iRGD peptide

As a tumor-targeting and ‑penetrating peptide, iRGD binds to αv integrins and neuropilin‑1 receptors, which are expressed at high levels on tumor cells and the surfaces of vasculature. Subsequently, iRGD penetrates deep into the tumor parenchyma with antitumor drugs, imaging agents, immune modulators and biological products. These substances are either chemically linked to the peptide or co‑injected with the peptide. The iRGD peptide can be readily synthesized, exhibits significantly improved penetration, compared with traditional peptides, and can effectively inhibit tumor metastasis. Therefore, the peptide is now used widely for the diagnosis and treatment of cancer. However, whether the peptide is able to promote the entry of drugs into non‑targeted cells remains to be fully elucidated. In this review, an overview of iRGD is presented, focusing on its identification, mechanism of action and previous studies on its roles in various types of cancer. Studies in previous years have demonstrated the potential of the iRGD protein for tumors diagnosis and targeted treatment, which warrants further investigation.

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.

The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood-brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability.