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：抗整合素被认为是血管生成相关疾病的有前途的替代药物 2 种疾病，包括癌症、克罗恩病和视网膜疾病。然而，最佳的纳米材料设计 3 考虑到应用和靶细胞受体表达对于成功至关重要 4配方。尽管聚合物纳米载体已表现出与抗- 5 整合素肽递送，肽价和表面距离很少共同优化以增强 6 治疗配体聚类。因此，该提案的主要目标是开发和验证一种新颖的 7 个生物响应水凝胶库，用于以最佳状态持续递送携带治疗肽的胶束 8价的治疗功效。该提案的一个关键创新是我们将使用自组装聚乙烯 9 乙二醇)-b-聚(丙烯硫醚) (PEG-b-PPS) 丝状胶束 (FM)，采用圆柱到球热力学 10 个转变，用于持续原位生成和递送肽负载胶束 (MC)。在这项拟议的工作中， 11 肽的化合价和距 MC 表面的距离将共同优化，以获得有效的治疗效果。 12 作为概念证明，当前提案将使用显示出治疗效率的抗整合素七肽 13.体外使用HUVEC细胞。有了强有力的初步结果，当前提案的目标是研究 14 通过体外、离体和体内研究对 FM-水凝胶储库进行机械研究 15 为未来涉及适当动物疾病的转化资助机制生成初步数据 16 个型号。该提案中的离体模型将有助于选择最佳配方并减少使用 17 只动物并符合当前的资助机制。将实现以下具体目标： 18 目标 1：用于缓释 MC 的 FM 库的合成、优化和体外表征 图19展示了抗整联蛋白肽(aANG-P)的共同优化的表面展示。目标 1a 将解决发展问题 20 个具有 aANG-P 构建体的 FM-depot，验证对 MC 释放速率的控制并确认肽价 21 和生物活性在 FM 向 MC 转变后保持不变。目标 1b 将研究炎症反应 22 使用原代巨噬细胞由 FM 仓库诱导，并使用使用确认释放的 MC 的治疗活性 23 HUVEC 和巨噬细胞。 24 目标 2：aANGP-MC 从 aANG-P FM 库释放的离体和体内组织分布和生物活性。 25 目标 2a 将研究脉络膜上腔注射 aANGP-FM 的胶束释放动力学和组织分布 摘除兔全眼26孔，采用脉络膜出芽实验和CAM实验研究其生物活性。目的 27 2b 将使用 Sprague Dawley 大鼠模型确认 aANGP-FM 库的组织分布并研究 28 脉络膜上腔注射后的炎症反应。 29 拟议项目的总体成果将是一种基于纳米材料的转化方法，该方法将 30 提供了一种用于配体靶向视网膜药物递送的新型持续和延长释放技术，该技术可以 31 应对当前技术的复杂性，这是 NIH/NIBIB 任务的重点。