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J Gene Med. 2006 Dec;8(12):1407-15.

A branched histidine/lysine peptide, H2K4b, in complex with plasmids encoding antitumor proteins inhibits tumor xenografts.

Author information

1
Department of Pathology, University of Maryland Baltimore, MSTF Building, 10 South Pine Street, Baltimore, MD 21201, USA.

Abstract

BACKGROUND:

In this study we investigated whether a particular branched HK polymer, H2K4b, was an effective in vivo carrier of plasmids expressing the antiangiogenic kringle 1-5 or the tumor suppressor p53.

METHODS:

H2K4b was synthesized on a solid-phase peptide synthesizer. Distribution, optimization and time course studies were done in tumor-bearing nude mice by systemically administering H2K4b in complex with a luciferase-expressing plasmid. We examined the amount of tumor angiogenesis in C6 with MDA-MB-435 xenografts utilizing the carmine dye. The ability of H2K4b to carry luciferase plasmids to different tissues was compared with several liposomal carriers. Medium from cells transfected with mKr1-5 was tested for its capacity to inhibit angiogenesis with an in vivo Matrigel assay. We then determined if systemically delivered H2K4b in complex with plasmid encoding mKr1-5 inhibited tumor growth; we also compared the antitumor activity of HK polyplexes containing hKr1-5, mKr1-5, and p53 plasmids.

RESULTS:

H2K4b carried the luciferase-expressing plasmid in order of descending efficacy to these tissues: lung, spleen, tumor, and liver. Compared to DOTAP-containing liposomes, H2K4b was a more effective carrier of a luciferase-containing plasmid to extrapulmonary tissues. We then determined that mKr1-5 in complex with H2K4b reduced MDA-MB-435 tumor growth by approximately 50% compared to the control group (P < 0.01). Similarly, H2K4b/mKr1-5 polyplexes reduced the growth of C6 xenografts. In MDA-MB-435 xenografts, p53- and Kr1-5-expressing plasmids in complex with H2K4b had comparable antitumor activity.

CONCLUSION:

H2K4b demonstrates potential as a carrier of plasmids encoding antiangiogenic and/or tumor suppressor proteins in a tumor-bearing mouse model.

PMID:
17133339
DOI:
10.1002/jgm.982
[Indexed for MEDLINE]

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