基于脑部OCT2特异性靶向的阿霉素转运脂质体的构建及其转运机制研究

The blood–brain barrier behaves as the main obstacle to chemotherapies and contributes to poor therapeutic of lot of drugs because of low concentration in brain. Liposome is interesting due to its basic functionality and the advantages that ensue. OCT2, a kind of transporter in brain, has specific affinity with organic cation. It's worth noting that OCT2 has not been used to enhance brain uptake of liposomes by specific interactions with surface of brain microvascular endothelial cell. Moreover, it is not clear that the transport mecanism based on specific interactions with OCT2 in brain. In view of the advantages of liposomes in drug delivery for glioma therapy, Alzheimer's disease and so on, it is necessary to explore new specific affinity site on surface of brain microvascular endothelial cell to promote drug uptake in liosomes. At present, we have successfully prepared N, N, N-trimethylethanaminium hydroxide derivative modified doxorubicin-loaded liposomes which called transliposomes. The brain distribution of doxorubicin was increased by 4.56-fold compared with DOX-Sol in mice. This project is designed to complete by following experiments: 1. synthesizing PEG-GCDS containing different N,N,N-trimethylethanaminium hydroxide derivative（N+TMEA-PEG-GCDS）; 2. preparing and evaluating doxorubicin transliposomes containing different density of organic cation; 3. using experiments of blood-brain barrier model in vitro, competitive inhibition of hOCT2, uptake in HBMEC cells, the inter-cell transportation to study transmembrane transport mechanism; 4. investigating the pharmacokinitics behaviors and in vivo anti-tumor activity of transliposomes. This research is trying to clarify the transport mechanisms of liposomes targeting OCT2 in barin and provide a theoretical basis for the transporter as a target for drugs delivery.

血脑屏障使脑部疾病的治疗面临极大的挑战，药物脑内浓度低导致治疗效果差，脂质体的脑部递药具有独特优势。有机阳离子转运蛋白2（OCT2）是脑部转运体的一种，对阳离子具有高度亲和性。将脑部OCT2作为特异性靶点提高脂质体的转运还未见报道，跨膜转运机制尚不明确。鉴于脂质体在脑肿瘤等疾病治疗中递药优势明显，寻找新的靶点并明确转运机制是十分必要的。目前我们已成功制备了N,N,N-三甲基乙铵衍生物修饰的阿霉素载药脂质体，小鼠组织分布表明其能够将阿霉素溶液脑内浓度提高4.56倍。本课题拟完成：1合成不同的N+TMEA-PEG-GCDS；2制备不同阳离子密度的阿霉素转运脂质体并进行评价；3 采用血脑屏障渗透性、hOCT2 竞争抑制、HBMEC摄取、跨细胞转运实验解析跨膜机制；4考察体内药动学和抗胶质瘤活性。通过研究，阐明脑部OCT2特异性靶向脂质体增加药物转运的跨膜转运机制，为转运脂质体的构建提供理论依据。