iRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery

Abstract

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.

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…In addition, a tumor-penetrating disulfide bridge harboring peptide, called iRGD (cyclo[CRGDK/RGPD/EC]; ligand 6 , Figure 7 ) was identified, targeting αv-integrins specifically expressed on endothelial cells of tumor vessels, i.e., αvβ3 together with αvβ5, when injected intravenously [ 338 , 339 ]. After integrin binding, iRGD is proteolytically cleaved within the tumor, leading to the peptide sequence CRGDK/R [ 22 , 340 ].…”

“…In general, for NRP-1 binding, Gly and Asp can be replaced by any amino acid, whereby instead of Arg, Lys can be used: R/KXXK/R [ 22 , 340 ]. Via the interaction of the CendR motif with NRP-1, tumor tissue penetration is triggered, and iRGD has been documented to deeply enter into extravascular tumor tissue [ 22 , 339 , 340 ]. iRGD can be conjugated to drugs or imaging agents or co-administered with them, allowing the extravasation and penetration of the co-applied agents after the binding process of CendR and NRP-1 [ 338 , 340 ].…”

Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders

“…These consolidated non-invasive strategies are perhaps best conceptualised by visual representation as given by Figure 3 [113]. Where the BBB is in its intact physiological state, however, more exquisite strategies are required, such as active peptide sequence targeting, i.e., using iRGD for BBB and tumour penetration enhancement [114]. A number of shuttle peptides have been developed as a consequence of improvements in phage display technology, and cell-based transportation technologies such as those highlighted by Li and colleagues and Batrakova and colleagues, respectively, are propitious, despite admitted limitations associated with heterogenous expression and limited loading capacities [115,116].…”

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

“…A variant is the cyclic iRGD peptide (CRGDKGPDC and variants). This binds as expected to integrins, and is subsequently cut by proteases to produce the CRGDK sequence (a "C-end Rule/CendR" motif: (R/K) XX(R/K)), which binds neuropilin-1 (NRP-1), extravasates, and penetrates the tumor (i.e., it is a "tumor penetrating peptide") [212][213][214] (for possible complications associated with the use of iRGD see [215]). Peptides with the CendR motif not only target the endothelia of tumoral vases, but also act as cell-penetrating peptides, undergoing transcytosis and allowing, in principle at least, the delivery of conjugated drugs, or of drugs co-transported in a nanovehicle, to the tumor parenchyma.…”