膀胱内灌注化疗用高分子载药体系临床应用前的关键基础科学问题研究

According to the clinical requirement of intravesical instilled chemotherapy of bladder cancer, the applicant has achieved many results on the preparation of polymer nanocarriers for target release of anticancer drugs in the previous project. This project will focused on two typical polymer nanocarriers with FDA approval and well dispersion in water phase, i.e. new water-soluble copolymers and polymer micelles self-assembled from amphiphilic block copolymers. The preparation and purification process will be studied for producing polymer nanocarrier materials with good biocompatibility. The stability, cellular interaction and drug delivery of polymer nanocarriers in the physiological environment of bladder cancer will be revealed. For the specific administration route of intravesical instillation for bladder cancer, animal models will be set up to study the possibility of polymer nanocarriers penetrating through bladder wall to take part in the systemic circulation and resultant cytotoxicity. Based on the above cell and animal tests, the influences of chemical structure, drug loading approach and drug loading capacity of polymer nanocarriers on biocompatibility, targeting to cancer cells and in vivo biodistribution will be demonstrated, which will provide important evidences for clinical application of polymer nanocarriers in intravesical instilled chemotherapy of bladder cancer.

针对膀胱浅表肿瘤灌注治疗临床应用中亟待解决的问题，申请人已在高分子纳米载药体系的构建及其与膀胱肿瘤细胞的靶向作用等方面取得了重要的基础研究成果。为推动临床应用，本项目将以FDA批准临床可用的生物降解高分子和水溶性高分子构建水相稳定分散的高分子纳米胶束和水溶性共聚物两种典型的高分子纳米载药体系，研究高分子纳米载药体系的制备过程对其生物相容性的影响，揭示其在模拟膀胱内生理环境中的稳定性、对膀胱肿瘤细胞和正常细胞的选择性、以及药物的释放行为。针对膀胱肿瘤灌注治疗的特定用药途径，通过小动物试验，采用经尿道灌注等方法，研究高分子纳米载药体系穿透膀胱壁进入动物体内其他部位和参与血液循环的可能性和毒性。通过上述细胞和动物试验，阐明高分子纳米载药体系的化学结构、载药方式和载药量等对其生物相容性、肿瘤细胞靶向性以及体内生物分布的影响，为高分子纳米载药体系在膀胱肿瘤灌注治疗中的临床应用提供重要理论依据。

四年来，本项目围绕原位膀胱肿瘤模型构建、主动靶向纳米载体的设计与评价、肿瘤细胞选择性前药纳米药物的设计与评价以及小分子药物和纳米药物体内安全性评价等课题开展了研究，成功构建了多种浅表性膀胱肿瘤模型用于深入研究膀胱灌注纳米药物与小分子药物在生物分布、生物安全等方面的差异。本项目系统地探索了具有应用前景的膀胱灌注化疗用纳米药物载体的设计、合成以及放大化生产工艺，在此基础上设计了多种能够选择性作用于膀胱肿瘤细胞的新型纳米药物。通过本项目的研究，我们发现相对于系统给药而言，膀胱灌注化疗是一种相对安全的给药方案，即使给予小分子药物也较少对动物其它组织器官造成明显损伤，相关灌注化疗用纳米药物的设计应主要关注其膀胱驻留能力以及对肿瘤细胞的选择性。本项目执行期间，申请人与合作者在Biomacromolecules等SCI收录期刊上发表标注资助论文11篇。共培养博士毕业生3名、硕士毕业生10名。