Novel therapeutic formulation for the anticancer drug valrubicin using human serum albumin and D-alpha-tocopheryl polyethylene glycol 1000 succinate

Purpose: Human serum albumin (HSA) and the bioavailability enhancer D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) are recognized as versatile biocompatible ingredients in drug nanoformulation. Due to its lipophilicity, the anticancer drug valrubicin is currently solubilized in cremophor EL which does not favor systemic delivery. Hence, even though valrubicin is less toxic and more potent than its widely used anthracycline parent compound doxorubicin, its administration and use are respectively restricted to intravesical route and bladder cancer. Since HSA is able to transport endogenous lipophilic compounds in the blood, and TPGS forms micelles, HSA and/or TPGS could increase the solubility of valrubicin in a preparation and extend its administration to alternative administration routes including systemic delivery. Thus, the goal of this study is to characterize and compare three formulations: HSA-Valrubicin (Val), TPGS-Val and HSA-TPGS-Val. Methods: The formulations were prepared using 0.5mg/mL Val, 50mg/mL HSA and different concentrations of TPGS. Each formulation was continuously stirred at room temperature for 2 hours. Centrifugation and filtration were used to remove unbound valrubicin. The particle size was estimated by dynamic light scattering while the amount of valrubicin incorporated was derived from absorbance reading at 490 nm. Results: Whereas only 61.5% of the feeding valrubicin was incorporated in the HSA-Val formulation, the amount of Val dissolved in TPGS followed the ratio of 1:6 (mol/mol). Addition of increasing amount of TPGS to HSA increased the amount of Val incorporated in HSA-TPGS-Val formulations. The mixture of 50mg/mL HSA, 0.5 mg/mL TPGS and 0.5 mg/mL Val showed 76% of Val incorporation and also displayed the lowest particle size with the highest homogeneity (56 nm±15.3, polydispersity index (PDI) 0.148). Conclusion: Although TPGS concentration could be a limiting factor for drug loading efficiency in TPGS-Val preparations, the combination of TPGS and HSA show the promise of an acceptable formulation. Perhaps, the optimization of HSA-TPGS-Val preparations can be achieved by reducing disulfide bridges in HSA to uncover more hydrophobic sites on the molecule.