的异质性，患者筛查是精准治疗的关键，筛查后如何对肺癌患者实现精准靶向治疗也存在巨大挑战。本项目将研发CT可视、肺癌靶向、双硫交联的碘化囊泡技术平台，首次实现肺癌CT筛查、精准靶向治疗和疗效评估。该多功能碘化囊泡尺寸小（50-100 nm）、含碘量高、体内稳定，可修饰不同靶向多肽（如GE11、cRGD），且靶分子密度可准确调控，可望实现不同肺癌的靶向CT成像，从而对肺癌实现准确筛查。当CT确认其可靶向富集到肺癌后，再通过同一靶向囊泡装载抗癌药物，实现肺癌的精准靶向治疗。抗癌药物将选用临床用多西他赛和阿霉素盐酸盐等。在治疗过程中和结束后，可用同一靶向空囊泡为CT造影剂、通过CT评价肿瘤治疗效果。该CT可视多功能碘代囊泡制备简单、生物可降解、具良好安全性，有望实现临床转化。

精准治疗可望有效提高肺癌等肿瘤的疗效。对于高异质性肿瘤的患者筛查是精准治疗的关键，筛查后如何对肺癌患者实现精准靶向治疗也存在巨大挑战。本项目主要基于专利单体2,2’-碘代甲基三亚甲基碳酸酯（IC）的聚合物制备的生物可降解富碘聚合物囊泡IC-Ps，（i）创新研究了其用于肺癌的靶向CT成像、治疗和病人筛选，及利用该富碘囊泡中的碘可稳定标记放射性碘125I和131I，设计了放射性碘标记的多功能SPECT/CT成像和高效放射性同位素体内肿瘤治疗；（ii）创新性探索了该富碘囊泡和HDAC抑制剂联合或和DTX联合、或是利用内放射富碘囊泡和免疫检查点抑制剂联合用于三阴乳腺癌的联合放疗；（iii）创新性探索了富碘囊泡在巨噬细胞靶向的非侵入性动脉粥样硬化斑块成像、多模态成像引导的肿瘤靶向治疗的应用，及多种肿瘤主动纳米药物用于包括原位肺癌在内的多种肿瘤的靶向治疗。本项目的创新研发产生了一系列具独立知识产权的富碘囊泡和肿瘤靶向交联稳定的多功能纳米药物，为高效肿瘤诊断和治疗提供了策略。项目执行期间研究成果已发表论文30篇，5篇已接受发表，授权中国发明专利18件、美国专利1件，很好地完成了研究目标。培养博士2人，硕士8人。项目负责人连续入选2018、2019、2020、2021年全球高被引科学家，应邀担任美国控制释放学会（CRS）会员，受邀担任美国药物释放学会2019年年会和展览的年会五名组委会成员之一（2019年7月19-25日西班牙瓦伦西亚）；担任美国控制释放学会官方期刊Drug Delivery and Translational Research (DDTR)期刊编委；应邀担任欧洲研究理事会的Consolidator Grant panel的特聘会评专家（2020-），和多个国内外知名研究机构和实验室开展合作研究。