Editors' ChoiceCancer Therapy

Food for Nanoworms

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Science Translational Medicine  26 Oct 2011:
Vol. 3, Issue 106, pp. 106ec173
DOI: 10.1126/scitranslmed.3003338

Glioblastoma is a deadly brain tumor, with a median survival of only 12 months despite multimodal therapy. Angiogenesis—the process of new blood vessel formation—has been investigated as a therapeutic target for these aggressive tumors. New blood vessels help tumors to grow, but also provide a highway for the delivery of cytotoxic drugs to tumor cells while sparing normal, surrounding brain tissue. Now, Agemy and colleagues have engineered a complex “nanoworm” that can ride this same highway into a glioblastoma and selectively target mitochondria, causing apoptosis and preventing tumor growth.

The nanoworm used in the study has three linked components: the CGKRK peptide that binds to tumor blood vessels, but not to normal vasculature; the D[KLAKLAK]2 peptide, which disrupts the mitochondrial membrane and causes cell death; and an iron oxide moiety for detection of the nanoworm by magnetic resonance imaging. Using a mouse model of glioblastoma, Agemy et al. found that intravenously injected nanoworms homed to tumor blood vessels but not to the vasculature of the intact brain. In vitro studies showed that the nanoworm was toxic to glioblastoma cells by inducing apoptosis. Importantly, the nanoworm showed therapeutic efficacy: systemic delivery cured 9 out of 10 mice in one model of glioblastoma and enhanced survival in another.

A major advantage conferred by the nanoworm is increased specificity of cytotoxic action. The D[KLAKLAK]2 peptide alone results in systemic toxicity at doses required for tumor inhibition. Combining D[KLAKLAK]2 with the tumor-specific CGKRK peptide helps to increase the selectivity of peptide delivery, thus reducing toxicity. The nanoworm used by Agemy and colleagues was still associated with signs of reversible liver toxicity, highlighting the need for more specific formulations. However, compared with the kidney toxicity caused by the unconjugated peptide—or the devastating effects of glioblastoma itself—the current results in mice are nonetheless encouraging. Future investigation should focus on reduced toxicity and studies of efficacy in nonhuman primates. Hopefully for the patients afflicted with glioblastoma, brain tumor cells will one day be reduced to food for nanoworms.

L. Agemy et al., Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc. Nat. Acad. Sci. U.S.A. 3 October 2011 (10.1073/pnas.1114518108). [Abstract]

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