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项目总结：抗整合素被认为是治疗血管生成相关疾病的有前途的替代方案 2种情况，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是通过 3考虑到应用和靶细胞受体的表达是非常重要的成功的 4配方。尽管聚合物纳米载体已经显示出相当大的潜力与抗- 5整合素多肽递送，多肽的价态和表面距离很少共同优化以增强 6治疗性配体聚集。因此，这项提案的主要目标是开发和验证一部小说 7生物响应性水凝胶库，用于以最佳状态持续输送携带治疗性多肽的胶束 8效价为治疗效果。这项提议的一个关键创新是我们将使用自组装的聚乙烯 9乙二醇)-b-聚丙硫醚(PEG-b-PPS)丝状胶束(FM)，采用柱面-球面热力学 持续原位生成和传递多肽胶束(MC)的10个转变。在这项拟议的工作中， 11多肽的价态和与MC表面的距离将被共同优化，以获得有效的治疗效果。 12作为概念验证，目前的提议将使用显示出治疗效果的抗整合素七肽 13体外培养人脐静脉内皮细胞。鉴于初步结果强劲，目前建议的目标是研究 14通过体外、体外和体内实验对FM-水凝胶库的力学性能进行研究 15为未来涉及适当动物疾病的转译赠款机制生成初步数据 16个型号。本方案中的体外模型将有助于选择最佳处方，并减少使用 17只动物，并与目前的赠款机制保持一致。实现以下具体目标： 18目的1：微球微球缓释载体的合成、优化及体外表征 19展示共优化的抗整合素多肽(Aang-P)表面展示。目标1a将针对这一发展 20个具有Aang-P结构的FM-库，验证对MC释放速率的控制，并确认多肽的价态 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原代巨噬细胞FM库诱导及释放的MC治疗活性的确认 23个人脐静脉内皮细胞和巨噬细胞。 24目的2：从Aang-P FM库中释放的aANGP-MC的体内外组织分布和生物活性。 25目标2a将研究ANGP-FM脉络膜上注射的胶束释放动力学和组织分布 26间隙，用脉络膜发芽实验和细胞黏附分子(CAM)实验研究其生物活性。目标 27 2b将利用SD大鼠模型确定aANGP-FM库的组织分布，并研究 28脉络膜上腔注射后炎症反应。 29拟议项目的总体成果将是一种基于纳米材料的翻译方法，它将 30提供了一种新的配体靶向视网膜药物释放的缓释技术，该技术可以 31应对当前技术的复杂性，这是NIH/NIBIB任务的一个关键重点。