cyclotides drugs

cyclotides drugs

Technical advance
2830 The Journal of Clinical Investigation http://www.jci.org Volume 119 Number 9 September 2009
Molecularly targeted nanocarriers deliver the
cytolytic peptide melittin specifically to tumor
cells in mice, reducing tumor growth
Neelesh R. Soman,1 Steven L. Baldwin,2 Grace Hu,2 Jon N. Marsh,2 Gregory M. Lanza,1,2
John E. Heuser,3 Jeffrey M. Arbeit,4 Samuel A. Wickline,1,2,3 and Paul H. Schlesinger3
1Department of Biomedical Engineering, 2Department of Medicine, 3Department of Cell Biology and Physiology, and
4Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity,
and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for
cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid
monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics
of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in
tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly
targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and
cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt
the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic
lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent
cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents
an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment
of cancer at multiple stages....

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