HSA IIA subdomain-based developing anticancer metal prodrug: a new and improved approach.

Abstract

Although cisplatin is a promising anticancer agent, multifactorial resistance, serious side effects and general toxicity have limited its use in cancer chemotherapy. Therefore, less toxic and more effective metal-based anticancer compounds have been sought and developed, and drug delivery systems have been exploited to improve the selectivity of anticancer drugs and decrease their side effects [1,2]. Metallic compounds offer distinct biological and chemical diversity from that of organic drugs [3]. The biological activity of various metals in complexes with organic ligands is higher than that of the ligands alone, particularly for antitumor activity. Therefore, designing and synthesizing a metal complex derived from ligands with anticancer activity may be a strategy for developing novel anticancer metallodrugs [4]. A large number of metallic compounds have been evaluated in vitro and in vivo and some have reached clinical trials, but improving the efficacy of metallic drugs and decreasing their side effects in vivo remains a major challenge. Solutions to overcome these problems may lie in finding a suitable drug delivery strategy [5]. Various delivery systems, such as prodrug, ligand designed and carrier systems, have been developed to enhance the performance of these novel metallodrugs. Human serum albumin (HSA) is the most abundant protein in plasma. HSA contains many active residues, including histidine, cysteine and lysine. Owing to the several binding sites in HSA, it can bind a diverse group of exogenous compounds [6–8]. HSAbased drug delivery systems are promising because HSA is a nontoxic, nonantigenic, biocompatible and biodegradable protein that lacks immunogenicity [9–11]. Owing to the unique properties of HSA, it can be applied as a carrier to design a metallic drug to synergistically improve anticancer activity and target metallic agents. HSA can be conjugated with a prodrug designed to contain a group that reacts with HSA special residues or an HSA complex can be formed by b inding the drug to HSA [12–18].