Biomacromolecules 2003, 4, 864-868
864
Synthesis of Biocompatible, Stimuli-Responsive, Physical Gels Based on ABA Triblock Copolymers Yinghua Ma, Yiqing Tang, Norman C. Billingham, and Steven P. Armes* School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer, Brighton BN1 9QJ, U.K.
Andrew L. Lewis Biocompatibles, Chapman House, Farnham Business Park, Weydon Lane, Farnham, Surrey GU9 8QL, U.K. Received April 16, 2003; Revised Manuscript Received May 19, 2003
ABA triblock copolymers [A ) 2-(diisopropylamino)ethyl methacrylate), DPA or 2-(diethylamino)ethyl methacrylate), DEA; B ) 2-methacryloyloxyethyl phosphorylcholine, MPC] prepared using atom transfer radical polymerization dissolve in acidic solution but form biocompatible free-standing gels at around neutral pH in moderately concentrated aqueous solution (above approximately 10 w/v % copolymer). Proton NMR studies indicate that physical gelation occurs because the deprotonated outer DPA (or DEA) blocks become hydrophobic, which leads to attractive interactions between the chains: addition of acid leads to immediate dissolution of the micellar gel. Release studies using dipyridamole as a model hydrophobic drug indicate that sustained release profiles can be obtained from these gels under physiologically relevant conditions. More concentrated DPA-MPC-DPA gels give slower release profiles, as expected. At lower pH, fast, triggered release can also be achieved, because gel dissolution occurs under these conditions. Furthermore, the nature of the outer block also plays a role; the more hydrophobic DPA-MPC-DPA triblock gels are formed at lower copolymer concentrations and retain the drug longer than the DEA-MPC-DEA triblock gels. The phosphorylcholine motif is an important component of cell membranes, and it is well-known that synthetic phosphorylcholine-based polymers can be used to produce surface coatings that are remarkably resistant to protein adsorption and bacterial/cellular adhesion.1,2 Based on this “bio-inspired” approach, various biomedical devices and implants with clinically proven enhanced biocompatibility have been developed over the past decade, including high performance surgical stents and extended-wear contact lenses.3 Usually, such coatings incorporate phosphorylcholine-containing vinyl monomers such as 2-methacryloyloxyethyl phosphorylcholine [MPC] and rely on conventional free radical polymerization chemistry to produce either statistical copolymers or macromonomers.4 We recently reported that atom transfer radical polymerization (ATRP)5 can be used for the controlled polymerization of MPC in either water or methanol under mild conditions.6 Herein, we describe the synthesis of novel, biocompatible pH-responsive gelators7 based on ABA triblock copolymers, where the central B block comprises MPC and the outer A blocks are composed of 2-(diisopropylamino)ethyl methacrylate (DPA), see Figure 1. A typical synthesis of a DPA-MPC-DPA triblock copolymer was carried out as follows. The MPC (>99% purity, donated by Biocompatibles, U.K.) was polymerized in methanol at 20 °C using standard Schlenk techniques with * To whom correspondence should be addressed.
a Cu(I)Br/2bpy catalyst as reported previously,6 using a commercially available bifunctional ATRP initiator (diethyl meso-2,5-dibromoadipate, obtained from Aldrich). After 4-5 h, the MPC conversion was typically more than 96% as judged by 1H NMR, and in each case, the MPC homopolymer obtained had a relatively low polydispersity (Mw/Mn ) 1.12-1.20) vs poly(ethylene oxide) standards. Then the DPA monomer was added to the dark brown reaction solution. After 24-48 h, the reaction solution was passed through a silica gel column to remove the spent ATRP catalyst, which resulted in the loss of around 10% copolymer because of adsorption onto the silica. After solvent evaporation, the solid copolymer was washed with excess n-hexane to remove any traces of residual DPA monomer and then freeze-dried overnight. The residual Cu catalyst levels in the DPA-MPC-DPA triblocks were determined to be approximately 1-2 ppm using inductively coupled plasma atomic emission spectroscopy [IEP-AAS], as described previously.6b The degree of polymerization, Dp, of each block was controlled by the initial monomer/initiator molar ratio. A summary of the various triblock compositions and molecular weight data are given in Table 1. Polydispersities of the initial MPC homopolymers prior to the addition of the DPA comonomer were typically less than 1.20, which is in good agreement with our earlier results and confirms the excellent living character of this first-stage polymerization.6 Final
10.1021/bm034118u CCC: $25.00 © 2003 American Chemical Society Published on Web 06/26/2003
Biomacromolecules, Vol. 4, No. 4, 2003 865
Communications
Figure 1. Reaction scheme for the synthesis of the DPA-MPC-DPA triblock copolymers via Atom Transfer Radical Polymerization (ATRP) using a commercially available bifunctional ATRP initiator. Table 1. Summary of the Triblock Compositions, Molecular Weight Data, and Gelation Behavior of the Various DPA-MPC-DPA and DEA-MPC-DEA Triblock Copolymers Investigated in This Study Mn reaction time (h) target ABA triblock composition
homo
ABA triblock
DPA30-MPC100-DPA30 DPA50-MPC100-DPA50 DPA30-MPC200-DPA30 DPA50-MPC200-DPA50 DPA80-MPC200-DPA80 DPA50-MPC250-DPA50 DPA30-MPC300-DPA30 DPA50-MPC300-DPA50 DPA100-MPC300-DPA100 DEA50-MPC250-DEA50 DEA100-MPC250-DEA100
3.5 3.5 4.0 4.0 4.0 4.5 5.0 5.0 5.0 4.5 4.5
20 24 24 30 36 36 30 36 48 30 48
conversion, %
Mw/Mn (GPC)
homo
ABA triblock
homo (GPC)
ABA triblock (GPC)
ABA triblock (theory)
homo
ABA triblock
residual Cu by ICP-AES/ppm
>99 >99 >98 >98 >98 >98 >96 >96 >96 >98 >98
>99 >99 >99 >98 >98 >98 >98 >98 >97 >98 >98
29 000 29 000 56 000 55 000 56 000 68 000 82 000 82 000 82 000 68 000 68 000
49 000 61 000 105 000 129 000 131 000 130 000 136 000 149 000 166 000 103 000 111 000
43 000 51 000 72 000 81 000 94 000 96 000 102 000 111 000 132 000 93 000 100 000
1.12 1.10 1.14 1.14 1.16 1.16 1.18 1.16 1.20 1.17 1.16
1.51 1.54 1.61 1.68 1.70 1.63 1.72 1.79 1.80 1.62 1.71
