Bioconjugate Chemistry
Bioconjugate Chemistry
5 years ago

Novel Strategy Utilizing Extracellular Cysteine-Rich Domain of Membrane Receptor for Constructing d-Peptide Mediated Targeted Drug Delivery Systems: A Case Study on Fn14

Novel Strategy Utilizing Extracellular Cysteine-Rich Domain of Membrane Receptor for Constructing d-Peptide Mediated Targeted Drug Delivery Systems: A Case Study on Fn14
Jie Shen, Ying Wang, Shan Peng, Zhuoxuan Li, Chong Li, Weiyue Lu, Sha Liu, Jing Xie
The development of proteolysis-resistant d-peptide ligands for targeted drug/gene delivery has been greatly limited, due to the challenge that lies in the chemical synthesis of membrane receptors without altering their structures. In the present research, a novel strategy utilizing self-stabilized extracellular CRD of the membrane receptor was developed to construct d-peptide ligands and their mediated targeted drug delivery systems. Fn14, a cell surface receptor overexpressed in many cancers including pancreatic and triple-negative breast cancers, was selected as the model receptor. Fn14 CRD was synthesized and folded, and used to screen Fn14 binding peptides using phage display (l-peptide) and mirror-image phage display (d-peptide) techniques, respectively. The d-peptide ligand successfully mediated targeted drug delivery to Fn14 positive tumor cells. In addition, the d-peptide possessed better target-binding affinity, stromal barrier permeability, and tumor targeting ability in vivo when conjugated with liposomes. More importantly, d-peptide mediated liposomal paclitaxel delivery significantly inhibited pancreatic tumor growth in a subcutaneous xenograft model and drastically prolonged survival in a lung metastasis of breast cancer mouse model. This study demonstrated that mirror-image phage display based on the CRD of membrane receptor can be a promising strategy to advance active targeted drug delivery via biostable d-peptides.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00326

DOI: 10.1021/acs.bioconjchem.7b00326

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