Brahim Sean, Narinesingh Dyer, Guiseppi-Elie Anthony
Department of Chemical Engineering and Center for Bioelectronics, Biosensors and Biochips (C3B), Virginia Commonwealth University, PO Box 843038, 601 West Main Street, Richmond, Virginia 23284-3038, USA.
Biomacromolecules. 2003 Sep-Oct;4(5):1224-31. doi: 10.1021/bm034048r.
An amphiphilic hydrogel of poly(2-hydroxyethyl methacrylate) cross-linked with tetraethyleneglycol diacrylate (TEGDA) was synthesized to contain the hydrophobic monomer 3-(trimethoxy-silyl) propyl methacrylate (PMA) and the pH-responsive, hydrophilic monomer N',N'-dimethylaminoethyl methacrylate (DMAEMA). The gels were separately loaded with two biomolecular probes, insulin and protamine, via both physical entrapment and equilibrium imbibition methods. The release profiles for these biomolecular probes, possessing similar MW (5.7 and 4-6 kDa, respectively) but different pI's (5.3 and 10.0, respectively), were investigated with respect to variation in the pH of the bathing medium as well as the DMAEMA content, and the cross-link density of the hydrogel. Gels exhibited classical Fickian diffusion release profiles. For a typical gel composition 66:15:10:09 mol % (HEMA:DMAEMA:PMA:TEGDA), as the pH of the release media decreased from 7.3 to 4.0, the rate of release of both biomolecular probes increased. When loaded via entrapment, the insulin release rate increased ca. 4-fold (1.0-3.7 x 10(-7) cm(2) s(-1)), whereas that of protamine increased 10-fold (0.3-3.3 x 10(-7) cm(2) s(-1)). When loaded by imbibition, the insulin diffusion coefficient increased 2-fold (3.8-7.2 x 10(-7) cm(2) s(-1)), whereas that of protamine increased 3-fold (1.9-5.5 x 10(-7) cm(2) s(-1)). The reduction of pH, through its protonation of the gel network, has a more dramatic influence on protamine release, the result of its higher pI (10.0) compared to that of insulin (5.3). As the DMAEMA content of the hydrogel was increased from 0 to 20 mol %, the diffusion coefficient of protamine increased by ca. 7-fold (1.7-12.2 x 10(-7) cm(2) s(-1)), whereas that of insulin increased only ca. 2-fold (1.7-4.0 x 10(-7) cm(2) s(-1)). This differential release confirms the role of internal protonation in effecting the greater release of the protonated drug molecule. Increasing the TEGDA content from 3 to 15 mol % reduced the diffusion coefficient ca. 3-fold for insulin (1.6-0.5 x 10(-7) cm(2) s(-1)) and 5-fold for protamine (4.0-0.8 x 10(-7) cm(2) s(-1)). The final D(ip) at 15 mol % TEGDA suggests that the smaller mesh size offsets any differential release that arises from protonation. The presence of PMA in the hydrogel formulation, which contributes additional cross-links by reason of the formation of siloxane macromers, did not change the usually observed Fickian diffusion mechanism.
合成了一种由聚甲基丙烯酸2-羟乙酯与二缩四乙二醇二丙烯酸酯（TEGDA）交联而成的两亲性水凝胶，其中含有疏水性单体甲基丙烯酸3-（三甲氧基甲硅烷基）丙酯（PMA）和pH响应性亲水性单体甲基丙烯酸N'，N'-二甲基氨基乙酯（DMAEMA）。通过物理包埋和平衡吸胀两种方法，将两种生物分子探针胰岛素和鱼精蛋白分别载入凝胶中。研究了这些生物分子探针（分子量相似，分别为5.7和4-6 kDa，但等电点不同，分别为5.3和10.0）在不同pH值的浴液介质、DMAEMA含量以及水凝胶交联密度下的释放曲线。凝胶呈现出典型的菲克扩散释放曲线。对于典型的凝胶组成66:15:10:09摩尔%（甲基丙烯酸2-羟乙酯：甲基丙烯酸N'，N'-二甲基氨基乙酯：甲基丙烯酸3-（三甲氧基甲硅烷基）丙酯：二缩四乙二醇二丙烯酸酯），随着释放介质的pH值从7.3降至4.0，两种生物分子探针的释放速率均增加。通过包埋载入时，胰岛素的释放速率增加了约4倍（从1.0-3.7×10⁻⁷ cm² s⁻¹），而鱼精蛋白的释放速率增加了10倍（从0.3-3.3×10⁻⁷ cm² s⁻¹）。通过吸胀载入时，胰岛素的扩散系数增加了2倍（从3.8-7.2×10⁻⁷ cm² s⁻¹），而鱼精蛋白的扩散系数增加了3倍（从1.9-5.5×10⁻⁷ cm² s⁻¹）。pH值降低通过使凝胶网络质子化，对鱼精蛋白的释放影响更为显著，这是因为其等电点（10.0）高于胰岛素（5.3）。随着水凝胶中DMAEMA含量从0增加到20摩尔%，鱼精蛋白的扩散系数增加了约7倍（从1.7-12.2×10⁻⁷ cm² s⁻¹），而胰岛素的扩散系数仅增加了约2倍（从1.7-4.0×10⁻⁷ cm² s⁻¹）。这种差异释放证实了内部质子化在促进质子化药物分子更大释放方面的作用。将TEGDA含量从3摩尔%增加到15摩尔%，胰岛素的扩散系数降低了约3倍（从1.6-0.5×10⁻⁷ cm² s⁻¹），鱼精蛋白的扩散系数降低了5倍（从4.0-0.8×10⁻⁷ cm² s⁻¹）。在TEGDA含量为15摩尔%时的最终扩散系数表明，较小的网孔尺寸抵消了由质子化引起的任何差异释放。水凝胶配方中PMA的存在，由于形成硅氧烷大分子而有助于额外的交联，但并未改变通常观察到的菲克扩散机制。
