Impact of Microgel Morphology on Functionalized Microgel-Drug Interactions Todd Hoare* and Robert Pelton Department of Chemical Engineering McMaster UniVersity 1280 Main St. W., Hamilton, Ontario, Canada L8S 4L7 ReceiVed August 8, 2007. In Final Form: September 18, 2007 The interactions of a range of water-soluble drugs of different charges and hydrophobicities with carboxylic acid- functionalized poly(N-isopropylacrylamide)-based microgels containing different functional group distributions are investigated to determine the impact of drug properties and microgel morphologies on drug uptake and release. The radial distribution of carboxylic acid functional groups in the microgel and the hydrophobicities of the cationic drugs both strongly affect drug partitioning between the solution and microgel phases. Microgels with surface-localized functional group distributions bind less cationic drug than bulk-functionalized microgels, likely due to the formation of a locally collapsed “skin layer” at the acid-base drug binding sites at the microgel surface. In this way, cationic drugs induce a local phase transition that can be used to regulate small molecule diffusion in and out of the gel. As the drug hydrophobicity is increased, the skin layer becomes more condensed and less drug uptake is achieved. In the case of anionic or neutral drugs, high drug uptakes are achieved independent of the functional group distribution within the microgel. High drug uptake is also observed when nonfunctionalized poly(N-isopropylacrylamide) microgels are used as the uptake matrix, suggesting the importance of hydrophobic partitioning in regulating drug-microgel interactions. Introduction Poly(N-isopropylacrylamide) (PNIPAM) microgels function- alized with carboxylic acid functional groups exhibit reversible volumetric swelling responses to the application of both thermal and pH stimuli. 1 As a result, PNIPAM-based microgels hold considerable potential in applications that demand environmen- tally triggered changes in gel hydrophobicity, pore size, or net charge for optimal functionality. Indeed, many proof-of-concept investigations have illustrated the potential of PNIPAM-based microgels in a range of environmental and biomedical applications. 2-10 However, the effective use of microgels in such applications depends on the optimization of both the chemical composition and the physical morphologies of the microgels according to each specific end use. For microgels containing reactive and/or ionizable functional groups, the radial and intrachain distributions of functional groups within the three- dimensional microgel network are particularly important. This is especially true for applications that rely on the specific interactions between the functional groups and other chemicals in the microgel environment. Previous studies investigating the uptake or partitioning of small molecules and macromolecules into bulk hydrogels have emphasized the importance of both the size and charge density of the target molecule as well as the number and distribution of functional monomers within the hydrogel network in regulating the uptake efficiency. 11,12 The potential of PNIPAM-based microgels as injectable drug delivery vehicles was first illustrated by Snowden using acetylsalicylic acid 13 and fluorescein-labeled dextran 14 as model compounds. The binding and release of macromolecules using PNIPAM-based microgels has since been demonstrated for both insulin 15 and bovine serum albumin. 16,17 A variety of microgel assembly approaches have also been used to construct microgel- based drug delivery devices, including polyelectrolyte-assembled microgel thin films, 18,19 surface-grafted microgel monolayers, 20 and bulk hydrogels comprised of cross-linked microgel particles. 21 However, up to this point, the morphologies of the microgels used in these applications have not been specifically controlled in order to engineer microgel properties to best suit the needs of the particular application. Such work is highly relevant, however, given that Eichenbaum et al. have shown that both the * To whom correspondence should be addressed. Telephone: (905) 525- 9140, ext. 27045. Fax: (905) 528-5114. E-mail: hoaretr@mcmaster.ca. (1) For example, (a) Zhou, S.; Chu, B. J. Phys. Chem. B 1998, 102, 1364- 1371. (b) Snowden, M. J.; Chowdhry, B. 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Controlled Release 2004, 94, 303-311. 1005 Langmuir 2008, 24, 1005-1012 10.1021/la7024507 CCC: $40.75 © 2008 American Chemical Society Published on Web 01/08/2008