Title
Targeted modification of the cationic anticancer peptide HPRP-A1 with iRGD to improve specificity, penetration, and tumor-tissue accumulation
Author
Cuihua Hu, Yibing Huang, Yuxin Chen
Year
2018
Journal
Molecular Pharmaceutics
Abstract
The chimeric peptide HPRP-A1-iRGD, composed of a chemically conjugated tumor homing/penetration domain (iRGD) and a cationic anticancer peptide domain (HPRP-A1), was used to study the effect of targeted modification to enhance the peptide’s specificity, penetration, and tumor accumulation ability. The iRGD domain exhibits tumor-targeting and tumor-penetrating activities by specifically binding to the neuropilin-1 receptor. Acting as a homing/penetration domain, iRGD contributed to enhancing the tumor selectivity, permeability, and targeting of HPRP-A1 by targeted receptor dependence. As the anticancer active domain, HPRP-A1 kills cancer cells by disrupting the cell membrane and inducing apoptosis. The in vitro membrane selectivity toward cancer cells, such as A549 and MDA-MB-23, and human umbilical vein endothelial cells (HUVEC) normal cells, the penetrability assessment in the A549 3D multiple cell sphere model, and the in vivo tumor tissue accumulation test in the A549 xenograft model indicated that HPRP-A1-iRGD exhibited significant increases in the selectivity toward membranes that highly express NRP-1, the penetration distance in 3D multiple cell spheres, and the accumulation in tumor tissues after intravenous injection, compared with HPRP-A1 alone. The mechanism of the enhanced targeting ability of HPRP-A1-iRGD was demonstrated by the pull-down assay and biolayer interferometry test, which indicated that the chimeric peptide could specifically bind to the neuropilin-1 protein with high affinity. We believe that chemical conjugation with iRGD to increase the specificity, penetration, and tumor tissue accumulation of HPRP-A1 is an effective and promising approach for the targeted modification of peptides as anticancer therapeutics.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Chemical stability, Pharmaceutical, Biochemistry