靶向乳腺肿瘤LAT1和乳酸转运特异性激活的吉西他滨-α-AHC小分子前药的设计与评价

尽管乳酸转运抑制剂协同化疗在乳腺癌领域具有良好的临床应用前景，但如何实现二者的高效同步递送是一个急需解决的问题。随着小分子前药策略的发展，将化疗药和乳酸转运抑制剂通过共价连接合成小分子前药有望提高递送效率。然而传统的前药存在稳定性差，肿瘤靶向性不足以及靶部位活化效率低等问题。为此本项目拟设计肿瘤LAT1靶向同步递送化疗药和乳酸转运抑制剂特异性激活的新型小分子前药策略。以LAT1底物为转运体识别基团，以吉西他滨和α-氰基-4氨基肉桂酸（α-AHC）为模型药，以邻硝基-对二苯甲酸为智能激活连接桥，合成酰胺前药用于乳腺癌的治疗。静脉给药后，前药首先通过乳腺癌高表达的LAT1介导，实现前药肿瘤的高效靶向递送；其次依靠酶激活和化学激活特异性释放药物，实现肿瘤细胞内快速释药，二者协同增效，提高抗肿瘤作用。本项目的研究将为肿瘤靶向小分子前药设计和联合给药提供一种新的设计思路。

Although the combination of chemotherapy and lactate transport inhibitors has good potential application in breast cancer treatment, how to realize efficient co-delivery of chemotherapeutic agents and inhibitors for better synergistic effect is still a major challenge. Some drawbacks of traditional prodrug have greatly limited their clinical application, such as weak stability, poor selectivity and low activation efficiency. Herein, this project plans to synthesize LAT1-targeting specific activatable prodrug to simultaneous delivery of gemcitabine and α-AHC for breast tumor therapy. In this study, 3-anion-Phe was used as transporter recognition group, gemcitabine and lactate delivery inhibitor were used as model drug, and 2-nitro-1, 4-dibenzoic acid was used as intelligent activated bridge. Firstly, LAT1 mediated efficient targeted delivery of prodrug to tumor. And then, specific activatable self-immolative bridge facilitates drug release from prodrug, resulting in improved synergistic combination of chemotherapy and lactic acid inhibitor. This strategy provides new design modality for the tumor-targeting prodrugs design and combined treatment.