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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

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 1

Synthesis of melittin-loaded nanoparticles and their interactions with red blood cells and cancer cells.

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Synthesis of melittin-loaded nanoparticles and their interactions with r...
(A) TEM of liposomes and perfluorocarbon nanoparticles before and after incorporation of melittin (lipid/melittin molar ratio, 40). Note the disruption of liposomes and the stable insertion of melittin into nanoparticles. Also shown are the freeze-fracture transmission electron micrographs of the hemifusion between a lipid monolayered nanoparticle and bilayered liposome. Scale bars: 200 nm. (B) Melittin-loaded nanoparticles (melittin NP) display reduced lysis of red blood cells. A standard hemolysis assay was performed on fresh umbilical cord blood (see Methods). Free melittin is highly lytic to red cells with an IC50 of 0.51 μM. (C) Melittin-loaded nanoparticles kill cancer cells. A 12-hour B16F10 melanoma cell proliferation was determined by MTT assay. Incorporation of melittin onto nanoemulsions produces a 7-fold protection from free peptide (IC50 of 0.7 μM for free melittin vs 5.1 μM for nanoemulsions). Data are represented as mean ± SD.
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