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Avichezer, Dody; Schechter, Bilha; Arnon, Ruth
Reactive & functional polymers, 02/1998, Letnik: 36, Številka: 1Journal Article
Complexing cis-dichlorodiammineplatinum (II) (CDDP) to the polycarboxylic carriers carboxymethyl dextran (CMdex, M r = 40 kDa) and poly- l-glutamic acid (p-Glu, M r = 40 kDa) yielded pharmacologically active platinum (II) multi-complexes of decreased drug toxicity. Displacement of CDDP chlorine atoms by hydrogens of carboxyl groups on polymer side-chains could give rise to mono-functional linkages capable of releasing the drug in favor of ligandsl exhibiting higher affinity toward Pt (II) (e.g. DNA, the target for drug activity in tumor cells). The CDDP-CM-dex complex, carrying up to 40 mol releasable CDDP per mol carrier, was cytotoxic against ovarian carcinoma cells in vitro with activity comparable to that of free CDDP (1.5 times lower). Its in vivo toxicity was influenced by drug: carrier molar ratio with a direct correlation between drug load and toxicity (a complex of 15: 1 was 4-fold less toxic than CDDP). The CDDP-p-Glu complex (60 mol drug/mol p-Glu) was characterized by higher thermodynamic stability, its reduced in vivo toxicity was not affected by CDDP load and its in vitro activity was lower than that of free CDDP (2.6-fold). Both CDDP complexes were effective in suppressing the growth of human ovarian carcinoma (OVCAR-3) in athymic mice. Due to them, decreased toxicity the complexes exerted a wider therapeutic dose range of activity (80% survival at 3–12 mg/kg) as compared to the narrow and inconsistent effective dose range of free CDDP (80% survival at 1–2.5 mg/kg).
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