Abstract
Auranofin (AF) and its iodido analog, i.e., Au(PEt3) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we explore whether encapsulation of these metallodrugs inside hydroxypropyl-beta–cyclodextrin (HPβ–CD) may lead to an improved biopharmaceutical profile for the resulting adducts. Phase solubility studies, performed at 25 °C in an aqueous buffer, revealed, in both cases, the formation of a 1:1 drug to cyclodextrin complex; a far greater apparent stability constant (K1:1) was measured for AFI compared to AF (331 M−1 versus ca. 30 M−1). NMR studies conducted on the AFI/HPβ–CD system confirmed the formation of a stable 1:1 adduct. Then, binary systems of AF and AFI with HPβ–CD were prepared by colyophilization and characterized by DSC and PXRD. The results revealed the occurrence of drug complexation and/or amorphization for the AFI/HPβ–CD binary system. Afterwards, the antiproliferative properties of the two cyclodextrin adducts and of the corresponding free drugs were comparatively evaluated in vitro in three representative ovarian cancer cell lines, i.e., A2780, SKOV3, and IGROV-1. The results, in all cases, point out that CD complexation of the two gold drugs does not substantially affect their biological activity. The implications of these findings are discussed in the frame of the current knowledge of AF and its analogs.
Highlights
Since the discovery of the anticancer activity of cisplatin in the early sixties and its subsequent approval by the FDA in 1978, metal-based drugs have gained growing attention and a role in the field of medicinal chemistry
Phase solubility measurements conducted on the two gold drugs revealed, in both cases, that the solubility of the drug linearly increases as a function of cyclodextrin concentration, showing an AL-type diagram according to the classification of Higuchi and Connors [11]
Auranofin, owing to its favorable pharmacological profile and the opportunities offered by drug repurposing, has recently been admitted to cancer clinical trials
Summary
Since the discovery of the anticancer activity of cisplatin in the early sixties and its subsequent approval by the FDA in 1978, metal-based drugs have gained growing attention and a role in the field of medicinal chemistry. For this reason, many other metalbased compounds have been prepared and screened in the last few decades as therapeutic agents against a variety of ailments, with some relevant results. Among the investigated metal-based drugs, auranofin (AF hereafter; Figure 1, left), a gold (I) compound for oral administration, is undoubtedly one of the most promising molecules. In the frame of the structure-activity studies of gold(I) drugs carried out in our laboratory, a number of halido and pseudohalido derivatives of auranofin have been designed and synthesized and subsequently tested as antibacterial and anticancer drug candidates [2,3]
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