Co-administration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs
Kazuki N. Sugahara, Tambet Teesalu, Priya Prakash Karmali, Venkata Ramana Kotamraju, Lilach Agemy, Daniel R. Greenwald, Erkki Ruoslahti
Science 328, 1031-1035 (2010)
Presenter：I-Chen Li
Date/Time：2011/03/31 16：10—17：00
Commentator：Dr. Chi-Wu Chiang
Place：Room 602, College of Medicine
Abstract:
Background
Poor penetration of anticancer drugs into tumors is a major obstacle in tumor treatment. In solid tumors,
many anti-cancer drugs penetrate only 3 to 5 cell diameters from the blood vessels, which leave some tumor
cells with a suboptimal dose, increasing the risk of both recurrence and drug resistance. The authors showed
in the 1980s that a 3 amino-acid peptide motif (RDG – Arginine-Glycine-Aspartic Acid) serves as a highly
selective identifier of malignant tissue, binding to αv integrins that are specifically found on blood vessels
that surround tumors. 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 after
binding to αv integrins, but unlike the earlier RGD peptides, it is modified such that it attracts neuropilin-1, a
mediator that activates an active transport system through tumor blood vessel walls into the tumor core.
Hypothesis
The iRGD peptide can enhance anti-cancer drug delivery and activity when it is administered as a
combination therapy with drugs that are not chemically conjugated to it.
Results
First, the authors xenografted human breast and prostate cancer cells into immunodeficient mice to
grow solid tumors. Anticancer drugs, such as Nab-paclitaxel, doxorubicin, doxorubicin liposomes, and
trastuzumab, were used to treat the tumors alone or in combination with iRGD. The authors demonstrated
that co-administration of iRGD increased the accumulation of anti-cancer drug levels in established tumors
and not in normal tissues. iRGD co-administration also enhanced the therapeutic effects of multiple types of
anti-cancer drugs, including a small molecule drug (doxorubicin), a monoclonal antibody (trastuzumab), and
two nanoparticle drugs (Nab-paclitaxel and doxorubicin liposomes). Lastly, co-administration of iRGD with
doxorubicin liposomes reduced the extent of cardiotoxicity, an adverse side-effect of doxorubicin.
Conclusions
The authors have conclusively demonstrated that it is not necessary for anti-cancer drugs to chemically
conjugate to iRGD and can still show excellent anti-cancer activity. Co-administration of iRGD could be
even more effective at delivering therapeutic agents in tumors than conjugating to the agents. This new
paradigm means that iRGD has the potential to improve the therapeutic index of already approved drugs
without creating new chemical entities while reducing their side effects, a primary goal of cancer therapy
research.
Reference:
K. N. Sugahara et al. (2009). Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors. Cancer Cell
16, 510-520.
K. N. Sugahara et al. (2010). Co-administration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer
Drugs. Science 328, 1031-1035.