Amphiphilic block copolymers are large structures which contain two regions of differing solubility properties. These polymers show great promise as potential drug delivery devices due to their ability to reversibly self-assemble into protective micelles. Narrowly disperse acrylate block copolymers were synthesized using the Reversible Addition Fragmentation chain Transfer (RAFT) polymerization method. A de-esterification reaction afforded the hydrophilic poly(acrylic acid) block with either an analogous sized or a three times longer hydrophobic block. Upon the increase of hydrophilic D2O solvent, a 2.4X decrease of the poly(methyl acrylate) methyl ester resonance on the triple lengthened hydrophobic block was observed when compared to a non-micellar environment using 1H-NMR. In addition, the copolymer solution became cloudy and viscous at higher concentrations of D2O which may confirm the effects of micellization observed in spectra. The addition of hexanes into the micelle environment further decreased the poly(methyl acrylate) methyl ester resonance on the hydrophobic block of similar length to the hydrophilic block. The hexanes methylene and methyl resonances were also decreased significantly, which likely indicated micelle formation occurred. It appears that additional hydrophobic interactions afforded by simulatory hydrophobic drug interactions may increase the effects of micellization over tripling the length of the hydrophobic core. Thus, spectroscopic evidence of micelles entrapping hydrophobic molecules indicates potential micellar use by combining acrylate copolymers and hydrophobic medicine to avoid drug precipitation in vivo.

1. Micellization of Acrylate-Based Amphiphilic Block Copolymers as a Function of Hydrophobic Core
Chain Length: An Investigation into the Effects of Chain Rigidity and Molecular Weight on Self-Assembly
Kevin S. Kawchak, Gregg M. Wilmes*
Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197
kkawchak@emich.edu, gwilmes@emich.edu*
Introduction: Amphiphilic block copolymers are large structures which contain two regions of differing solubility properties. These polymers show great promise as potential drug delivery devices due to their ability to reversibly self-assemble into protective micelles. Narrowly
disperse acrylate block copolymers were synthesized using the Reversible Addition Fragmentation chain Transfer (RAFT) polymerization method. A de-esterification reaction afforded the hydrophilic poly(acrylic acid) block with either an analogous sized or a three times longer hydrophobic
block. Upon the increase of hydrophilic D2O solvent, a 2.4X decrease of the poly(methyl acrylate) methyl ester resonance on the triple lengthened hydrophobic block was observed when compared to a non-micellar environment using 1H-NMR. In addition, the copolymer solution became
cloudy and viscous at higher concentrations of D2O which may confirm the effects of micellization observed in spectra. The addition of hexanes into the micelle environment further decreased the poly(methyl acrylate) methyl ester resonance on the hydrophobic block of similar length to the
hydrophilic block. The hexanes methylene and methyl resonances were also decreased significantly, which likely indicated micelle formation occurred. It appears that additional hydrophobic interactions afforded by simulatory hydrophobic drug interactions may increase the effects of
micellization over tripling the length of the hydrophobic core. Thus, spectroscopic evidence of micelles entrapping hydrophobic molecules indicates potential micellar use by combining acrylate copolymers and hydrophobic medicine to avoid drug precipitation in vivo.
Chain Rigidity (non-micellar) Chain Length (micellar) Entrapment (micellar)
*
Flexible Flexible
Hydrophobic + Hydrophobic
Block Block
Poly(methyl acrylate-b-acrylic acid) (66-b-60)
Poly(acrylic acid-b-methyl acrylate) (65-b-194) Hexanes + Poly(acrylic acid-b-methyl acrylate) (65-b-54)
1H-NMR 1H-NMR 1H-NMR
Hydrophilic Non-Micellar Environment
Hydrophilic 25% * Non-Micellar Resonance1
75% D2O
1,4-Dioxane-d8
Non-Broadened
Hydrophobic 75% Broadened Micellar Environment
1,4-Dioxane-d8
Background/Methods Hypothesis Current/Future Work
Reversible Addition Fragmentation chain Transfer When acrylate-based amphiphilic diblock copolymer 25% D2O (Hydrophobic) + Hayashi, et al.4
(RAFT) Polymerization2 Amphiphilic Diblock Copolymer Sodium
is present in an aqueous solution, an increase in Dodecyl
hydrophobic forces associated with the hydrophobic NaCl (sat.)
(Theoretical) Sulfate
block assists in micelle formation. (SDS)
Monomer Versatility Low Dispersity End Functionality
or
Nuclear Magnetic Resonance (1H-NMR) - 400 MHz JEOL + 0.45M, 0.60M, 0.80M NaCl
Polymer hydrophobic block resonances observed for broadening.
Wilmes et al. (aqueous)
Increase Include small Growth
Size Exclusion Chromatography (SEC) - Tosoh M0049 GPC hydrophobic hydrophobic
0.50M, 0.75M NaCl
block length molecules
Homopolymer molecular weight and dispersity obtained by Hypothesis: an increase in solvent ionic character of
Gel Permeation Chromatography (GPC) with Shimadzu HPLC. (Hydrophobic Block Collapse Theory)3 a hydrophobic solution will assist in micelle formation
Acknowledgements Hydrophilic Blood
References
Hydrophobic Drug Kawchak, K. M.S. Thesis, commons.emich.edu/cgi/viewcontent.cgi?article=1753&context=theses
Eastern Michigan University Department of Chemistry for research support. www.kevinskawchak.com/Kevin S Kawchak Thesis Eastern Michigan University.pdf
1 Wilmes, G. M.; Arnold, D. J.; Kawchak, K. S. Effect of chain rigidity on block copolymer micelle formation and
Hydrophobic Drug
Eastern Michigan University Office of the Provost for research support. dissolution as observed by 1H-NMR spectroscopy. J. Polym. Res. 2011,18, 1787-1797. http://www.kevinkawchak.com
2 Chiefari, J. et al. Living Free Radical Polymerization by Reversible Addition-Fragmentation Chain Transfer: The
RAFT Process. Macromolecules. 1998, 31, 5559-5562.
EMU Prof. Ruth Ann Armitage and Prof. Heather Holmes - SEC. Hydrophilic Blood 3 Kataoka, K.; Harada, A.; Nagasaki, Y. Block Copolymer micelles for drug delivery: design,
characterization and biological significance. Adv. Drug Deliver Rev. 2001, 47, 113-131.
David Arnold / Cayman Chemical Ann Arbor for SEC support. Medicinal Micelle Model 4 Hayashi, S.; Ikeda, S. Micelle size and shape of sodium dodecyl sulfate in concentrated sodium chloride solutions.
J. Phys. Chem. 1980, 84, 744-751.