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 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.
Dal Pozzo
Alma
A
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milano, Italy. dalpozzo@ronzoni.it
Esposito
Emiliano
E
Ni
Minghong
M
Muzi
Laura
L
Pisano
Claudio
C
Bucci
Federica
F
Vesci
Loredana
L
Castorina
Massimo
M
Penco
Sergio
S
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D009842:Oligopeptides / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; C531200:namitecan; D002166:Camptothecin