pH敏感靶向肿瘤新生血管多肽纳米纤维抗三阴性乳腺癌研究

Chemotherapy is almost the only systemic therapy for triple-negative breast cancer, but is of limited efficacy due to poor targeting efficiency. In this project, novel peptides amphiphiles with hydrophobic, β-sheet forming, protein screening, pH-responsive, angiogenesis-targeting domains will be designed and synthesized to construct pH-responsive peptide nanofibers (PNFs) with prolonged circulation and neovascular targeting capability. Techniques such as X-ray scattering, transmission electron microscopy, isothermal titration calorimetry and etc will be applied to determine the self-assembly, secondary structure and molecular stacking of the peptide amphiphiles in PNFs, the morphology, stability and pH responsiveness of the formed PNFs, and the ability of PNFs in protein repelling, macrophage clearance escaping, endothelial cell binding, tumor accumulation, and triple-negative breast cancer metastasis inhibition. Based on these results, the mechanism through which the peptide sequence determines the physiochemical properties and biological effect of PNFs will be revealed, and an effective nanomedicine for the treatment of triple-negative breast cancer and its metastasis will be developed. The project proposes a novel strategy to create peptide-based nanomedicine for the treatment of triple-negative breast cancer, and will deepen our understanding in the mechanism of peptide sequence-based biological function determination of nanomedicine.

三阴性乳腺癌预后差，化疗几乎是其全身治疗的唯一手段，但治疗效果不佳。本项目拟设计并合成含载药、β-折叠、蛋白屏蔽、pH响应和新生血管靶向功能模块的两亲性多肽，利用多肽自组装技术制备在血液中稳定、靶向肿瘤新生血管并富集于肿瘤的多肽纳米纤维（PNFs）。通过X-射线散射、电子显微镜和等温微量热等技术，考察不同多肽自组装能力、二级结构、排列规律、形成PNFs形貌及pH响应能力的差异，揭示多肽序列决定自组装PNFs理化特性的规律；评价不同PNFs的血液蛋白结合屏蔽、巨噬细胞吞噬逃避、新生内皮细胞靶向、肿瘤组织蓄积和抗三阴性乳腺癌及其转移的能力，阐明PNFs与蛋白、细胞和机体相互作用的规律；最终筛选出有效抗三阴性乳腺癌及其转移的纳米药物。本项目思路新颖，创新性强，对加深多肽序列和其自组装纳米粒生物学效应间关系的理解，对构建新型抗三阴性乳腺癌纳米药物均具有重要意义。

提高三阴性乳腺癌化疗效果和安全性是临床亟待解决的关键问题，如何合理设计药物递送系统实现肿瘤靶向和协同治疗是其核心问题之一。本项目以多肽仿生材料为突破点，设计合成了一系列不同结构的两亲性多肽，考察了其自组装能力、形貌、载释药行为、药动学性质、药效和安全性等。研究发现：带有柔性疏水链的两亲性多肽易组装成带有疏水内核的线状纳米纤维并有效包载疏水药物，而带有刚性疏水基团的两亲性多肽倾向组装为球状颗粒，对多肽进行新生血管靶向序列修饰不影响其自组装行为；纳米纤维可形成水凝胶并在肿瘤部位持续释放洛沙坦长达7天，有效抑制肿瘤相关成纤维细胞，促进化疗药物肿瘤蓄积；自组装前药纳米粒能够降低活性药物在非靶向器官的最高暴露剂量，延长瘤内药物暴露时间，在提高疗效同时将化疗药物最大耐受剂量提高8倍；发现同时靶向新生血管和肿瘤细胞能够抑制三阴性乳腺癌肺转移灶的生长。相关研究在国内外重要学术期刊上发表高质量论文7篇，包括Chem Soc Rev (IF=42.82)、ACS Nano (IF=14.58)、Nano Lett (IF=12.27)、Biomaterials (IF=10.31)和J Control Release (IF=7.72 )等，申请发明专利1项，共培养博士研究生1人，硕士研究生4人。该项研究揭示了两亲性多肽分子设计影响其理化特性和生物效应的机制，并筛选获得了具有良好效果和安全性的功能多肽纳米纤维用于三阴性乳腺癌的治疗，为新型多肽自组装纳米载体的设计提供了理论基础，促进了该类纳米载体的临床转化。