Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature.

Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature. Research Abstract Details 

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Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature. Abstract Text:

Sumitra Mukhopadhyay,Carmen M ,Ariel Haskel,Sarah M Short,Katie R Barnes,Stephen J Lippard,Sumitra Mukhopadhyay,Carmen M ,Ariel Haskel,Sarah M Short,Katie R Barnes,Stephen J Lippard,Sumitra Mukhopadhyay,Carmen M ,Ariel Haskel,Sarah M Short,Katie R Barnes,Stephen J Lippard,

The integrins alpha vbeta 3 and alpha vbeta 5 and the membrane-spanning surface protein aminopeptidase N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono- and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing RGD, (CRGDC)c, (RGDfK)c, or NGR, is appended as a "tumor-homing device" to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with nonspecific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinum-based chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to cell lines containing alpha vbeta 3 and alpha vbeta 5, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin alpha vbeta 3 mediated, at least in part, the anti-proliferative effect of a Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of alpha vbeta 3/alpha vbeta 5-specific RGD pentapeptides or (2) transfected with RNAi for beta 3, but not beta 1, integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.

Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature. Publishing Authors By Initials

S Mukhopadhyay,CM ,A Haskel,SM Short,KR Barnes,SJ Lippard,S Mukhopadhyay,CM ,A Haskel,SM Short,KR Barnes,SJ Lippard,S Mukhopadhyay,CM ,A Haskel,SM Short,KR Barnes,SJ Lippard,

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Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Bioconjugate chemistry

VOLUME: 19

Page Numbers: 39-49

Journal Abbreviation: Bioconjug. Chem.

ISSN: 1043-1802

DAY: 11

MONTH: 09

YEAR: 2007

Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Conjugated Platinum(IV)-Peptide Complexes for Targeting Angiogenic Tumor Vasculature.

AFFILIATION: carmen.barnes@childrens.harvard.edu, lippard@mit.edu.

Country: United States

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MEDLINETA: Bioconjug Chem

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