pubs.acs.org/Macromolecules Published on Web 11/15/2010 r 2010 American Chemical Society Macromolecules 2010, 43, 10017–10030 10017 DOI: 10.1021/ma102044n Preparation and Characterization of Novel Amphiphilic Hydrogels with Covalently Attached Drugs and Fluorescent Markers Caiping Lin † and Ivan Gitsov* ,†,‡,§ † Department of Chemistry, and ‡ The Michael M. Szwarc Polymer Research Institute , College of Environmental Science and Forestry, State University of New York, Syracuse, New York 13210, United States, and § Syracuse Biomaterials Institute, Syracuse, New York 13210, United States Received September 2, 2010; Revised Manuscript Received October 22, 2010 ABSTRACT: This paper describes the synthesis of styrene-based macromonomers with covalently attached model drugs (ibuprofen and naproxen) or fluorescent markers (pyrene) and their incorporation into linear or hyperbranched p-(chloromethyl)styrene copolymers. Alternatively the copolymers were produced by post- polymerization modification of linear or hyperbranched poly[p-(chloromethyl)styrene], PPCMSt, with the same compounds. The incorporation of these copolymers into amphiphilic conetworks was achieved by two methods: Williamson ether synthesis between PPCMSt and poly(ethylene glycol), PEG, with hydroxyl end groups or by nucleophilic substitution between the chloromethyl moieties in PPCMSt and the amine end groups in poly(oxyalkylenediamine), Jeffamine. The dynamic and equilibrium swelling properties were studied on representative Jeffamine hydrogels. The swelling studies showed that the conetworks absorb water quickly and reach equilibrium in 1-2 h, the equilibrium swelling ratio of gels based on linear or hyperbranched copolymer being 181-358% and 244-480%, respectively. Preliminary drug release studies in different aqueous media showed that the release kinetics and the amount of drugs released from hydrogels depend on the physical properties of drugs, the microstructure of polymer network, and the drug-polymer interaction and more particularly on the hydrolysis dynamics of ester linkage between the drug and the polymer matrix. Introduction The development of novel techniques for drug delivery and controlled release is part of the continuing efforts toward more efficient therapeutic strategies. 1-5 In recent years, amphiphilic hydrogels and polymer conetworks have attracted significant attention as promising materials for drug delivery and wide range of other applications due to their unique structure and proper- ties. 6-14 Since the amphiphilic cross-linked materials often contain hydrophilic and hydrophobic chains, they are able to swell in and interact with both aqueous and organic media and under certain conditions they can absorb increased amounts of hydrophobic molecules, which then can be controllably released by application of external stimulus. That is why the creation of new hydrogels of improved binding and release capabilities continues to be extensively pursued. Often the research has been focused on conetworks, consisting of polymers with block structures, which are prepared by copolymerization of comonomers with different hydrophilic/ hydrophobic balance. 15 Alternatively, amphiphilic hydrogels, formed by dendrimers 16 as the cross-linking agents, have been developed by us and other research groups. 17-19 The dendritic conetworks represent interesting substitutes of the traditional systems with their well-defined highly branched and globular domains. In our previous studies we have explored the synthesis of hydrogels based on dendritic poly(benzyl ether)s and linear poly(ethylene glycol)s, PEG. 17,18 The synthetic strategy was based on the reaction of PEG with isocyanate or epoxy end groups as the hydrophilic component and hydrophobic dendritic poly(benzyl ethers) with amino groups at the periphery. The hydrogels obtained had high degree of cross-linking and swelled in both water and organic solvents. In aqueous media these networks were also able to encapsulate pH sensitive stains or model compounds and release them over a period of time, 18b and thus have intriguing potential for biomedical and biotechnological applications. The hyperbranched polymers are imperfect analogues of dendrimers sharing many of their unique characteristics, including the well-defined globular shape and the presence of multiple and modifiable surface and interior functionalities. 20 These proper- ties, combined with the much lower cost, make these macro- molecules attractive dendrimer substitutes for use in biological and pharmaceutical applications. Despite their promising potential the hyperbranched structures have been rarely used as cross-linking agents. In an interesting series, Wooley and co-workers have prepared amphiphilic networks by in situ cross-linking of mixtures, containing hyperbranched fluoropolymer (HBFP) and diamino-terminated PEG. 21-24 The changes in the PEG/HBFP ratio influenced not only the compo- sition, but also the degree of cross-linking and the topology of resulting network. Recently we have shown that another factor, which strongly affects the characteristic properties of the hyper- branched conetworks, is the macromolecular architecture of the hydrophilic and hydrophobic constituents. 25 In this paper, we describe the synthesis and characterization of novel model drug-containing p-chloromethylstyrene derivatives and the copolymerization of these derivatives with p-chloromethyl- styrene to afford new copolymers with covalently attached drugs. They are further combined with PEG or poly(oxyalkylenedia- mine), Jeffamine, to prepare amphiphilic hydrogels via Williamson ether synthesis or nucleophilic substitution. Conetworks of dif- ferent cross-linking densities and hydrophilicity are obtained by varying the amount of the two polymeric components, the archi- tecture, and the molecular weight of the poly(styrene) derivatives. *Corresponding author.