Abstract
To improve the specificity and penetration of anticancer peptides against tumors, in this study, we examined the effects of co-administration of the membrane-active peptide HPRP-A1 and the tumor homing/penetrating peptide iRGD. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide targeting to αvβ3 integrins and neuropilin-1 (NRP-1) receptors, which show high expression in many tumor cells. The anticancer activity, cancer specificity and penetration activity in vitro and in vivo of the co-administered peptides were examined on 2D monolayer cells, 3D multi-cellular spheroids (MCS) and xenograft nude mice. Co-administration of iRGD and HPRP-A1 exhibited stronger anticancer activity and tumor specificity against A549 non-small cell lung cancer cells with NRP-1 receptor overexpression compared with HPRP-A1 alone. A549 cells showed uptake of the peptide combination and destruction of the integrity of the cell membrane, as well as adherence to the mitochondrial net, resulting in induction of apoptosis by a caspase-dependent pathway. The iRGD peptide dramatically increased the penetration depth of HPRP-A1 on A549 MCS and anticancer efficacy in an A549 xenograft mouse model. Our results suggest that the co-administration strategy of anticancer and penetrating peptides could be a potential therapeutic approach for cancer treatment in clinical practice.
Highlights
During the past two decades, the development of cancer treatment has evolved from nonspecific cytotoxic agents to selective, mechanism-based therapeutics, such as chemotherapeutics, targeting agents, monoclonal antibodies and other targeted therapeutics
The iRGD peptide contains a C-end rule (CendR) motif, which is a specific sequence located in the C-terminal of peptides that require proteolytic processing for exposure of the biologically active motif required for binding to NRP-1, which triggers internalization of the peptide. iRGD homes to tumors through three steps: the RGD sequence binds to αv integrins on the tumor endothelium and undergoes proteolytic cleavage, which results in the exposure of the binding motif for NRP-18
We first examined the secondary structures of HPRP-A1 with or without co-administration of iRGD using circular dichroism (CD) spectroscopy in benign condition as well as in an α-helix-inducing solvent in the presence of 50% trifluoroethyl alcohol (TFE), as described in Methods[23]
Summary
During the past two decades, the development of cancer treatment has evolved from nonspecific cytotoxic agents to selective, mechanism-based therapeutics, such as chemotherapeutics, targeting agents, monoclonal antibodies and other targeted therapeutics. We showed that HPRP-A1 functions by two mechanisms: by disrupting the cell membrane and inducing cell apoptosis[6] Together these results suggest that HPRP-A1 is a promising candidate as an anticancer drug. IRGD can increase vascular and tissue permeability when chemically conjugated with other drugs by specific binding with the NRP-1 receptor, which is overexpressed in tumor cells, and allows co-administered drugs to penetrate into extravascular tumor tissue[9]. The iRGD peptide contains a CendR motif, which is a specific sequence located in the C-terminal of peptides that require proteolytic processing for exposure of the biologically active motif required for binding to NRP-1, which triggers internalization of the peptide. IRGD homes to tumors through three steps: the RGD sequence binds to αv integrins on the tumor endothelium and undergoes proteolytic cleavage, which results in the exposure of the binding motif for NRP-18. NRP-1 binds the RTK c-Met, leading to increased proliferation, survival and migration of tumor cells in human glioma and pancreatic cancer[14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
