Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM), found in species ranging from Drosophila to humans.

[3] Depending on the application and the integrin targeted, RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.

RGD was identified as the minimal recognition sequence within fibronectin required for cell attachment by Ruoslahti and Pierschbacher in the early 1980s.

[9][10] Understanding of the molecular basis of binding to integrins has enabled the development of several drugs for cardiovascular disease and cancer, including eptifibatide, tirofiban and cilengitide.

Eptifibatide (marketed as Integrilin) is a cyclic (circular) seven amino acid peptide, whereas tirofiban is a small molecule designed to mimic the chemistry and binding affinity of the RGD sequence.

[16][17] Cilengitide, a cyclic pentapeptide (RGDfV), is an investigational drug intended to block the growth of new blood vessels in tumors by interfering with the activation of integrin αVβ3.

Radiolabeled peptides containing RGD show high affinity and selectivity for integrin αVβ3 and are being investigated as tools to monitor treatment response of tumors via PET imaging.

Like other chemotherapeutics of its class, doxorubicin causes hair loss, nausea, vomiting, and myelosuppression, and can lead to cardiomyopathy and congestive heart failure.

[28][29] Active targeting strategies aim to increase drug transport into cells to improve efficacy and counter multidrug resistance.

[30] While viral vectors demonstrate high transfection efficiency and protect delivered genes, there are safety concerns associated with immune responses to the virus.

Therefore, RGD has been coupled to nonviral vectors to target delivery of genetic material to the desired cells, thereby increasing transfection efficiency.

A key method of doing so utilizes ECM-derived ligands such as RGD to control cellular responses to a biomaterial, such as attachment, proliferation, and differentiation.

[3] Modifying vascular tissue grafts with RGD has been shown to inhibit platelet adhesion, improve cell infiltration and enhance endothelialization.

In silk biomaterial scaffolds which replicate the hierarchical structure of the cornea, the addition of RGD improved cell attachment, alignment, proliferation, and ECM protein expression.

These studies also showed that RGD density could change integrin expression, which has been postulated to enable control of biochemical signaling pathways.

[41] Artificial amino acid sequences, which bear no biological similarity to ECM proteins, have also been synthesized, and include the α5β1-specific peptide RRETAWA.

[31][43] Linear RGD peptides suffer from low binding affinity, rapid degradation by proteases, and lack of specificity for integrin type.

[30] The structural rigidity of cyclic RGD peptides improves their binding properties and prevents degradation at the highly susceptible aspartic acid residue, thereby increasing their stability.