化疗药物的反晶体工程：双功能离子液体的构建及其脑部递释和协同增效机理的研究

As an anti-crystal engineering technology, ionic liquid technology is capable of improving the solubility and permeability of crystalline solid drug by forming salt with appropriate counterions. Nowadays, ionic liquid technology is becoming a research focus in the area of pharmaceutics in terms of enhancing the permeability, meanwhile, literature reports regarding ionic liquids with dual biological functions are emerging. Brain tumor represents a big threat to human health, mainly because of the existence of blood brain barrier (BBB), which prevents the accumulation of chemotherapeutic drugs in the brain tumor and leads to low efficacy. The current strategies to improve brain delivery of chemotherapeutic drugs are invasive and expensive, thus a cost-effective technology with good patient compliance is in urgent need. This project aimed to prepare dual-functional ionic liquid of chemotherapeutic drugs with the help of functional counterions, i.e. counterions with antitumor activities. The dual-functional ionic liquid is expected to improve the brain accumulation of drugs by increased lipophilicity which facilitates the transportation across BBB and enhances the efficacy by synergy with functional counterioins. The project belongs to the fields of chemical engineering, crystal engineering and pharmaceutics. The successful implementation of this project will provide a novel strategy for the application of ionic liquid technology in the field of pharmaceutics, thus adding new insight into the ionic liquid technology both in theory and practice.

离子液体技术是一种反晶体工程技术，通过与合适的反离子成盐将药物液态化能克服晶型固体药物在溶解度和渗透性方面的缺点。采用离子液体技术改善药物的渗透性正成为其在药学领域应用的热点，而通过功能性反离子的选择制备具有双重生物学功能的药物离子液体也初现端倪。脑部肿瘤是危害人类健康的大敌，目前脑部肿瘤治疗的主要问题在于药物难以透过血脑屏障进入脑部发挥作用，而现有技术手段多为侵入性，患者顺应性差，代价昂贵。本项目拟采用具有抗癌活性的反离子与化疗药物制备双功能离子液体，一方面增加药物的亲脂性，提高药物跨越血脑屏障的能力，从而增加药物在脑部的蓄积；另一方面通过反离子抑制肿瘤的协同作用，进一步提高药物疗效，从而研制出一种减毒增效，患者顺应性好的化疗药物新型物理形态。本项目是化学、晶体和药学多学科交叉领域，将对离子液体技术在医药领域的应用提供新的研究思路和新方法，具有重要的理论意义和应用前景。

药物离子液体技术具有消除固体药物多晶型现象，调控药物溶解度和渗透性，协同增效等优势。本项目分别以布洛芬、多奈哌齐和米托蒽醌为模型药物，展开系统性的离子液体研究，探索利用离子液体技术提高药物透血脑屏障和皮肤屏障的可行性。.以布洛芬为模型药物，成功制备并表征9种离子液体。离子液体的形成影响布洛芬的溶解度和亲脂性。BBB PAMPA和Skin PAMPA实验表明非质子型离子液体可以提高药物透过血脑屏障和皮肤屏障的能力。采用Lee-wheaton电导方程和NOESY二维核磁波谱分析表明离子液体在水相中有明显的离子缔合作用，进而影响其渗透性。该部分研究为后续选择合适配体反离子以提高药物的渗透性提供基本方向。.以多年哌齐为模型药物，首次成功制备并表征6种离子液体。离子液体的形成维持了多奈哌齐的亲脂性，提高了多奈哌齐的水溶性。在维持跨血脑屏障能力的基础上，多奈哌齐离子液体的经皮渗透性优于多奈哌齐，验证了以离子液体技术提高药物渗透性以促进药物跨越皮肤屏障的可行性。成功制备多奈哌齐离子液体DIA贴剂，其在药物释放与药物渗透两方面均优于原型药的贴剂，拓展了离子液体商业化应用的可能性。.以米托蒽醌为模型药物，首次成功制备并表征4种离子液体。离子液体形成提高了药物的亲脂性，体外细胞实验表明米托蒽醌离子液体对于脑胶质瘤细胞毒性有显著增强，其抗肿瘤活性提高；体外BBB PAMPA和小鼠组织分布实验均表明,离子液体的形成可以加速米托蒽醌透过血脑屏障，验证了利用离子液体技术提高药物渗透性、克服血脑屏障、提高药物抗肿瘤活性的项目既定目标。.研究内容在国内外未见文献报道，属首创。这一研究课题的完成，为渗透性差的药物或者靶部位具有渗透屏障的药物提供了一条新的捷径，具有较高的临床应用前景和良好的社会效益；同时，药物离子液体这种新型药物物理形态可形成具有自主知识产权的专利药物，有益于对现有专利的突破，具有较高的经济效益。