Valency and distance co-optimized peptide bound PEG-b-PPS Filomicelles hydrogel depot for anti-integrin therapeutics

用于抗整合素治疗的效价和距离共同优化的肽结合 PEG-b-PPS Folomicelles 水凝胶储库

• 批准号: 10354427
• 负责人: Divya Rani Bijukumar
• 金额: $ 8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354427
• 关键词: Address; Angiogenic Peptides; Animal Disease Models; Animal Diseases; Animals; Antibodies; Attention; Binding; Biological Assay; Cells; Choroid; Clinical; Clinical Trials; Complication; Crohn' s disease; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Targeting; Drug or chemical Tissue Distribution; Engineering; Ethylenes; Event; Eye; Formulation; Freedom; Future; Generations; Glycols; Goals; Grant; Human; Human Activities; Hydrogels; In Situ; In Vitro; Inflammatory Response; Injections; Integrins; Investigation; Kinetics; Ligands; Malignant Neoplasms; Micelles; Mission; Modeling; National Institute of Allergy and Infectious Disease; National Institute of Biomedical Imaging and Bioengineering; Oryctolagus cuniculus; Outcome; Peptides; Pharmaceutical Preparations; Polymers; Production; Public Health; Publishing; Rattus; Receptor Cell; Research; Retina; Retinal Diseases; Signal Transduction; Sprague-Dawley Rats; Sulfides; Surface; Sustainable Development; System; Technology; Therapeutic; Therapeutic Effect; Thermodynamics; Treatment Efficacy; United States National Institutes of Health; Vascular Endothelial Cell; Work; angiogenesis; base; cellular targeting; cost; density; design; ethylene glycol; improved; in vivo; in vivo Model; innovation; macrophage; molecular size; nanocarrier; nanomaterials; nanomicelles; nanoparticle; nanotherapeutic; new technology; novel; overexpression; peptide drug; pre-clinical; preclinical study; propylene; receptor; receptor expression; side effect; success; targeted treatment; translational approach

1 Project Summary: Anti-integrins are considered as promising alternative for angiogenesis related disease 2 conditions including cancer, Crohn’s, and retinal diseases. However, an optimal nanomaterial design by 3 considering the application and target cell receptor expression is extremely vital for the success of the 4 formulation. Although polymeric nanocarriers have demonstrated considerable potential associated with anti- 5 integrin peptide delivery, the peptide valency and surface distance are rarely co-optimized to enhance 6 therapeutic ligand clustering. Hence, the primary goal of this proposal is to develop and validate a novel 7 bioresponsive hydrogel depot for the sustained delivery of micelles carrying therapeutic peptides at an optimal 8 valency for therapeutic efficacy. A key innovation of this proposal is that we will use self-assembled poly(ethylene 9 glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filomicelles (FM) that use cylinder-to-sphere thermodynamic 10 transitions for sustained in situ generation and delivery of peptide-loaded micelles (MC). In this proposed work, 11 the peptide’s valency and distance from the MC surface will be co-optimized for an efficient therapeutic effect. 12 As proof of concept, the current proposal will use an anti-integrin heptapeptide that showed therapeutic efficiency 13 in vitro using HUVEC cells. With the strong initial results, the objective of the current proposal is to study the 14 mechanistic investigation of the FM-hydrogel depot through in vitro, ex vivo and in vivo investigations and 15 generate preliminary data for future translational grant mechanisms involving appropriate animal disease 16 models. Ex vivo model in this proposal will assist in selecting the optimum formulation and reduce the use of 17 animals and align with the current grant mechanism. The following specific aims will be achieved: 18 AIM 1: Synthesize, optimization and In vitro characterization of FM-depots for the sustained release of MCs 19 displaying a co-optimized surface display of anti-integrin peptide (aANG-P). Aim 1a will address the development 20 of FM-depots with aANG-P constructs, verify control over the MC release rate and confirm that peptide valency 21 and bioactivity remain unchanged following the FM-to-MC transition. Aim 1b will study the inflammatory response 22 induced by FM depot using primary macrophages and confirm of therapeutic activity of the released MC using 23 HUVECs and macrophage cells. 24 AIM 2: Ex vivo and in vivo tissue distribution and bioactivity of aANGP-MC released from aANG-P FM-depots. 25 Aim 2a will study the micellar release kinetics, and tissue distribution from aANGP-FM injected suprachoroidal 26 space of excised rabbit whole eye and study the bioactivity using choroid sprouting assay and CAM assay. Aim 27 2b will confirm the tissue distribution of the aANGP-FM depot using Sprague Dawley rat model and study the 28 inflammatory response after injecting at suprachoroidal space. 29 The overall outcomes of the proposed project will be a nanomaterial-based translational approach that will 30 provide a novel sustained and prolonged release technology for ligand targeted retinal drug delivery which can 31 counter the complication of current technologies, which is a key focus of the NIH/NIBIB mission.

1项目摘要：抗积蛋白被认为是血管生成相关疾病的承诺替代方案 2种疾病，包括癌症，克罗恩斯和残留疾病。但是，由 3考虑应用和靶细胞受体表达对于成功的成功至关重要 4配方奶 5整联蛋白肽的递送，肽的价值和表面距离很少合作以增强 6治疗性配体聚类。因此，该提案的主要目标是开发和验证一种新颖 7个生物辅助水凝胶沉积物，以持续携带治疗性胡椒的胶束的持续输送 8治疗效率的价值。该提案的关键创新是我们将使用自组装的聚（乙烯） 9乙二醇）-b-poly（丙烯硫化物）（PEG-B-PPS）纤维细胞（FM），使用圆柱至球体热力学 10次​​过渡，用于持续的原位产生和加载的胶束（MC）。在这项建议的工作中， 11胡椒的价值和距MC表面的距离将获得有效的治疗效果。 12作为概念证明，当前的提案将使用抗整合蛋白的七肽，显示出治疗效率 13在体外使用HUVEC细胞。有了很强的初步结果，目前的建议的目的是研究 14通过体外，体内和体内调查的FM-Hydrogel沉积机械投资 15生成未来翻译赠款机制的初步数据涉及适当的动物疾病 16个型号。本提案中的离体模型将有助于选择最佳公式并减少使用 17只动物，并与当前的赠款机制保持一致。将实现以下特定目标： 18 AIM 1：合成，优化和体外表征FM-Depots持续释放MCS 19显示抗整合蛋白肽（Aang-P）的合作表面显示。 AIM 1A将解决发展 20具有AANG-P构建体的FM-Depots，验证对MC释放速率的控制并确认肽价 FM到MC转变后，21和生物活性保持不变。 AIM 1B将研究炎症反应 22使用原发性巨噬细胞诱导FM仓库，并使用释放MC的治疗活性。 23个HUVEC和巨噬细胞。 24 AIM 2：在体内和体内组织分布以及AANGP-MC从Aang-P FM-Depots释放的AANGP-MC。 25 AIM 2A将研究胶束释放动力学，以及来自AANGP-FM注射的suphoroidal的组织分布 26卓越空间兔子全眼，并使用脉络膜发芽测定法和CAM分析研究生物活性。目的 27 2b将使用Sprague Dawley大鼠模型确认AangP-FM仓库的组织分布，并研究 28在甲状腺类空间注射后的炎症反应。 29拟议项目的总体结果将是一种基于纳米材料的翻译方法 30为配体靶向视网膜药物提供了一种新颖的持续且延长的释放技术，可以 31应对当前技术的并发症，这是NIH/NIBIB任务的重点。