title: Characterization of the self assembly of methoxy poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) for the solubilization and in vivo delivery of valspodar.
abstract: The aim of this study was to characterize the nanostructures formed from assembly of poly(ethylene oxide)-bpoly( α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) in water, determine the effect of weight fraction of the hydrophilic block( fEO) on their morphology, and to investigate their potential for solubilization and delivery of P-glycoprotein (P-gp) inhibitor, valspodar. Three PEO-b-PBCL block copolymers having fEO ranging from 0.18-0.40 were synthesized. Assembly of PEO-b-PBCL was triggered through a co-solvent evaporation method. The average critical aggregation concentration (CAC) for PEO114-b-PBCL₃₀, PEO₁₁₄-b-PBCL₆₀, and PEO₁₁₄-b-PBCL₉₅ was found to be 62, 41, and 23 nM, respectively. A lower rigidity of the hydrophobic domain in nanostructures formed from the assembly of PEO₁₁₄-b- PBCL₆₀ and PEO₁₁₄-b-PBCL₉₅ in comparison to PEO₁₁₄-b-PBCL₃₀ was observed. The morphology of the assembled structures was characterized by transmission electron microscopy (TEM). The TEM images of PEO₁₁₄-b-PBCL₃₀ (fEO = 0.40) showed the formation of spherical micelles with high polydispersity, whereas the assembly of PEO₁₁₄-b-PBCL₆₀ (fEO = 0.25) and PEO₁₁₄-b-PBCL95 (fEO = 0.18) resulted in a mixed population of spherical micelles and vesicles. Valspodar achieved high loading in all the three PEO-b-PBCL nanocarriers reaching aqueous solubility of nearly 2 mg/mL. The morphology of PEO-b-PBCL carrier did not seem to influence the pharmacokinetics of the encapsulated valspodar in rats following intravenous administration. In conclusion, the results show a potential for PEO-b-PBCL nanocarriers as efficient solubilizing agents for delivery of valspodar.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada. zbinkhathlan@ksu.edu.sa
authors.forename: Ziyad
authors.initials: Z
authors.lastname: Binkhathlan
authors.forename: Sara
authors.initials: S
authors.lastname: Elhasi
authors.forename: Dion R
authors.initials: DR
authors.lastname: Brocks
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D003524:Cyclosporins / Q000008:administration & dosage* / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008823:Micelles; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D008823:Micelles; D011091:Polyesters; C547053:poly(ethylene oxide)-b-poly(alpha-benzyl carboxylate epsilon-caprolactone); D011092:Polyethylene Glycols; C070272:valspodar