Clinical data | |
---|---|
Routes of administration | Intravenous |
Pharmacokinetic data | |
Bioavailability | 100% |
Metabolism | n/a |
Elimination half-life | 1-3 hours |
Duration of action | up to 24 hours |
Excretion | Renal (100%) |
Identifiers | |
CAS Number | |
PubChem CID | |
UNII | |
Chemical and physical data | |
Molar mass | (948.04 g/mol after conversion) |
iRGD is a 9-amino acid cyclic peptide (sequence: CRGDKGPDC) and a molecular mimicry agent that was originally identified in an in vivo screening of phage display 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 due to the bifunctional action of the molecule: after the initial RGD-mediated tumor homing, another pharmacological motif is able to manipulate tumor microenvironment, making it temporarily accessible to circulating drugs. This second step is mediated through specific secondary binding to neuropilin-1 receptor, and subsequent activation of a trans-tissue pathway, dubbed the C-end Rule, or CendR pathway. [2]
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.[ citation needed ]
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] Lisata Therapeutics Inc. (https://www.lisata.com/), is currently testing iRGD-based therapy called LSTA-1 in clinical studies in solid tumor patients. [6] The U.S. Food and Drug Administration (FDA) awarded CEND-1 orphan drug status in 2019, and fast track designation in 2020. [7]
Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.
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Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.
Programmed cell death protein 1, also known as PD-1 and CD279, is a protein on the surface of T and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
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Erkki Ruoslahti is a cancer researcher and distinguished professor at Sanford Burnham Prebys Medical Discovery Institute. He moved from Finland to the United States in 1976.
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