二聚肽介导的多功能脂质载体靶向联合治疗乳腺癌的应用及其机制研究

Breast cancer is the most worldwide cancer affecting females’ health. Breast cancer heterogeneity has emerged as a major hindrance to improving cancer patient care. Based on the overexpression of EphB receptors in dissimilar breast cancer subtypes, the aim of this project is to construct a bi-functional dimeric peptide, which can target EphB receptors specifically, simultaneously activate EphB receptor and initiate the downstream tumor-suppressing signaling pathway. Modified with this dimeric peptide, a multi-functional co-delivery liposomal system is designed and fabricated for combination therapy against heterogeneous breast cancer. Loading with doxorubicin conjugated therapeutic peptide, this co-delivery liposomal system could target various breast cancer subtypes selectively, inhibit tumor localized growth and metastases through distinct pathways, suppress several drug resistance mechanisms, and eventually enhance the antitumor efficacy. We will investigate the detailed mechanisms involved in tumor-targeting delivery, activation of Eph receptors, intracellular traffic and release, and inhibition of drug resistance. In addition, the relationship among dimeric peptides, liposomal composition and synergistic anti-tumor effects will be explored and subsequently applied to optimize the design of multi-functional liposomal system. We hope this sort of multi-functional co-delivery liposomal system, which exhibits synergetic effect on growth inhibition of heterogeneous breast cancer, could solve some scientific and technical problems and pave the way for improving combination treatment of breast cancer.

对乳腺癌异质性的研究和治疗，是改善女性健康和生存条件的主要途径。针对异质性乳腺癌的靶向和治疗难题，本课题旨在利用乳腺癌细胞表面高表达的EphB受体为分子靶，构建具有双重功能的二聚多肽，不仅特异性识别EphB受体并能激活其抑癌的下游信号通路。二聚多肽与多种药物组装而成的共输送脂质载体，通过二聚多肽的介导能够实现多种乳腺癌亚型的主动靶向药物传递，阻断胞内多个靶点不同通路的信号传导，抑制肿瘤的增殖和转移，同时抑制耐药性相关的机制，从而提高乳腺癌的靶向联合治疗效果。主要研究和探讨脂质载体的主动靶向、药物传递、信号阻断和肿瘤抑制的多重机制，揭示脂质载体的组成结构、性质和功能之间的联系，指导对二聚多肽和载体性能的优化。本课题使用二聚多肽修饰的靶向多功能共输送载体，协同作用联合治疗异质性乳腺癌，有望能够克服和解决单纯化疗中的一些科学和技术难题，促进乳腺癌联合治疗的发展。

肿瘤治疗是全球面临的一个难题，特别是治疗过程中患者很容易产生自发或获得性多药耐药，造成临床化疗的失败。本研究设想结合靶向识别和协同治疗两方面的内容，针对耐药性肿瘤治疗中的问题进行相关研究。在肿瘤特异性识别的研究中，旨在设计能够高效识别肿瘤细胞表面高表达的Eph受体的二聚肽，通过计算机辅助模拟与Eph受体的对接来优化二聚肽的结构，达到靶向识别和激发下游信号通路的目的。同时构建治疗肽-阿霉素结合物，通过两种药物的协同作用同时阻断多条的肿瘤信号通路，抑制肿瘤细胞的增殖和转移。为了靶向递送治疗肽-阿霉素结合物，二聚肽修饰的新型共输送靶向递送系统能够实现高效装载，肿瘤选择性靶向递送，以及避免耐药性外排泵P-gp的识别。制备的共输送纳米颗粒具有合适的粒径和表面电位，粒径分布较窄。体外细胞实验表明二聚肽具有高效肿瘤识别的特性，并且能够激活Eph下游信号通路，但只有通过共输送纳米颗粒的靶向递送，治疗肽-阿霉素结合物才能有效克服耐药性机制的作用，对耐药性肿瘤细胞表现出最理想的抗癌效果。进一步通过荷瘤裸鼠模型，证实共输送靶向递送系统能够充分发挥协同给药的优势，有效抑制耐药性肿瘤的生长，并且可以降低阿霉素的心脏毒性，具有较高的安全性。.本项研究为耐药性肿瘤的协同给药治疗提供了新的策略和平台，建立了关键的技术，确保了高效的肿瘤靶向识别和递送、结合物的胞内输送和释放、以及表现出较好的体内外药效相关性，具有潜在的临床应用价值。