A novel formulation for amphotericin B (AmB) delivery has been developed using micelle-forming 5 kDa monomethoxy-polyethylene glycol functionalized with cholanic acid (PEG(5kDa)-cholane). This polymer was foundto increase103timesthe AmB solubilitywith a 12:1 AmB/PEG(5kDa)-cholanemolarratio (2:1 w/w ratio). Dynamic light scattering and transmission electron microscopy analyses showed that PEG(5kDa)-cholane associated with AmB to form 30 nm micelles. Isothermal titration calorimetry analyses performed at different pH showed that PEG(5kDa)-cholane interacts with AmB according to multiple-site association profiles. Affinity constants and enthalpy and entropy changes were found to depend on pH, suggesting that the polymer interaction depends on the AmB ionization and aggregation. The freeze-dried product could be promptly re-dispersed forming a colloidal dispersion with the biopharmaceutical features of the freshly prepared micelles, namely AmB solubility and micelle size. The dispersion was stable over one month incubation at room temperature. FT-infrared spectrometry, differential scanning calorimetry and X-ray diffractometry showed that in the freeze-dried product, AmB intimately interacts with PEG(5kDa)-cholane. In presence of serum albumin, AmB formulated with PEG(5kDa)-cholanewas found to undergo less extensive and slower disaggregation than in Fungizone (R). Antifungal activity studies performed using Candida albicans showed that AmB/PEG(5kDa)-cholane was 15% more active than AmB in buffer.
A novel performing PEG-cholane nanoformulation for Amphotericin B delivery
MALFANTI, ALESSIO;BERSANI, SARA;SALMASO, STEFANO;CALICETI, PAOLO
2015
Abstract
A novel formulation for amphotericin B (AmB) delivery has been developed using micelle-forming 5 kDa monomethoxy-polyethylene glycol functionalized with cholanic acid (PEG(5kDa)-cholane). This polymer was foundto increase103timesthe AmB solubilitywith a 12:1 AmB/PEG(5kDa)-cholanemolarratio (2:1 w/w ratio). Dynamic light scattering and transmission electron microscopy analyses showed that PEG(5kDa)-cholane associated with AmB to form 30 nm micelles. Isothermal titration calorimetry analyses performed at different pH showed that PEG(5kDa)-cholane interacts with AmB according to multiple-site association profiles. Affinity constants and enthalpy and entropy changes were found to depend on pH, suggesting that the polymer interaction depends on the AmB ionization and aggregation. The freeze-dried product could be promptly re-dispersed forming a colloidal dispersion with the biopharmaceutical features of the freshly prepared micelles, namely AmB solubility and micelle size. The dispersion was stable over one month incubation at room temperature. FT-infrared spectrometry, differential scanning calorimetry and X-ray diffractometry showed that in the freeze-dried product, AmB intimately interacts with PEG(5kDa)-cholane. In presence of serum albumin, AmB formulated with PEG(5kDa)-cholanewas found to undergo less extensive and slower disaggregation than in Fungizone (R). Antifungal activity studies performed using Candida albicans showed that AmB/PEG(5kDa)-cholane was 15% more active than AmB in buffer.
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