iRGD

IRGD
Clinical data
Synonyms CEND-1
Routes of
administration		 Intravenous
Pharmacokinetic data
Bioavailability 100%
Metabolism n/a
Elimination half-life 0.5-4 hours (preclinically)
Excretion Renal (100%)
Chemical and physical data
Molar mass (989.1 g/mol after conversion)

iRGD is a 9-amino acid cyclic peptide (sequence: CRGDKGPDC) that was originally identified in an in vivo screening of phage libraries in tumor-bearing mice [1]. The peptide was able to home to tumor tissues, but in contrast to standard RGD (Arginylglycylaspartic acid) peptides, also spread much more extensively into extravascular tumor tissue. It was later identified that this extravasation and transport through extravascular tumor tissue was mediated through specific secondary binding to neuropilin-1 receptor, and subsequent activation of a trans-tissue pathway, dubbed the C-end Rule (CendR) pathway [2].

Method of action

The iRGD peptide homes and penetrates tumors through a 3-step process: First, the RGD sequence motif mediates binding to αVβ3 and αVβ5 integrins that are expressed on tumor endothelial cells. Second, upon αV binding, a protease cleavage event is activated, revealing the c-terminal CendR motif (R/KXXR/K) of the peptide. Third, the CendR motif is now able to bind to neuropilin-1, activating an endocytotic/exocytotic transport pathway [3]. The pathway triggered by iRGD can be used for the enhanced transport of coupled and coadministered anti-cancer drugs into tumors.

Uses

iRGD peptide has been shown to increase accumulation and penetration of anticancer drugs into tumors, but not into normal tissues - whether the drug is coupled to the peptide or given together with it[4]. iRGD-mediated increased penetration and anti-cancer efficacy has been demonstrated with a variety of anti-cancer small molecules, nanoparticles and antibodies [5]. A San Diego -based biotech company, DrugCendR Inc., is currently testing iRGD in clinical studies in pancreatic cancer patients[6]

References

  1. ↑ Sugahara, Kazuki N.; Teesalu, Tambet; Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Agemy, Lilach; Greenwald, Daniel R.; Ruoslahti, Erkki (21 May 2010). "Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs". Science. 328 (5981): 1031–1035. doi:10.1126/science.1183057. PMC 2881692. PMID 20378772. Retrieved 1 November 2017.
  2. ↑ Ruoslahti, Erkki (1 February 2017). "Tumor penetrating peptides for improved drug delivery". Advanced Drug Delivery Reviews. 110-111 (Supplement C): 3–12. doi:10.1016/j.addr.2016.03.008. Retrieved 1 November 2017.
  3. ↑ Teesalu, Tambet; Sugahara, Kazuki N.; Kotamraju, Venkata Ramana; Ruoslahti, Erkki (22 September 2009). "C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration". Proceedings of the National Academy of Sciences. 106 (38): 16157–16162. doi:10.1073/pnas.0908201106. PMC 2752543. PMID 19805273. Retrieved 1 November 2017.
  4. ↑ Haas, Michael J. (29 April 2010). "Coupled, but not conjugated, in cancer". SciBX: Science-Business eXchange. 3 (17). doi:10.1038/scibx.2010.514. Retrieved 1 November 2017.
  5. ↑ Ruoslahti, Erkki (1 May 2017). "Access granted: iRGD helps silicasome-encased drugs breach the tumor barrier". The Journal of Clinical Investigation. 127 (5). doi:10.1172/JCI93955. Retrieved 1 November 2017.
  6. ↑ https://www.drugcendr.com/news
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