IRGD: A Promising Peptide for Cancer Imaging and a Potential Therapeutic Agent for Various Cancers.

Houdong Zuo

doi:10.1155/2019/9367845

Abstract

Poor penetration into the tumor parenchyma and the reduced therapeutic efficacy of anticancer drugs and other medications are the major problems in tumor treatment. A new tumor-homing and penetrating peptide, iRGD (CRGDK/RGPD/EC), can be effectively used to combine and deliver imaging agents or anticancer drugs into tumors. The different “vascular zip codes” expressed in different tissues can serve as targets for docking-based (synaptic) delivery of diagnostic and therapeutic molecules. αv-Integrins are abundantly expressed in the tumor vasculature, where they are recognized by peptides containing the RGD integrin recognition motif. The iRGD peptide follows a multistep tumor-targeting process: First, it is proteolytically cleaved to generate the CRGDK fragment by binding to the surface of cells expressing αv integrins (αvβ3 and αvβ5). Then, the fragment binds to neuropilin-1 and penetrates the tumor parenchyma more deeply. Compared with conventional RGD peptides, the affinity of iRGD for αv integrins is in the mid to low nanomolar range, and the CRGDK fragment has a stronger affinity for neuropilin-1 than that for αv integrins because of the C-terminal exposure of a conditional C-end Rule (CendR) motif (R/KXXR/K), whose receptor proved to be neuropilin-1. Consequently, these advantages facilitate the transfer of CRGDK fragments from integrins to neuropilin-1 and consequently deeper penetration into the tumor. Due to its specific binding and strong affinity, the iRGD peptide can deliver imaging agents and anticancer drugs into tumors effectively and deeply, which is useful in detecting the tumor, blocking tumor growth, and inhibiting tumor metastasis. This review aims to focus on the role of iRGD in the imaging and treatment of various cancers.

Highlights

Cancer is a prominent disease and a leading cause of mortality worldwide [1]
This review aims to highlight the role of iRGD peptide in cancer imaging and therapy
The iRGD peptide facilitated and increased the binding ability and cellular uptake of crosslinked multilamellar liposomal vesicle (cMLV) in breast cancer cells. They found that iRGD-conjugated cMLVs delivered into cells were regulated by the clathrin-mediated pathway. These findings suggest that the iRGD peptide can overcome the transport limitation of the targeted payload into the tumor parenchyma and establish tissue-penetrating anticancer drug delivery

Summary

Introduction

Cancer is a prominent disease and a leading cause of mortality worldwide [1]. In 2018, 1,735,350 new cancer cases and 609,640 cancer-related deaths were estimated to occur in the United States. The interaction between the CendR motif and NRPs activates the bulk delivery process, allowing anticancer drugs to penetrate deeply into the tumor tissue through conjugation to or even coadministration with iRGD [14, 15]. Conventional RGD binds to integrin αvβ on the surface of the tumor vasculature [16] and plays an important role in delivering anticancer drugs, imaging agents, nanoparticles, and virus vectors to blood vessels [13, 14, 17]. Tumor tissue penetration is triggered by peptide binding to integrins through the interaction of the CendR motif with NRP-1 This binding process allows the extravasation and penetration of imaging agents or drugs either conjugated to the iRGD peptide or coadministered with iRGD into the target tumor tissues and cells [13, 14, 19]. IRGD has no adverse effect or cytotoxicity on healthy cells [22], which has caused it to gain considerable attention in targeted research

The Process of iRGD Peptide Penetration into Tumors

Findings

Conclusion