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Cancer drug effectiveness substantially advanced: Co-administered peptide directs medicines deep into tumor tissue

Date:
April 11, 2010
Source:
Sanford-Burnham Medical Research Institute
Summary:
Researchers have shown that a peptide (a chain of amino acids) called iRGD helps co-administered drugs penetrate deeply into tumor tissue. The peptide has been shown to substantially increase treatment efficacy against human breast, prostate and pancreatic cancers in mice, achieving the same therapeutic effect as a normal dose with one-third as much of the drug.

A tumor-penetrating peptide allows co-injected drugs to penetrate into tumor tissue.
Credit: Image created by Peter Allen, UCSB

Researchers have shown that a peptide (a chain of amino acids) called iRGD helps co-administered drugs penetrate deeply into tumor tissue. The peptide has been shown to substantially increase treatment efficacy against human breast, prostate and pancreatic cancers in mice, achieving the same therapeutic effect as a normal dose with one-third as much of the drug.

In a transformative paper published in the online edition of the journal Science, Erkki Ruoslahti, M.D., Ph.D., distinguished professor at Sanford-Burnham Medical Research Institute and founding member of the UC Santa Barbara-Sanford|Burnham Center for Nanomedicine, Kazuki N. Sugahara, M.D., Ph.D., Tambet Teesalu, Ph.D., and fellow researchers at the Center for Nanomedicine and the Cancer Center of Santa Barbara, announced this significant advance in cancer therapy.

"Drugs generally have difficulty penetrating tumors beyond a few cell diameters from a blood vessel," said Dr. Ruoslahti. "This leaves some tumor cells with a suboptimal dose, increasing the risk of both recurrence and drug resistance. The iRGD peptide solves this problem by activating a transport system in tumors that distributes co-injected drugs into the entire tumor and increases drug accumulation in the tumor."

Dr. Ruoslahti showed in the 1980s that a 3 amino-acid peptide motif (RGD -- Arginine-Glycine-Aspartic Acid) serves as a highly selective identifier of malignant tissue, binding to unique re-ceptors in the vasculature of cancers. The RGD peptide's ability to home to tumors has been used to design new compounds for cancer diagnosis and treatment.

The new variant of RGD (iRGD -- internalizing RGD) combines the RGD motif with a tissue penetration element called CendR. Like the earlier RGD peptides, iRGD homes to tumors, but exposure of the CendR motif when the iRGD is enzymatically cleaved activates a transport system through tumor blood vessel walls into the tumor core. In a paper published in Cancer Cell late last year, the research team showed that coupling iRGD to anti-cancer drugs allowed them to penetrate deep into tumors, effectively increasing the activity of the drugs.

The research reported in this latest Science paper adds a new and important twist to the story: The researchers made the unanticipated discovery that anti-cancer drugs do not need to be chemically attached to the iRGD peptide for iRGD to boost their efficacy. Simply co-administering iRGD with a drug enhances the drug's anti-cancer properties. Co-administration could be even more effective at delivering therapeutic agents inside tumors than conjugating the agents with the peptide. This new paradigm means that iRGD has the potential to enhance the efficacy of already approved drugs without creating new chemical entities, which would complicate the path to approval for clinical use.

In addition to being effective against human breast, prostate and pancreatic cancers grown in mice, iRGD can penetrate other tumor types and could possibly be used to treat most, if not all, solid tumors. The iRGD peptide was also shown to enhance the therapeutic effects of multiple types of anti-cancer drugs, including a small molecule drug, a monoclonal antibody and two nanoparticle drugs. Tumors essentially resistant to a particular drug showed good responses when the drug was combined with iRGD, and tumors partially responsive to another drug were eradicated by the combination.

"We are really excited about the potential of iRGD, and I'd like to thank my colleagues, Kazuki Sugahara and Tambet Teesalu in particular, who made this all happen," said Dr. Ruoslahti. "These results with human tumors in mice are very promising, but we still have to demonstrate the value of iRGD in treating cancers in humans."


Story Source:

The above story is based on materials provided by Sanford-Burnham Medical Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Kazuki N. Sugahara, Tambet Teesalu, Priya Prakash Karmali, Venkata Ramana Kotamraju, Lilach Agemy, Daniel R. Greenwald, and Erkki Ruoslahti. Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science, 2010; DOI: 10.1126/science.1183057

Cite This Page:

Sanford-Burnham Medical Research Institute. "Cancer drug effectiveness substantially advanced: Co-administered peptide directs medicines deep into tumor tissue." ScienceDaily. ScienceDaily, 11 April 2010. <www.sciencedaily.com/releases/2010/04/100408160905.htm>.
Sanford-Burnham Medical Research Institute. (2010, April 11). Cancer drug effectiveness substantially advanced: Co-administered peptide directs medicines deep into tumor tissue. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2010/04/100408160905.htm
Sanford-Burnham Medical Research Institute. "Cancer drug effectiveness substantially advanced: Co-administered peptide directs medicines deep into tumor tissue." ScienceDaily. www.sciencedaily.com/releases/2010/04/100408160905.htm (accessed October 23, 2014).

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