PH SENSITIVE COMPLEX HYDROGEL FOR PROTEIN DRUG RELEASE

通过自由基聚合、紫外光引发和热引发聚合，合成了新型的聚甲基丙烯酸(PMAA)接枝聚乙二醇(PEGg)水凝胶。这些凝胶表现出可逆的、依赖于pH的溶胀行为，这是由于接枝链的酸性侧基和醚基之间形成或解离了聚合物间的络合物。我们实验室以前的实验研究表明，这些凝胶是很有希望的口服蛋白质药物的载体，包括胰岛素。这些输送特性是由于形成了聚合物间络合物，在相对较窄的pH值范围内，网状结构发生了很大的变化。此外，这些凝胶可以用作药物的载体，包括奥普洛尔、丙氧非林、地尔硫卓和博莱霉素，这些药物呈现出一系列的电离特性和溶解度参数，聚合物间络合物的形成有助于保护药物不与聚合物载体结合。这一建议的假设是，正如Lehr最近所表明的那样，由于聚乙二醇链对蛋白质的保护以及结构中PMAA成分表现出的酶抑制，这些接枝到聚乙二醇水凝胶上的水凝胶可以促进蛋白质的传递。另一种假设是，这些载体在肠粘膜上表现出长期的粘附性。因此，这项工作的目标包括优化聚乙二醇接枝水凝胶的结构，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与药物之间的相互作用，以从根本上了解聚合物载体作为蛋白质输送系统的能力。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使用核磁共振波谱进行研究。将进行蛋白质和药物的体外扩散和释放实验。为了分析游离聚乙二醇链锚定在粘膜上的情况，我们将研究这些体系的粘附性。将使用单层Caco-2细胞系来研究蛋白质跨细胞和旁细胞转运的机制。最后，这些新设备的胰岛素输送效率将通过活体实验进行测试。

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.