Tau Antibody-Conjugated, Photonic Nanoparticle-Based Theranostics for Alzheimer's Disease

Tau 抗体偶联、基于光子纳米粒子的阿尔茨海默病治疗诊断学

• 批准号: 9907449
• 负责人: Anamika Ray
• 金额: $ 26.27万
• 依托单位: INNOSENSE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907449
• 关键词: Alzheimer' s Disease; American; Amyloid beta-Protein; Antibodies; Biological Availability; Blood - brain barrier anatomy; Brain; Carbodiimides; Cerebrospinal Fluid; Chemistry; Clinical; Clinical Trials; Communities; Contrast Media; Coupled; Curcumin; Dementia; Detection; Devices; Disease; Disease Outcome; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Encapsulated; Experimental Designs; Formulation; Human; Image; Impaired cognition; In Vitro; Incidence; Indocyanine Green; Industrialization; Intranasal Administration; Investigation; Kinetics; Manufacturer Name; Masks; Medical; Micelles; Modeling; Monitor; Mucous Membrane; Mus; Nasal cavity; Nerve; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neuronal Dysfunction; Nose; Olfactory Nerve; Oryctolagus cuniculus; PEO-PPO-PEO; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pluronics; Polyethylene Glycols; Polypropylenes; Preparation; Proteins; Regulation; Reproducibility; Route; Safety; Senile Plaques; Severity of illness; Surface; Symptoms; Tauopathies; Texas; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Trigeminal nerve structure; United States Food and Drug Administration; Universities; antibody conjugate; antibody inhibitor; base; biomaterial compatibility; brain pathway; brain tissue; cohort; contrast imaging; copolymer; effective therapy; imaging agent; improved; improved outcome; in vivo Model; nanoparticle; nanosized; neuron loss; olfactory bulb; overexpression; photonics; pre-clinical; prevent; product development; side effect; tau Proteins; tau aggregation; tau mutation; theranostics

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, characterized by both senile plaques composed of Amyloid-β (Aβ) peptide and neurofibrillary tangles (NFTs) composed of tau protein. By 2050, 13 million Americans and 160 million people globally are projected to develop AD. With the increasing incidence of AD and neurodegenerative tauopathies, the need to develop reliable therapies to slow or prevent disease progression is critical. A drug that can halt the progression of AD would improve outcomes for millions of patients. Therefore, InnoSense LLC (ISL) and collaborator, the University of Texas Medical Branch (UTMB), propose to develop CyphonatolTM (indocyanine photonanoparticle for tau oligomers), an AD theranostic using selective tau oligomer antibodies conjugated on photonic nanoparticles (pNP) which are loaded with indocyanine green (ICG) and curcumin (Cur). These nanosized (<50 nm) pNP will be delivered intranasally and will penetrate the blood brain barrier (BBB) without any side effect. Recently, UTMB developed tau soluble oligomer (Tolig) antibodies (Abs) T22 (rabbit polyclonal), and TOMA (mouse monoclonal) targeting Tolig, both showing significant correlation with AD severity. We will conjugate Tolig Ab on the surface of pNP using standard carbodiimide chemistry. This pNP will contain ICG, a near infrared (NIR) imaging agent, and Cur, a well-known drug for pathogenic protein disaggregation. ICG and Cur are Food and Drug Administration (FDA) and Generally Recognized as Safe (GRAS)-approved agents, while the micelles will be formulated from biocompatible, carboxyl-functionalized polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymers. Recently, NIR imaging has raised the importance of long wavelength (650–1450 nm) in illuminating tissue (up to 10 centimeters). The ICG in Cyphonatol will illuminate the tau aggregate in the brain tissue for easy detection and monitoring. In Phase I ISL will validate a proof-of-concept of Cyphonatol pNP formulation for intranasal delivery. We will (1) formulate pNP to contain ICG and Cur, (2) conjugate Tolig-specific Abs on the surface of the pNP to form Cyphonatol, (3) determine the release kinetics and toxicity of Tolig in vitro, (4) establish the feasibility of packaging Cyphonatol in an intranasal delivery device and (5) establish Cyphonatol bioavailability and bioefficacy in a working model. In Phase II, we will (1) expand our study with overexpressing human tau mice (Htau and P301L mice) in a larger cohort and (2) establish reproducibility, stability, pharmacokinetics, and bioefficacy within safe dose. Teaming with the university and industrial partners, ISL will build an efficient Tolig targeting drug to successfully reduce tau aggregation. We anticipate Cyphonatol will be safe, non-toxic, effectively disperse throughout the nasal cavity and reach the olfactory bulb mucosa/nerves. It will penetrate the BBB to target tau aggregates. Cyphonatol will improve AD outcomes by providing a therapy that will slow disease progress and/or cure AD.

