Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin
Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin
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DOI：
10.1023/a:1026243000320
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发表时间：
2003-11-01
影响因子：
3.4
通讯作者：
Sava, G
中科院分区：
文献类型：
--
作者：
Bergamo, A;Messori, L;Sava, G
NaMI-A是一种创新的Ru(III)络合物，具有非常令人鼓舞的临床前抑制转移的特征，目前正在进行临床试验的初始阶段。为了评价药物部分与血浆蛋白的相关性，制备了NAMI-A与血清白蛋白或血清转铁蛋白的加合物，并测定了它们的体外和体内生物学效应。具体地说，以Ru：蛋白质摩尔比4：1制备和表征的NAMI-A与血清白蛋白或血清转铁蛋白的加合物在体外对KB人肿瘤细胞株进行了评估，并在体内对MCA乳腺癌肿瘤进行了评估。研究发现，NAMI-A/蛋白加合物对细胞活力和细胞周期进程的影响远小于游离NAMI-A产生的影响。GFAAS测量指出，当NAMI-A以蛋白质结合的形式出现时，进入细胞的Ru的数量急剧减少。在体内，使用含有白蛋白和转铁蛋白的NaMI-A加合物在减少肺转移方面的效果明显低于游离的NaMI-A。总体而言，目前的结果表明，与血浆蛋白结合导致NAMI-A的生物利用度急剧下降，随后其生物活性降低，这意味着与血浆蛋白的结合基本上代表了药物失活的一种机制。
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.