Conjugates of a novel 7-substituted camptothecin with RGD-peptides as α(v)β₃ integrin ligands: An approach to tumor-targeted therapy

Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragme...

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Bibliographic Details
Published in:Bioconjugate chemistry 2010-11, Vol.21 (11), p.1956-1967
Main Authors: Dal Pozzo, Alma, Esposito, Emiliano, Ni, Minghong, Muzi, Laura, Pisano, Claudio, Bucci, Federica, Vesci, Loredana, Castorina, Massimo, Penco, Sergio
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - blood
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Camptothecin - analogs & derivatives
Camptothecin - blood
Camptothecin - chemistry
Camptothecin - pharmacology
Cell Proliferation - drug effects
Drug Screening Assays, Antitumor
Humans
Integrin alphaVbeta3 - metabolism
Ligands
Mice
Molecular Conformation
Oligopeptides - blood
Oligopeptides - chemistry
Oligopeptides - metabolism
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified with the purpose to understand their effect on receptor affinity, systemic stability, cytotoxicity, and solubility of the corresponding conjugates. Among the new conjugates prepared, C6 and C7 showed high receptor affinity and tumor cell adhesion, acceptable stability in murine blood, and high cytotoxic activity (IC₅₀ = 8 nM). The rationale, synthetic strategy, and preliminary biological results will be presented.
ISSN:1520-4812
DOI:10.1021/bc100097r