两疏性抗癌药物新载体磷脂化多孔碳纳米球的构建及其体内释药机制研究

Cancer is one of the most malignant diseases threatening human life and health. To research and develop novel anticancer drugs is representing the focal interest of modern drug discovery. However, there exist serious problems associated with solubility and toxicity for many anticancer entities that are newly discovered. It is the key obstacle, being difficultly formulated into suitable dosage forms and lack of tumor specificity, of amphiphobic drugs for their clinic applications. Some pharmacologically highly active drug candidates are not only poorly soluble in water, but also in oil, belonging to amphiphobic ones. The solubility has been a bottleneck to systemically administrate amphiphobic drugs. Because of severe drug precipitation, the current nanocarriers such as liposomes, micelles, and micro/nano emulsions fail to load such drugs, e.g. raloxifene, SNX-2112. For this reason, it is obligated to explore novel drug delivery systems to resolve the formulation issue of amphiphobic drugs and administration thereof. In our previous work, we found that amphiphobic drugs could be effectively loaded onto absorbable materials followed by a stabilization strategy, making the formulation satisfactory to the requirement of intravenous administration. Based on previous investigations, porous carbon nanospheres are synthesized to load amphiphobic drugs through the adsorption mechanism combined with a coating strategy with phospholipid to stabilize the nanocarriers. We will comprehensively evaluate and investigate the drug release behavior in vitro and in vivo, tumor targeting, and transport mechanism of this novel drug delivery system in this program.

癌症是威胁人类生命健康的严重疾患之一。研究和开发新型抗肿瘤药物是现代药物研究的热点。然而，很多新发现的抗肿瘤药物存在严重的溶解性和毒性问题，难以系统给药和缺乏肿瘤细胞特异性成为其走向临床的关键障碍！一些具有高活性的药物候选物不仅难溶于水，而且难溶于油及脂质材料，可谓水油两疏。溶解度问题一直是两疏性抗癌药物系统给药难以突破的瓶颈。现有的纳米载体系统如脂质体、胶束、微纳米乳等，因存在严重的药物析出，均难以实现对两疏性药物如雷诺昔芬、SNX-2112等有效载药。因此，亟待寻找新的传递系统解决这类药物的剂型化和给药问题。我们在前期的工作中发现，可以通过吸附载药的方式对两疏性药物进行载药，并结合一定的制剂手段可使吸附载体满足血管内系统给药的要求。本项目拟在前期工作基础上，利用多孔性碳纳米球的强吸附性和表面磷脂稳定化策略构建两疏性抗癌药物新型纳米载体系统，研究其体内外释药行为、肿瘤组织靶向能力

癌症是严重威胁人类生命健康的重大疾病之一。很多高活性抗癌药物存在溶解性问题，其中不乏油水两难溶的两疏性药物。解决两疏性药物载药和给药问题是药剂学面临的巨大挑战。本项目发展了新型介孔纳米材料，通过吸附原理解决两疏性药物的载药问题；同时，利用载体材料的自靶向性提高两疏性药物的体内传递效率，实现高效抗肿瘤和改善药物吸收的目的。在本项目中，我们选择了SNX-2112和雷诺昔芬作为代表性两疏性药物，通过水热反应制备了葡萄糖介孔碳纳米球，分别进行了血管内和口服给药研究。研究结果表明，基于葡萄糖的介孔碳纳米球可以有效荷载两疏性药物，通过葡萄糖转运体实现药物靶向递送和改善药物胃肠道吸收。碳纳米球显著改善SNX-2112的细胞摄取、跨膜转运和组织分布，不仅实现了高载药，而且提高了SNX-2112的体内抗肿瘤效应；碳纳米球也通过改善的肠道吸收和淋巴转运提高了雷诺昔芬的口服生物利用度。这两方面的研究工作与本项目直接相关，研究成果分别发表在药剂学权威期刊European Journal of Pharmaceutics and Biopharmaceutics和Pharmaceutical Research上。同时，在本自然科学基金项目资助下，也做了其他方面的工作，共发表SCI论文5篇，取得了丰硕的科研成果。本项目提出的“两疏性药物”概念，即是对药物的生物药剂学分类系统（BCS）的丰富和扩展，发展的吸附载药技术也是对现有制剂技术的补充和完善。本项目的完成，将为两疏性药物的传递问题提供借鉴思路和解决方案，具有显著的科学意义。