Recent advances in the tumor‐penetrating peptide internalizing RGD for cancer treatment and diagnosis

Abstract

Cancer has become a prominent disease that seriously endangers human health. The complexity of the biological characteristics of the tumor makes it challenging for traditional therapeutic drugs to penetrate tumor tissues and exert their antitumor effects. Internalizing RGD peptide (iRGD) is a novel tumor‐homing peptide that binds to αvβ3 and αvβ5 integrins on the surface of tumor vessels through the C‐end rule (CendR) motif. The CendR motif binds to the neuropilin‐1 (NRP‐1) receptor on tumor cells, initiating NRP‐1‐mediated transcytosis to facilitate drug entry into the tumor tissue. Multiple studies demonstrated that iRGD improved the penetration and targeting of antitumor drugs, thereby enhancing their antitumor efficacy. In this review, we initially described the origins of iRGD and its penetration mechanism. Furthermore, we presented updates on the application of iRGD in cancer chemotherapy, photodynamic therapy, gene therapy, immunotherapy, treatment with antibodies or protein‐based biologics, and tumor imaging.

Molecular View on the iRGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles

“…Thus, the Lys 5 –Gly 6 bond is easily accessible for proteolytic cleavage, which releases the NRP-1-recognizing CendR/K sequence (CRGDK). On the other hand, the solvent exposure of the Cys 9 carboxylate explains why the bioconjugation of this group with bulky molecules, for either therapeutic or diagnostic purposes, is safely permitted. − Both of these findings strengthen the reliability and increase the scientific impact of the obtained atomistic i RGD–integrin binding complexes.…”

“…For these reasons, anticancer compounds often need to be administered at high doses to exert relevant pharmacological effects, with the rise of serious adverse reactions. − A feasible solution to the tissue penetration problem is represented by smart carriers that can vehicle the desired drug to extravascular cancer tissue. Carriers of different natures have been developed such as gold nanoparticles, − liposomes, , polymer micelles, or receptor-selective peptides. − In this context, Ruoslahti and co-workers identified an RGD integrins-targeting cyclic nonapeptide, namely, i RGD (internalizing RGD, CRGDKGPDC, 1 Chart ), endowed with remarkable tumor-homing properties. , Notably, this peptide can improve the tumor penetration and efficacy of chemotherapeutics through two alternative mechanisms. ,− In fact, i RGD can be either covalently bioconjugatedusually functionalizing the C-terminal Cys 9 to organic and peptidic drugs or attached to the surface of other delivering systems like nanoparticles, liposomes, or oncolytic viruses. − On the other hand, the tumor endocytosis of cytotoxic agents such as cisplatin, gemcitabine, doxorubicin, nab-paclitaxel, and trastuzumab is enhanced by the simple coadministration of 1 . ,, As a result, hundreds of distinct applications involving i RGD have been published during the past decade, − claiming the p...…”

RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions

“…This can aid in the optimization of treatment procedures and give crucial information on the efficacy of the therapy. [38][39][40][41][42] By inhibiting the interaction between integrins and their ligands, RGD peptides can be utilized alone to limit tumor development and angiogenesis. This has the potential to alter signaling pathways involved in cancer cell survival, migration, and invasion.…”

Integrin Facilitates the Internalization of TAT Peptide Conjugated to RGD Motif in Model Lipid Membranes

“…[13] The penetration mechanism of iRGD follows three main steps: iRGD cyclic peptides (CRGDK/RGPD/EC) bind to integrins (α v β 3 and α v β 5 ), then the cycle is proteolytically cleaved to CRGDK/R and the penetrating CendR motif (R/KXXR/K) is exposed and finally, CendR binds to NRP-1 receptor and penetrate the tumour tissue. [14,15,16] Conjugation or even the simple co-administration of TAT or RGD peptides with an anticancer drug substantially increased the therapeutic effect. For example, Doxorubicin (DOX), a widely used anticancer drug, after conjugation with TAT peptide was used to induce cell apoptosis in the breast cancer-resistant cells MDA-MB 231 at lower concentration than the drug alone.…”

“…c[RGDfVG] binding to integrin α II bβ 3 , c[RGDfV] binding to integrin α ν β 3 , c[RGDfK] or c[RGDf−N(Me)V] binding to α ν β 3 integrins) have shown high affinity for integrins [13] . The penetration mechanism of iRGD follows three main steps: iRGD cyclic peptides (CRGDK/RGPD/EC) bind to integrins (α v β 3 and α v β 5 ), then the cycle is proteolytically cleaved to CRGDK/R and the penetrating CendR motif (R/KXXR/K) is exposed and finally, CendR binds to NRP‐1 receptor and penetrate the tumour tissue [14,15,16] …”