脑肿瘤严重危害人类身体健康，然而由于血脑屏障（BBB）的存在，限制了药物进入脑中发挥治疗效果，BBB已成为中枢给药的瓶颈。本课题组在以维生素C作为载体的脑靶向前药研究的基础上，结合具有肿瘤靶向及脑(脑肿瘤时)靶向的叶酸，以广谱抗肿瘤药物阿霉素作为模型药物，设计并合成一类新型的叶酸-维生素C-阿霉素(Folate-VitC-Dox)的三元偶联物, 分子中的维生素C能够识别BBB上的SVCT2,血液中氧化形成的脱氢维生素C识别BBB上的GLUT1，从而可使得该偶联物高效地转运透过BBB。进入脑中后，分子中的叶酸部分识别肿瘤细胞高度表达的叶酸受体FR，将药物靶向进入到肿瘤细胞释放原药，必将对脑肿瘤起到很好的治疗作用。通过对Folate-VitC-Dox的靶向性、动力学和药效学研究及安全性评价，有望解决困扰医药学界治疗脑肿瘤的难题，为脑肿瘤的治疗创立新的思路和新方法，具有极高的学术和应用价值。

Brain tumors remain a significant human health problem worldwide. Compared to radiation and surgical treatment, chemotherapy has shown a survival benefit to high-grade glioma patients. To be effective, a chemotherapy agent must be exposed to brain tumor cells at concentraitons tha can overcome intrinic resistance mechanisms. However, this is difficult for most drugs, owing to the blood-brain barrier (BBB), which is formed by a network of closely sealed endothelial cells in the brain’s capillaries. BBB only allows hydrophobic molecules with MW < 400 Da to pass through it, while blocks over 98% small molecule drugs and almost 100% large-molecule drugs such as recombinant proteins and monoclonal antibodies into the brain. Moreover it is difficult to maintain the therapeutic agents mainly accumulating in the tumor site but not to diffuse in the normal tissues due to the short duration time and non-specific binding in vivo, thus causing harmful side effects and even death of the patients..To meet the requirement of brain cancer therapy, there is a need for developing drug delivery systems with the double functions of passing through the BBB and targeting the tumor cells, thus reducing the adverse effects to the normal cells. Our research group has developed a widely known ligand, L-ascorbic acid (AA) familiar to us as vitamin C, as brain targeting carrier, because sodium-dependent vitamin C transporters (SVCT2) is highly expressed on the brain capillaries endothelial surfaces. With the targeting ligand of AA, the drug delivery systems can across the BBB through a receptor-mediated transport mechanism to reach the brain and further accumulate in tumor cells. The vitamin folic acid is another widely known ligand that displays extremely high affinity for the folate receptor on the tumor cells surface, and are internalized via receptor-mediated endocytosis. Because the FR is overexpressed on certain malignant cell types and is undetectable or present only at low levels in most normal tissues, targeting of the FR has been proposed as a potential mechanism for delivery of drugs to treat cancer. In this regard, combined brain-targeting of AA and tumor targeting or brain (brain tumors) targeting of folic acid, with broad-spectrum antitumor drugs doxorubicin as a model drug, we prepared to design and synthesize novel prodrugs of Folate-VitC-Dox 1. Thus, these folate-Vit C conjugates are expected to act synergistically, recognized by SVCT2 and induced by folate to efficiently transport through BBB. After entering the brain, the cojugations are accumulated in tumor cells via FR-mediated endocytosis and released drugs via a disulfide bond to reach the good therapeutic effect in the treatment of brain tumors.