PH SENSITIVE COMPLEX HYDROGEL FOR PROTEIN DRUG RELEASE

用于蛋白质药物释放的 PH 敏感复合水凝胶

• 批准号: 6385966
• 负责人: NICHOLAS A PEPPAS
• 金额: $ 29.75万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6385966
• 关键词: acidity /alkalinity; carbonates; cell adhesion; chemical structure; copolymer; drug delivery systems; drug design /synthesis /production; ethylene glycols; gel; hydropathy; insulin; intermolecular interaction; intestinal mucosa; laboratory rat; nuclear magnetic resonance spectroscopy; peptides; pharmacokinetics; polymerization; polymers; polymethacrylate; protein transport; tissue /cell culture

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.

本文将通过自由基聚合、紫外引发聚合和热引发聚合三种方式合成聚甲基丙烯酸（PMAA）接枝聚乙二醇（PEG）的新型水凝胶。这些凝胶表现出可逆的、ph依赖的膨胀行为，这是由于接枝链的酸性悬垂基团和醚基团之间的聚合物间配合物的形成或解离。我们实验室之前的实验研究表明，这些凝胶是口服蛋白质药物（包括胰岛素）的有希望的载体。这些传递特性是由于在相对较窄的pH值范围内，由于聚合物间络合物的形成，网状物发生了很大的变化。此外，这些凝胶可以作为药物的载体，包括奥普那洛尔、普罗菲林、地尔硫卓和博来霉素，这些药物具有一系列的电离特性和溶解度参数。聚合物间复合物的形成有助于保护药物不与聚合物载体结合。该提议的假设是，这些peg接枝的水凝胶可以促进蛋白质的递送，这是由于聚乙二醇链对蛋白质的保护，以及由于结构的PMAA成分所表现出的酶抑制，正如Lehr最近所表明的那样。另一种假设是，这些载体在肠粘膜上表现出长时间的粘附。因此，本工作的目标包括优化peg接枝的水凝胶结构，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。凝胶中的络合机制和聚合物与蛋白质之间的相互作用将使用核磁共振波谱进行研究。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在粘膜上的锚定作用，我们将研究这些系统的黏附行为。利用单层Caco-2细胞系研究蛋白质转运的跨细胞和细胞旁机制。最后，这些新型装置的胰岛素输送效果将通过体内实验进行测试。

项目成果

Highly crosslinked, PEG-containing copolymers for sustained solute delivery.

• DOI: 10.1016/s0142-9612(99)00040-x
• 发表时间: 1999-08
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Robert A. Scott;N. Peppas

Building vascular networks.

• DOI: 10.1126/scitranslmed.3003688
• 发表时间: 2012-11-14
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Bae H;Puranik AS;Gauvin R;Edalat F;Carrillo-Conde B;Peppas NA;Khademhosseini A
• 通讯作者: Khademhosseini A

α-Galactosylceramide and peptide-based nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma.

• DOI: 10.1016/j.actbio.2018.06.029
• 发表时间: 2018-08
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Sainz V;Moura LIF;Peres C;Matos AI;Viana AS;Wagner AM;Vela Ramirez JE;S Barata T;Gaspar M;Brocchini S;Zloh M;Peppas NA;Satchi-Fainaro R;F Florindo H
• 通讯作者: F Florindo H

A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets.

• DOI: 10.1021/js9802291
• 发表时间: 1999
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: J. Siepmann;J. Siepmann;Kairali Podual;M. Sriwongjanya;N. Peppas;R. Bodmeier

FTIR spectroscopic investigation and modeling of solute/polymer interactions in the hydrated state.

水合状态下溶质/聚合物相互作用的 FTIR 光谱研究和建模。

• DOI: 10.1163/156856299x00081
• 发表时间: 1999
• 期刊: Journal of biomaterials science. Polymer edition
• 作者: amEnde,MT;Peppa,NA
• 通讯作者: Peppa,NA