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Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth
Neelesh R. Soman, … , Samuel A. Wickline, Paul H. Schlesinger
Neelesh R. Soman, … , Samuel A. Wickline, Paul H. Schlesinger
Published August 10, 2009
Citation Information: J Clin Invest. 2009;119(9):2830-2842. https://doi.org/10.1172/JCI38842.
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Technical Advance Oncology Article has an altmetric score of 20

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

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Abstract

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.

Authors

Neelesh R. Soman, Steven L. Baldwin, Grace Hu, Jon N. Marsh, Gregory M. Lanza, John E. Heuser, Jeffrey M. Arbeit, Samuel A. Wickline, Paul H. Schlesinger

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Figure 6

Role of cholesterol in the induction of apoptotic cell death by αvβ3 integrin–targeted melittin-loaded nanoparticles.

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Role of cholesterol in the induction of apoptotic cell death by αvβ3 int...
(A) C32 melanoma cells were treated with 2 concentrations of methyl-β-cyclodextrin (MBCD) to remove cholesterol as described in Methods and in Results. These cells were washed and exposed to the αvβ3 integrin–targeted nanoparticles. After incubation in culture, cell proliferation was determined by MTT assay as described in Methods. Data are represented as mean ± SD. **P < 0.01. (B–G) Cells treated as described in A were stained with annexin V–FITC and 7-AAD before analysis by cell sorting after treatment with the nanoparticles: (B) nanoparticles; (C) 2.5 μM αvβ3 integrin-targeted melittin-loaded nanoparticles; (D) 0.25 mM MBCD; (E) 0.5 mM MBCD; (F) 0.25 mM MBCD and 2.5 μM αvβ3 integrin–targeted melittin-loaded nanoparticles; and (G) 0.5 mM MBCD and 2.5 μM αvβ3 integrin–targeted melittin-loaded nanoparticles. Cells stained with annexin V–FITC were considered early in apoptosis, and those stained with 7-AAD also were late apoptotic cells. Numbers show the percentage of cells in the respective quadrants. (H) Schematic depiction of interaction of C32 melanoma cells with αvβ3 integrin–targeted melittin-loaded nanoparticles.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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