Delivery of Agents by Modulating Junctions with Zot

通过使用 Zot 调节连接点来交付代理

• 批准号: 6734595
• 负责人: NATALIE D EDDINGTON
• 金额: $ 25.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6734595
• 关键词: biological transport; blood brain barrier; cyclosporines; enterotoxins; enzyme linked immunosorbent assay; high performance liquid chromatography; immunocytochemistry; insulin; intercellular connection; inulin; laboratory rat; mannitol; paclitaxel; pharmacokinetics; polymerase chain reaction; protein structure function; radiography; tight junctions; tissue /cell culture

DESCRIPTION (provided by applicant): The identification of potent macromolecules is increasing at a staggering rate, however many are not delivered effectively due to physiochemical limitations. A viable approach to drug delivery may be to exploit the physiological regulation of intercellular tight junctions, to enhance paracellular drug transport. We have recently demonstrated that Zonula Occludens Toxin (Zot) Zot, a 45kDa protein, exerts its permeating effect by mimicking a eukaryotic analogue in charge of modulation of intercellular tight junctions This technology allows for enhanced paracellular flux and has the potential to effectively deliver low bioavailable therapeutic macromolecules. Thus our hypothesis is that the Zot technology can enhance drug delivery by reversibly opening tight cellular junctions via oral, BBB and nasal delivery. The following specific aims will be pursued. SAI. To define the structure-function relationships between the major domains of Zot and regulation of the transepithelial/endothelial paracellular pathway. SA2. To determine the dose response, pharmacokinetics (PK) and acute toxicity of Zot. We will define the complete dose-response profile of the Zot (or derivative) in vivo. SA3. To examine the ability of Zot to enhance the oral bioavailability of the hydrophilic agents (mannitol, inulin) and therapeutic macromolecules (insulin, cyclosporin A, paclitaxel). Preliminary data displays that Zot enhances oral absorption of therapeutic molecules. SA4. To examine the ability of Zot to enhance the BBB delivery of the minimally transported CNS therapeutic macromolecules. Zonulin, the ligand for the Zot receptor has been found in the brain and data has shown that Zot enhances the BBB delivery of therapeutic agents (doxorubicin, inulin, acyclovir). SA5. To examine the ability of Zot to act as a novel mucosal adjuvant that enhances the systemic bioavailability of large molecular weight therapeutic macromolecules (e.g., peptides, Protective antigen to B. anthracis) after nasal delivery. Zot has been found to significantly enhance the production of tetanus toxin (TT) antibodies after nasal delivery. The in vivo studies proposed for SA 3-5 will evaluate the ability of Zot to enhance the systemic levels of structurally diverse therapeutic macromolecules. The potential impact of the Zot technology is significant and comprehensive, since it may be applied to delivering a diversified range of macromolecules to their targets via oral, BBB or nasal delivery.

描述（由申请人提供）：有效大分子的鉴定正在以惊人的速度增加，但由于物理化学限制，许多大分子无法有效递送。一种可行的药物输送方法可能是利用细胞间紧密连接的生理调节来增强细胞旁药物转运。我们最近证明，闭锁小带毒素 (Zot) Zot（一种 45kDa 的蛋白质）通过模仿负责调节细胞间紧密连接的真核类似物来发挥其渗透作用。该技术可以增强细胞旁通量，并有可能有效提供低生物利用度的治疗性大分子。因此，我们的假设是，Zot 技术可以通过口服、血脑屏障和鼻腔递送可逆地打开紧密的细胞连接来增强药物递送。将追求以下具体目标。赛伊。定义 Zot 主要结构域与跨上皮/内皮细胞旁路通路调节之间的结构-功能关系。 SA2。确定 Zot 的剂量反应、药代动力学 (PK) 和急性毒性。我们将定义 Zot（或衍生物）在体内的完整剂量反应曲线。 SA3。检测 Zot 增强亲水剂（甘露醇、菊粉）和治疗性大分子（胰岛素、环孢素 A、紫杉醇）口服生物利用度的能力。初步数据显示，Zot 可以增强治疗分子的口服吸收。 SA4。检测 Zot 增强最低限度转运的中枢神经系统治疗大分子的 BBB 递送的能力。 Zonulin 是 Zot 受体的配体，已在大脑中被发现，数据表明 Zot 可以增强治疗药物（阿霉素、菊粉、阿昔洛韦）的血脑屏障输送。 SA5。检测 Zot 作为新型粘膜佐剂的能力，增强大分子量治疗性大分子（例如肽、炭疽杆菌保护性抗原）鼻腔给药后的全身生物利用度。人们发现，经鼻分娩后，Zot 可显着增强破伤风毒素 (TT) 抗体的产生。针对 SA 3-5 提出的体内研究将评估 Zot 增强结构多样的治疗性大分子的全身水平的能力。 Zot 技术的潜在影响是重大且全面的，因为它可用于通过口服、BBB 或鼻腔递送将多种大分子递送至目标。