Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin.
NAMI-A is an innovative ruthenium(III) complex with a very encouraging preclinical profile of metastasis inhibition, which is undergoing initial phases of clinical trials. To assess the pharmacological relevance of the drug fraction associated to plasma proteins, adducts of NAMI-A with either serum albumin or serum transferrin were prepared and their biological effects tested in vitro and in vivo. Specifically, adducts of NAMI-A with either serum albumin or serum transferrin, prepared and characterized at a ruthenium-to-protein molar ratio of 4:1, were evaluated in vitro on the KB human tumor cell line and in vivo on the MCa mammary carcinoma tumor. The effects of NAMI-A/protein adducts on cell viability and on cell cycle progression were found to be far smaller than those produced by free NAMI-A. GFAAS measurements point out that the amount of ruthenium that gets into cells is drastically reduced when NAMI-A is presented in its protein-bound form. In vivo use of NAMI-A adducts with albumin and transferrin resulted markedly less effective on lung metastasis reduction, than free NAMI-A. Overall, the present results suggest that binding to plasma proteins causes a drastic decrease of NAMI-A bioavailability and a subsequent reduction of its biological activity, implying that association to plasma proteins essentially represents a mechanism of drug inactivation.
Callerio Foundation Onlus, Via A. Fleming 22-31, 34127 Trieste, Italy. a.bergamo@callerio.org
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Bergamo
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Messori
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Piccioli
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Cocchietto
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Sava
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008808:Mice, Inbred CBA; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011990:Receptors, Transferrin; D017975:Ruthenium Compounds; D012709:Serum Albumin / Q000378:metabolism* / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C068126:CD71 antigen; D009942:Organometallic Compounds; D011990:Receptors, Transferrin; D017975:Ruthenium Compounds; D012709:Serum Albumin; D014168:Transferrin; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D004121:Dimethyl Sulfoxide