Targeted in situ self-assembly augments peptide drug conjugate cell-entry efficiency.

Peptide drug conjugate (PDC) has emerged as one of the new generations of targeted therapeutics for cancer, which owns the advantages of improved drug targetability and reduced adverse effects compared with traditional chemotherapy. However, the poor permeability of PDC drugs regarding tumor cells is an urgent problem to be solved. Herein, we design a PDC drug molecule, which is composed of three modules: targeting motif (RGD target), assembly motif (GNNNQNY) and cytotoxic payload (CPT molecule). This PDC in situ forms nanoclusters upon binding cellular receptor, resulting in improved PDC cell-entry efficiency and treatment efficacy. In addition, the PDC shows increased therapeutic efficacy and raises the maximum tolerance dose of the drug in breast and bladder xenografted mice models. This strategy leverages the assembly principle to promote penetration of peptide molecules into cells and increase intracellular drug bioavailability, which is of great significance for the development of PDC drugs in the future.

Biomaterials. 2021 Oct 02 [Epub ahead of print]

Man-Di Wang, Da-Yong Hou, Gan-Tian Lv, Ru-Xiang Li, Xing-Jie Hu, Zhi-Jia Wang, Ni-Yuan Zhang, Li Yi, Wan-Hai Xu, Hao Wang

CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190, Beijing, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China., CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190, Beijing, China; Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China; NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China., CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190, Beijing, China; School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China., CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190, Beijing, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450052, China., Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China; NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China. Electronic address: ., CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190, Beijing, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450052, China. Electronic address: .

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