Optimization of the hydrophobic domain in poly(ethylene oxide)-poly(ɛ-caprolactone) based nano-carriers for the solubilization and delivery of Amphotericin B

The aim of the study was to develop a polymeric nano-carrier based on methoxy poly(ethylene oxide)-b-poly(ɛ-caprolactone) (MePEO-b-PCL) for the optimum solubilization and delivery of Amphotericin B (AmB). For this purpose, MePEO-b-PCL block co-polymers containing palmitoyl substituent on PCL (at a 100% substitution level) were synthesized through preparation of substituted monomer, that is, α-palmitoyl-ɛ-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol−1) using stannous octoate as catalyst. Prepared block co-polymers were characterized for their molecular weight by 1H NMR and gel permeation chromatography, and assembled to polymeric nano-carriers. The self-assembly of synthesized MePEO-b-PPaCL to spherical particles of nanometer size range was shown by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The efficacy of nano-carriers formed from this structure (abbreviated as MePEO-b-PPaCL) in comparison to unmodified MePEO-b-PCL and those with benzyl and cholesteryl substituent on PCL (abbreviated as MePEO-b-PBCL and MePEO-b-PChCL, respectively) on the solubilization and hemolytic activity of AmB against rat red blood cells was assessed. Under identical conditions, the maximum solubilization of AmB was achieved by nano-carriers prepared from MePEO-b-PPaCL (436 μg/mL), followed by MePEO-b-PChCL (355 μg/mL), MePEO-b-PBCL (296 μg/mL) and MePEO-b-PCL (222 μg/mL). The hemolytic activity of AmB was reduced the most by its encapsulation in MePEO-b-PChCL nano-particles which showed only 7% hemolysis at 30 μg/mL AmB concentration. This was followed by MePEO-b-PCL nano-particles which illustrated 15% hemolysis, MePEO-b-PPaCL with 40% hemolysis and MePEO-b-PBCL with 60% hemolysis at 30 μg/mL AmB concentrations, respectively. In contrast Fungizone® showed 90% hemolysis at 30 μg/mL AmB concentration. Based on the improved solubility and reduced hemolytic activity, the MePEO-b-PChCL nano-carriers are considered as optimum structures for AmB delivery.