Self-Assembly of Therapeutic Peptide into Stimuli-Responsive Clustered Nanohybrids for Cancer-Targeted Therapy.

Abstract

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 β-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/β-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.

• Authors: Wangxiao He, Simeng Wang, Jin Yan, Yiping Qu, Liang Jin, Fang Sui, Yujun Li, Weiming You, Guang Yang, Qi Yang, Meiju Ji, Yongping Shao, Peter X Ma, Wuyuan Lu, Peng Hou
• Journal: Advanced functional materials (Adv Funct Mater) Vol. 29 Issue 10 (Mar 07 2019) ISSN: 1616-301X [Print] Germany
• PMID: 32982625 (Publication Type: Journal Article)