基于肿瘤新生血管靶向的多肽自组装纳米药物的设计和机制研究

Angiogenesis plays fundamental roles in tumor growth and metastasis, which has emerged as one of the most critical targets for antitumor therapy. Antiangiogenic peptides have low toxicity, high specificity and the ability to be easily functionalized. However, the majority of peptides suffer from short serum half-life, which has largely impeded the development of peptide drugs. Nanotechnology can be applied to the design of multifunctional drug carriers and the improvement of pharmacokinetic and pharmacodynamic properties, thus having great potential to overcome the bottlenecks of antitumor drug development. Through the integration of nanotechnology and antiangiogenic peptides, this project aims to establish a novel peptide-based nanosystem which can achieve tumor vascular targeting, long-lasting and combination therapy, ultimately inhibiting tumor growth and metastasis. We firstly design and characterize self-assembled antiangiogenic peptide nanoparticles that are sensitive to weakly acidic pH. After validating their serum stability and response to tumor microenvironment, we detect their roles in the suppression of angiogenesis and tumor progression, investigate the underlying molecular mechanism, and evaluate their safety profiles. This study will open a new avenue for the drug development of self-assembled peptide nanoparticles and provide a potential vascular-targeting drug candidate for antitumor therapeutics.

肿瘤新生血管对肿瘤的生长和转移发挥至关重要的作用，成为肿瘤治疗的关键靶标之一。抗肿瘤血管新生多肽毒性低、靶向性高且易于改造，但体内半衰期短，在很大程度上制约了其药物研发的进程。新兴的纳米技术可被用于调控药物运载体系，改善药物的药代动力学和药效学性质，具有解决抗肿瘤药物研发瓶颈问题的潜力。本项目旨在将纳米技术与抗血管新生多肽有机结合，设计并构建一种新型的多肽纳米体系，从而实现肿瘤血管靶向、长效和联合治疗，有效抑制肿瘤生长和转移。我们将构建肿瘤弱酸性pH响应的抗血管新生多肽自组装纳米颗粒，表征其理化性质，确定其体内稳定性及肿瘤微环境响应性，验证其抗新生血管和抗肿瘤作用，阐明分子作用机理，并评价其体内安全性，为其成药研究提供一定的理论基础，并为多肽纳米药物的研发提供新思路。

肿瘤新生血管普遍存在于实体瘤组织中，在肿瘤生长和转移过程中发挥重要作用，是抗肿瘤治疗的关键靶标。多肽自组装纳米载体具有生物相容性好、易修饰靶向分子和药物可控释放等特点，可极大地改善药物的体内半衰期和生物利用度。本项目针对肿瘤新生血管和血管周围的肿瘤相关成纤维细胞的生理病理特征，以及肿瘤微环境的生化特征，设计了一系列靶向和调控肿瘤血管和成纤维细胞的多肽自组装纳米药物：利用抑制肿瘤新生血管内皮细胞表面整合素受体的多肽C16Y和响应微酸性pH的硫代异氰酸酯分子设计了两亲性多肽，通过自组装为纳米结构，显著提高了多肽的体内稳定性、以及抑制肿瘤血管新生、肿瘤生长和远端转移的治疗效果；利用多聚精氨酸穿膜肽和胆固醇分子形成的两亲性多肽构建自组装纳米载体，同时表面吸附靶向肿瘤相关成纤维细胞表面成纤维细胞激活蛋白的抗体，显著提高了疏水性化疗药物的肿瘤靶向性，且通过清除成纤维细胞形成的基质屏障，提高了药物在肿瘤组织中的渗透效率和抗肿瘤效果；利用成纤维细胞激活蛋白的底物肽和硬脂酸形成的两亲性多肽构建了纳米载体，实现了疏水性小分子药物在肿瘤部位的响应性释放，提高了药物在肿瘤组织中的渗透和分布，引起肿瘤退缩。本项目的研究工作较好的解决了目前多肽类药物普遍存在的体内循环时间短和生物利用度差的问题，为多肽类药物的开发及应用拓宽了前景；同时基于肿瘤微环境特征设计的多肽自组装纳米载体为提高小分子抗肿瘤药物的输运效率提供了新策略。

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