普罗布考是临床广泛应用的口服降血脂和抗动脉粥样硬化药物。但该药水溶性极差，口服后胃肠道的溶出少、跨膜吸收差且不规则，严重影响了该药的药效和临床应用。树状高分子纳米载体具有独特的多分支的结构、表层亲水、内核疏水的特性，为嫁接和装载药物以改善药物的溶解性和透生物膜吸收提供了优越条件。本研究以G5-PEG 和G7-PEG树状高分子为载体，采用复合法、化学键合法、纳米脂质体、纳米脂质载体等方法构建载体-普罗布考纳米给药系统，研究载体、不同构建方法和条件对药物的理化性质、溶解与释放的影响；以Caco-2细胞单层为小肠吸收模型，研究载体及纳米给药系统对药物跨膜转运的促进作用及其机制；以LDLR-/-小鼠喂饲高脂饲料造成高脂血症和动脉粥样硬化模型，研究纳米给药系统的口服生物利用度、降脂及抗动脉粥样硬化的药效和生物安全性。阐明以树状高分子为载体构建纳米给药系统对提高难溶性药物的口服吸收及相关功效的作用。

Probucol is a cholesterol-lowing and anti-atherosclerosis drug. However, the therapeutic effects and clinic application of this drug have been limited by its poor water solubility in gastrointestinal fluid, low transportation and irregular absorption through intestine barriers. PAMAM dendrimers are branched nano-sized polymers with hydrophilic surface and hydrophobic internal structure, which benefit to conjugate or encapsulate drugs to increase dissolution, trans-membrane transportation and absorption of the water insoluble drugs. In this project, G5-PEG and G7-PEG are used as drug carriers, four different pharmaceutical techniques (complex, conjugate, nano-liposome, nano-structured lipid carrier) will be applied to prepare dendrimer-probucol nano-scale drug delivery system (NDDS). The physical-chemical characteristics, dissolution and drug release efficiencies of the NDDS will be studied. The trans-membrane uptakes, transportation and mechanisms of the dendrimer-probucol NDDS will be studied on Caco-2 cell monolayers, which are broadly used as the in vitro intestinal absorption model. With western diet fed LDL receptor deficient (LDLR-/-) mice as the hyperlipidemia and atherosclerosis disease models, and commercialized probucol tablets as positive drug control, the oral absorption bioavailability, therapeutic effects (cholesterol-lowing, anti-arteriosclerosis, etc), bio-security （toxicities, side effects, etc）of the dendrimer-probucol NDDS will be studied. This study will illuminate the improvement effects and mechanisms of dendrimer-based NDDS on the oral absorption and therapeutic effects of water-insoluble drugs.