title: Optimization of the hydrophobic domain in poly(ethylene oxide)-poly(varepsilon-caprolactone) based nano-carriers for the solubilization and delivery of Amphotericin B.
abstract: The aim of the study was to develop a polymeric nano-carrier based on methoxy poly(ethylene oxide)-b-poly(epsilon-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, alpha-palmitoyl-epsilon-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 (1)H 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 microg/mL), followed by MePEO-b-PChCL (355 microg/mL), MePEO-b-PBCL (296 microg/mL) and MePEO-b-PCL (222 microg/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 microg/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 microg/mL AmB concentrations, respectively. In contrast Fungizone showed 90% hemolysis at 30 microg/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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Arash
authors.initials: A
authors.lastname: Falamarzian
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002214:Capsules; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006461:Hemolysis / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D008956:Models, Chemical; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D002214:Capsules; D004337:Drug Carriers; D007783:Lactones; C473831:poly(ethylene oxide)-b-poly(caprolactone); D011092:Polyethylene Glycols; D000666:Amphotericin B