PH SENSITIVE COMPLEX HYDROGEL FOR PROTEIN DRUG RELEASE

通过自由基聚合、紫外光引发聚合和热引发聚合合成了聚甲基丙烯酸接枝聚乙二醇水凝胶。 这些凝胶表现出可逆的，pH依赖性的溶胀行为，由于形成或解离的共聚体复合物之间的酸性侧基和醚基团的接枝链。我们实验室以前的实验研究表明，这些凝胶是口服蛋白质药物（包括胰岛素）的有前途的载体。这些递送特性是由于在相对窄的pH值范围内由于互聚物复合物的形成而导致的网络网孔的大的变化。另外，这些凝胶可用作药物的载体，所述药物包括氧烯洛尔、丙茶碱、地尔硫卓和博来霉素，所述药物呈现一系列电离特性和溶解度参数。互聚物复合物的形成用于保护药物免于与聚合物载体结合。该提议的假设是，这些PEG接枝的水凝胶可以促进蛋白质递送，这是由于聚（乙二醇）链对蛋白质的保护以及结构的PMAA组分所表现出的酶抑制，如Lehr最近所示。 另一个假设是，这些载体在肠粘膜上表现出长期粘附。因此，这项工作的目标包括PEG接枝的水凝胶结构的优化，研究蛋白质药物在这些络合网络中的扩散，以及分析水凝胶载体和药物之间的相互作用，以获得对聚合物载体作为蛋白质递送系统的能力的基本理解。将使用NMR光谱研究凝胶中的络合机制以及聚合物和蛋白质之间的相互作用。 将进行蛋白质和药物的体外扩散和释放实验。将研究这些系统的粘膜粘附行为，以分析游离聚（乙二醇）链锚定到粘膜。 将使用单层Caco-2细胞系研究蛋白质转运的跨细胞和细胞旁机制。 最后，将使用体内实验来测试这些新型装置的胰岛素递送功效。

Novel hydrogels of poly(methacrylic acid) (PMAA) grafted with poly(ethylene glycol) (PEG) will be synthesized by free radical, UV-initiated, and thermally initiated polymerizations. These gels exhibit reversible, pH-dependent swelling behavior due to the formation or dissociation of interpolymer complexes between the acidic pendant groups and the ether groups of the grafted chains. Previous experimental studies in our laboratory have shown that these gels are promising carriers for oral delivery of protein drugs, including insulin. These delivery characteristics are due to large changes in the network mesh over a relatively narrow range of pH values due to the formation of the interpolymer complexes. Additionally, these gels can be used as carriers of drugs including oxprenolol, proxyphilline, diltiazem and bleomycin, drugs that present a range of ionization characteristics and solubility parameters, The formation of the interpolymer complexes serves to protect the drugs from binding with the polymeric carrier. The hypothesis of this proposal is that these PEG-grafted hydrogels can promote protein delivery due to protein protection by the poly(ethylene glycol) chains and due to the enzyme inhibition exhibited by the PMAA component of the structure, as recently shown by Lehr. An additional hypothesis is that these carriers exhibit prolonged adhesion on the intestinal mucosa. Therefore, the goals of this work include optimization of the PEG-grafted hydrogel structure, study of the diffusion of protein drugs in these complexation networks, and analysis of the interactions between the hydrogel carrier and the drugs to gain a fundamental understanding of the ability of the polymeric carriers to serve as protein delivery systems. Complexation mechanisms in the gels and interactions between polymers and proteins will be investigated using NMR spectroscopy. In vitro diffusion and release experiments of proteins and drugs will be conducted. The mucoadhesive behavior of these systems will be studied in order to analyze the anchoring of free poly(ethylene glycol) chains to the mucosa. The transcellular and paracellular mechanisms of protein transport will be investigated using monolayer Caco-2 cell lines. Finally, the insulin delivery efficacy of these novel devices will be tested using in vivo experiments.