Investigating the affinity of human plasma lipoproteins and albumin to the anti-cancer drug valrubicin
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Background: Reconstituted lipoproteins and albumin are promising targeted drug delivery agents. Valrubicin is a hydrophobic anti-cancer drug currently approved for the treatment of in situ BCG –resistant bladder carcinoma through intra-vesical instillation. An injectable formulation with the patients’ own lipoproteins or albumin as carriers would not only make valrubicin an attractive therapy candidate for other types of cancer, but also limit immunological response and off-target effects including cardiotoxicity. Purpose: This study aimed to assess the binding of valrubicin to human plasma lipoproteins and serum albumin (HSA) under different incubation conditions. We hypothesize valrubicin will preferentially associate with high density lipoprotein (HDL) due to its high hydrophobicity index. Materials and Methods: A solution of valrubicin in dimethyl sulfoxide was incubated for up to 24 hours with either pooled whole human plasma or with individual plasma components at room temperature (RT) or 37 degrees Celsius. Plasma component fractions were separated by ultracentrifugation. A 45 mg/mL albumin solution was used for individual incubation. Absorbance at 490 nm was used to estimate valrubicin concentration in low density lipoprotein (LDL), HDL and HSA. Results: Incubation for 2 hours at RT yielded the highest valrubicin concentration in plasma components. Overall, valrubicin association with plasma components moderately increased with the amount of valrubicin added prior to incubation. For instance, 0.185 mg and 1.121 mg of valrubicin was recovered with respectively 1 mg and 5 mg of valrubicin initially added to 1 mL of plasma. About 4%, 10% and 86% of the initial valrubicin added to whole plasma were respectively distributed in the LDL, HDL and the HSA –containing plasma fractions after ultracentrifugation. The incorporation of valrubicin in HDL increased-though not proportionally- with 10 fold concentration of HDL. However, prolonged incubation of valrubicin with 45mg/mL HSA resulted in the dissociation of valrubicin and HSA. Conclusions: Our preliminary data suggests differential interaction of valrubicin with plasma components with preferential binding to HSA. The optimization of the HSA/ valrubicin complex will be required to develop an efficient drug transport formulation. HSA stabilizing agents such as sodium acetyltryptophanate and sodium caprylate could potentially facilitate and stabilize the binding of valrubicin to HSA.