What is iRGD?

iRGD is an interesting peptide that has a ton of potential by enhancing traditional medications and treatments!  Like a lot of modern peptides, the identification and replication of its structure took place after it was identified in an in vivo screening of phage libraries.

Its original application was published in 2010 when a group of California researchers showed iRGD could boost the efficacy of cancer drugs without having to be conjugated to them.  Usually, conjugation is a painstaking step that can reduce a drug’s potency.

However, with iGRD, this step is not necessary.

The original study was quickly picked up and featured in many review articles like nature.

In effect, this study showed a couple of interesting points that affect our use of the molecule in practice now.

It showed that doxorubicin, liposomal doxorubicin, Herceptin trastuzumab or Abraxane nab-paclitaxel had greater drug accumulation in the tumor by up to 40-fold than mice injected with one of the drugs alone. The equaled greater reductions in tumor growth. In all, the drug-peptide combination was as effective as threefold higher doses of drug alone.


In addition, the group from UC Santa Babara and Stanford-Burnham showed that organs from mice co-treated with drug and peptide had no macroscopic metastases. Meaning that the treatment demonstrated that increasing the permeability of tumor vasculature to cancer drugs did not enhance the ability of tumor cells to migrate and metastasize. Also, this uptake is selective for cancer tissues and not normal tissues. This means that patients could in effect experience much lower side effects of the cancer drugs they are currently prescribed.

Since then a lot has been understood about this process. iGRD works in a couple of ways detailed below.

  1. The iRGD sequence motif mediates binding to integrins that are expressed on tumor endothelial cells.
  2. Second, upon αV binding, a protease cleavage event is activated, revealing the c-terminal CendR motif (R/KXXR/K) of the peptide.
  3. The CendR motif is now able to bind to neuropilin-1, activating an endocytotic/exocytotic transport pathway.

iRGD is unique in the fact that it is a type of peptide that starts out as a 3 amino acid sequence known as homing peptides. The most common homing peptides, RGD and NGR specifically bind to a surface molecule on tumor cells or tumor vasculature. RGD (Arg-Gly-Asp) is known to bind alpha integrins and NGR (Asn-Gly-Arg) is known to bind to a receptor aminopeptidase N present on the surface of tumor endothelial cells. This is a critical step in their mechanism of action as they are targeting the angiogenesis taking place within and around the tumor; and, very importantly, are independent of tumor type. Because they can target the vasculature in this way, they are able to be used as delivery vehicles for imaging agents, drug molecules, oligonucleotides, liposomes, and inorganic nanoparticles to tumors and other tissues.

Now, this research has been expanded to the delivery of multiple drugs.  One familiar to most of the readers of the International Peptide Society is Thymosin Alpha-1.


As expected, the combination study had very positive results, as the conclusion to the article states.

“Tumor cell proliferation experiments revealed that Tα1-iRGD has higher antitumor activity than Tα1. In the melanoma cell attachment assay, we found that Tα1-iRGD has higher attachment activity than Tα1. In the cancer cell inhibition assay, we also found that Tα1-iRGD has a better anti-proliferation activity in several cancer cell lines than Tα1, particularly in mouse mel

anoma cell line B16F10 and human lung cancer cell line H460. With the aid of the iRGD, Tα1-iRGD directly inhibited the proliferation of human lung cancer cell line H460 and mouse melanoma cells line B16F10 at very low concentrations in contrast to the slight inhibition exhibited by Tα1.”

In addition to this, the immunomodulatory properties of the Tα1 still remain intact with this modification!

iRGD is just another peptide expanding the clinical approach for cancer patients.  By using it with other drugs, these therapies can target specific tissues and become less detrimental to the patients with less side effect.  In addition, it’s specific binding to integrins is another impressive feature that adds to the benefits of peptides as a molecule and adds to the growing body of evidence surrounding peptides.