靶向ATB0,+的DOX/JPH203纳米递送系统调控肿瘤氨基酸代谢协同化疗抗肿瘤研究

Chemotherapy is an important approach for clinical cancer treatment, but how to avoid the resistance and improve the therapeutic efficacy is still a major challenge. With the development of molecular biology, a novel cancer starvation therapy via inhibiting tumor-overexpressed amino acid transporters to modulate the metabolism of amino acid in tumors aroused the increasing attention of researchers. It has great potential to combine this approach with chemotherapy to sensitize tumor cells to chemotherapeutics and to improve the anticancer efficacy. However, the traditional drug delivery method usually resulted in low efficiency, lack of drug distribution at target site, and even leading to serious side effects. Herein, this project aims to develop tumor-overexpressed transporter ATB0,+ targeted nanoparticle to co-deliver JPH203, an inhibitor of a key transporter (LAT1) in amino acid metabolism in tumor, and doxorubicin as a chemotherapeutic agent, combining tumor starvation therapy based on modulating amino acid metabolism with chemotherapy by using nano-drug delivery system. JPH203 inhibits the activation of mTOR signaling pathway through inhibiting LAT1 activity to induce tumor cell apoptosis, synergistically exerting an effective anti-tumor efficacy with doxorubicin. In addition, ATB0,+ targeted nanoparticles down-regulate the target ATB0,+, further inhibiting amino acid metabolism in tumors. This project will provide new ideas for combination therapy via nano-drug delivery system.

化疗是临床上肿瘤治疗的重要手段，但如何避免药物耐受性的产生、提高肿瘤治疗效果仍是一个亟待解决的难题。随着分子生物学的发展，通过抑制肿瘤高表达氨基酸转运体来调控肿瘤细胞氨基酸代谢的“饥饿疗法”日益引起研究者的关注，该疗法有望增强肿瘤对化疗药物的敏感性，提高治疗效果。然而，传统的药物联合递送方式递送效率差、靶部位分布不足，且容易导致严重的毒副作用。本项目拟构建肿瘤高表达氨基酸转运体ATB0,+靶向纳米粒，联合递送氨基酸代谢关键位点LAT1转运体抑制剂JPH203和化药阿霉素，利用纳米递送系统实现氨基酸代谢调控与化疗的协同抗肿瘤作用。JPH203通过抑制LAT1偶联抑制mTOR信号通路，诱导肿瘤细胞凋亡，协同阿霉素发挥高效抗肿瘤作用；同时，ATB0,+靶向纳米粒在细胞摄取过程中下调靶点ATB0,+，进一步强化肿瘤氨基酸代谢调控效果。本项目的研究将为基于纳米载体的肿瘤联合用药提供一种新思路。

化疗是临床上肿瘤治疗的重要手段，但如何避免药物耐受性的产生、提高肿瘤治疗效果仍是一个亟待解决的难题。随着分子生物学的发展，通过抑制肿瘤高表达氨基酸转运体来调控肿瘤细胞氨基酸代谢的“饥饿疗法”日益引起研究者的关注，该疗法有望增强肿瘤对化疗药物的敏感性，提高治疗效果。然而，传统的药物联合递送方式递送效率差、靶部位分布不足，且容易导致严重的毒副作用。本项目构建了肿瘤高表达氨基酸转运体ATB0,+靶向纳米粒，联合递送氨基酸代谢关键位点LAT1转运体抑制剂JPH203和小分子治疗药物拉帕替尼，利用纳米递送系统实现氨基酸代谢调控与化疗的协同抗肿瘤作用。该纳米递送系统（LJ@Trp-NPs）经注射进入循环系统偶，能够有效蓄积在肿瘤部位，通过靶向作用提高在肿瘤细胞内的摄取；摄取后的LJ@Trp-NPs能够下调ATB0,+的表达、并抑制LAT1功能，二者协同调控肿瘤细胞的氨基酸代谢，并耦连抑制mTOR信号通路；该效应可以与拉帕替尼协同诱导肿瘤细胞凋亡，高效发挥抗肿瘤作用。本项目的研究为基于氨基酸代谢调控的纳米药物开发及应用提供了实验基础，为肿瘤临床治疗提供一种新思路。