Self-Assembly of Therapeutic Peptide into Stimuli-Responsive Clustered Nanohybrids for Cancer-Targeted Therapy
Self-Assembly of Therapeutic Peptide into Stimuli-Responsive Clustered Nanohybrids for Cancer-Targeted Therapy
复制标题
将治疗性肽自组装成刺激响应簇状纳米杂化物，用于癌症靶向治疗
DOI：
10.1002/adfm.201807736
复制
发表时间：
2019-03-07
影响因子：
19
通讯作者：
Hou, Peng
中科院分区：
文献类型：
--
作者：
He, Wangxiao;Wang, Simeng;Hou, Peng
治疗性多肽的临床翻译，特别是那些针对细胞内蛋白-蛋白相互作用(PPI)的多肽，由于它们在疾病组织中无效的细胞内化而受到阻碍。将治疗性多肽设计成具有稳定空间结构和智能疾病靶向能力的纳米结构，可能为克服多肽的药物障碍提供一种可行的策略。这项研究描述了一种策略，将治疗多肽组装成稳定的多肽-Au纳米杂化，然后进一步自组装成对肿瘤微环境具有响应性的更高阶纳米簇。作为概念的证明，一种名为β-连环蛋白/Bcl9抑制剂的抗癌多肽与金离子共聚，并组装成一簇纳米杂化材料(PClub)。通过一系列的体外和体内测试，pCluster通过损害Wnt/β-catenin途径在几个动物模型中有效地抑制肿瘤的生长和转移，同时保持高度有利的生物安全性。此外，还发现pCluster与PD1/PD-L1检查点阻断免疫治疗有协同作用。这种多肽递送的新策略可能会对多肽衍生的治疗性纳米医学的发展产生广泛的影响，并重振发现针对多种人类疾病(包括癌症)的细胞内PPI的多肽药物的努力。
Clinical translation of therapeutic peptides, particularly those targeting intracellular protein-protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide-Au nanohybrid, followed by further self-assembling into higher-order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed beta-catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/beta-catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD-L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide-derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.