Abstract
Human serum albumin (HSA)-based drug delivery systems are promising for improving delivery efficiency, anticancer activity and selectivity of anticancer agents. To rationally guide to design HSA carrier for anticancer metal agent, we built a breast mouse model on developing anti-cancer copper (Cu) pro-drug based on the nature of IIA subdomain of HSA carrier and cancer cells. Thus, we first synthesized a new Cu(II) compound derived from tridentate (E)-N'-(5-bromo-2-hydroxybenzylidene)benzohydrazide Schiff base ligand (HL) containing 2 potential leaving groups [indazole (Ind) and NO3−], namely, [Cu(L)(Ind)NO3]. Structural analysis of the HSA complex showed that Cu(L)(Ind)(NO3) could bind to the hydrophobic pocket of the HSA IIA subdomain. Lys199 and His242 coordinate with Cu2+ by replacing the indazole and NO3 ligands of [Cu(L)(Ind)NO3]. The release behavior of the Cu compound from the HSA complex is different at different pH levels. [Cu(L)(Ind)NO3] can enhance cytotoxicity by 2 times together with HSA specifically in cancer cells but has no such effect on normal cells in vitro. Importantly, our in vivo results showed that the HSA complex displayed increased selectivity and capacity to inhibit tumor growth and was less toxic than [Cu(L)(Ind)NO3] alone.
Highlights
After the unexpected discovery of the antiproliferative activity of cisplatin, many studies have highlighted potent metal-based drugs for treating cancers [1, 2]
We developed a Cu-containing pro-drug with improved in vivo selectivity and drug delivery and anticancer efficiency using the structure of cancer cells as well as by using the Human serum albumin (HSA) IIA subdomain
We used a tridentate (E)-N'-(5-bromo-2-hydroxybenzylidene) benzohydrazide Schiff base ligand (HL) for developing the Cu compound because the hydrazone class ligands are promising anticancer agent [45,46,47] and because its hydrophobic and rigid structure may facilitate the binding of the Cu compound to the HSA IIA subdomain [37]
Summary
After the unexpected discovery of the antiproliferative activity of cisplatin, many studies have highlighted potent metal-based drugs (metallodrugs) for treating cancers [1, 2]. Even though progress has been made to understand the chemistry of metallodrugs, these emerging therapeutics are associated with concerns such as a lack of water solubility and chemical deficiencies [3, 6,7,8]. To overcome these concerns, novel drug delivery vehicles must be developed [9,10,11,12,13]. The efficiency and selectivity of anticancer agents can be improved by chemically coupling these agents with the special residues of albumin [21,22,23,24,25,26,27]
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