title: Rational design of block copolymer micelles to control burst drug release at a nanoscale dimension.
abstract: To circumvent the problem of burst drug release from polymeric micelles, we designed three layered ABC micelles consisting of methoxy poly(ethylene oxide) (PEO) as the shell layer (A block); poly(lactic acid) (PLA) of different stereo-chemistries as the outer core (B block) and poly(α-benzylcarboxylate-ε-caprolactone) (PBCL) or poly(ε-caprolactone) (PCL) as the inner core (C block). The micelles were used to encapsulate a model hydrophobic drug, nimodipine. The effect of PLA (B block) incorporation and stereochemistry on the formation of semi crystalline outer cores in ABC triblock copolymer micelles, micelle stability, drug loading and release was then assessed in comparison to diblock copolymer micelles. The PLA outer core was expected to act as a barrier lowering the rate of drug diffusion out of the micellar carrier owing to a high Flory Huggins interaction parameter between nimodipine and PLA (χ=1.35). Introduction of PLA outer cores in ABC block copolymer micelles reduced the burst release of nimodipine from polymeric micelles without jeopardizing its high encapsulation efficiency. In ABC polymeric micelles with stereo-regular PLA blocks; semi-crystalline outer PLA cores were not formed, which was in contrast to PEO-PLA diblock copolymer micelles. Accordingly, PLA stereo-chemistry had no significant effect on drug release in ABC polymeric micelles. In contrast to diblock copolymers, no sign of stereo-complexation in mixed micelles composed of a 50:50 mixture of PdLA and PlLA containing ABC triblock copolymers was observed. The results showed the capability of properly designed ABC triblock copolymer micelles as reservoirs for drug solubilization and depot release at nanoscale dimensions.
  
  
  CONCLUSIONS
  Polymeric micelles are core-shell nanostructures that are widely used for drug delivery. Their hydrophobic core accommodates poor water soluble drugs and their hydrophilic shell allows the whole structure to be water soluble. A common problem with the use of polymeric micelles is leakage of the incorporated drug from these carriers. Here we have shown that a properly designed three layered (ABC) block copolymer micelle with drug compatible blocks at the inner core and drug incompatible blocks at the outer core can be used to reduce the initial fast rate of drug release while providing high amount of drug encapsulated in the core. Moreover, changes in the chemical structure of the inner core may be used to modify the stability of these systems.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Hoda
authors.initials: H
authors.lastname: Soleymani Abyaneh
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Vakili
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada.
authors.forename: Phillip
authors.initials: P
authors.lastname: Choi
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada. Electronic address: afsaneh@ualberta.ca.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D004337:Drug Carriers / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid / Q000737:chemistry*; D008823:Micelles; D009553:Nimodipine / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C016240:polycaprolactone; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D009553:Nimodipine
keywords: ABC triblock copolymer; Drug release; Poly caprolactone; Poly lactic acid; Polymeric micelle