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

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.