项目摘要 阿尔茨海默氏病（AD）是最常见的痴呆形式，其特征在于老年斑 由β淀粉样蛋白（Aβ）肽和tau蛋白组成的神经元缠结（NFT）组成。到2050年， 预计有1300万美国人和全球1.6亿人患有AD。的增加 AD和神经退行性tau蛋白病的发病率，需要开发可靠的疗法来减缓或 预防疾病进展至关重要。一种可以阻止AD进展的药物将改善结果 为数百万患者。因此，InnoSense LLC（ISL）和合作者德克萨斯大学医学院（University of Texas Medical） 分支（UTMB），建议开发Cyphonatol TM（用于tau寡聚体的吲哚菁光子纳米粒子）， 使用缀合在光子纳米颗粒（pNP）上的选择性tau寡聚体抗体的AD治疗诊断， 载有吲哚菁绿色（ICG）和姜黄素（Cur）。这些纳米尺寸（<50 nm）的pNP将是 鼻内给药，可穿透血脑屏障（BBB），无任何副作用。最近， UTMB开发了tau可溶性寡聚体（Tolig）抗体（Abs）T22（兔多克隆）和TOMA（小鼠多克隆）。 单克隆）靶向Tolig，两者均显示与AD严重程度显著相关。我们将Tolig Ab 在pNP的表面上使用标准的碳二亚胺化学。这种pNP将含有ICG，一种近红外 (NIR)成像剂，和Cur，一种众所周知的用于致病蛋白解聚的药物。ICG和Cur是 食品和药物管理局（FDA）和公认安全（GRAS）批准的药物，而 胶束将由生物相容的羧基官能化聚环氧乙烷-聚丙烯 氧化物-聚环氧乙烷（PEO-PPO-PEO）三嵌段共聚物。最近，NIR成像已经提高了 长波长（650-1450 nm）在照射组织（高达10 cm）中的重要性。ICG在 Cyphonatol将照亮脑组织中的tau聚集体，便于检测和监测。 在I期，ISL将验证用于鼻内递送的Cyphonatol pNP制剂的概念验证。我们将 (1)配制pNP以含有ICG和Cur，（2）在pNP的表面上缀合Tolig特异性Ab以形成 （3）测定Tolig的体外释药动力学和毒性;（4）建立 在鼻内递送装置中包装环己那醇，和（5）建立环己那醇的生物利用度， 在工作模型中的生物功效。在第二阶段，我们将（1）扩大我们的研究与过表达人类tau蛋白 小鼠（Htau和P301 L小鼠）的研究，以及（2）建立再现性、稳定性、药代动力学， 安全剂量范围内的生物有效性。与大学和工业合作伙伴合作，ISL将建立一个 有效的Tolig靶向药物，成功减少tau聚集。我们预计赛佛那托会很安全 无毒，有效地分散在整个鼻腔中并到达嗅球粘膜/神经。它将 穿透BBB以靶向tau聚集体。Cyphonatol将通过提供一种治疗方法来改善AD的结局 这将减缓疾病进展和/或治愈AD。