Ionic Liquid-Coated NIR-II Polymer Conjugates as Targeted Brain Theranostics

离子液体涂层 NIR-II 聚合物缀合物作为靶向脑治疗诊断

• 批准号: 10588717
• 负责人: Davita L. Watkins
• 金额: $ 54.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588717
• 关键词: Acute; Adult; Affinity; Anions; Astrocytes; Behavior; Biodistribution; Biological; Bioluminescence; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Cancerous; Catheters; Cations; Cell Death; Cells; Charge; Coculture Techniques; Data; Development; Diagnosis; Diffuse; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Dyes; Encapsulated; Erythrocytes; Excision; Fluorescence; Fluorescent Probes; Formulation; Glioblastoma; Glioma; Goals; Growth; Hemolysis; Hour; Human; Hydrophobicity; Image; Immune Sera; Immune response; In Vitro; Incubated; Injections; Intracarotid; Lasers; Libraries; Light; Liquid substance; Literature; Longevity; Luciferases; Malignant neoplasm of brain; Measures; Mediating; Microglia; Modality; Modeling; Monitor; Mus; Nature; Neuroimmune; Noise; Organ; Organic Synthesis; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Polymers; Property; Rattus; Reporting; Resolution; Route; Safety; Salts; Signal Transduction; Slice; Specificity; Stains; Surface; Technology; Temperature; Tissues; Visualization; Water; Work; Xenograft procedure; base; bioimaging; biomaterial compatibility; brain tissue; cell type; chemotherapy; copolymer; delivery vehicle; fluorescence imaging; frontal lobe; high resolution imaging; hydrophilicity; improved; in vitro Model; in vivo; in vivo Model; lead candidate; light scattering; liquid formulation; molecular imaging; nanocarrier; nanoparticle; nanoparticle delivery; nanotheranostics; neoplastic cell; nervous system disorder; neuro-oncology; novel; particle; patient prognosis; preference; reproductive; small molecule; theranostics; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT There are currently limited treatments available to treat non-operable brain cancers, and none that meaningfully extend the lifespan of patients. Imaging these diffuse tumors is also a challenge, and current fluorescent probes emit in wavelengths with high biological background fluorescence. This proposal describes the development of novel dye molecules that emit in the near-infrared II (NIR-II)/shortwave infrared (SWIR) region (1000 – 2000 nm). Within the NIR-II/SWIR region, higher resolution images are found at longer wavelengths. No small molecule emitters have peak emission beyond 1400 nm and only one known molecule has peak emission >1250 nm. We have preliminarily synthesized two fluorescent materials with emission maxima conservatively projected at ~1700 nm and >1900 nm. These dyes offer the ability to see further into the SWIR region than any other reported organic small molecules where image resolution is the highest. Additionally, we proposed to synthesize materials with shorter wavelength emission than these materials >2000 nm where imaging depth and contrast both are suggested to continually improve based on the current literature. In order to effectively deliver the dye molecules into the brain, we have to encapsulate them into nanocarriers. Linear-dendritic block-copolymers (LDBCs) represent a highly functionalizable material for drug delivery vehicles. Its dual linear/dendritic nature makes it excellent at encapsulating a variety of molecules. We use biocompatible ionic liquids (ILs), molten salts comprised of asymmetric cations and anions, to `tune' the affinity of nanoparticles to different cell types. Using this strategy, we have developed an IL that promotes nanoparticle `hitchhiking' on erythrocytes to deliver them to the brain, and achieves cell-selective targeting of microglia once delivered to the central compartment. Preliminary data in rats demonstrate ~48% of injected nanoparticles accumulating in the brain within 6 hours, a vast improvement over current nanoparticle delivery strategies. To this end, we will (Aim 1) generate a library of novel NIR-II candidates, in addition to our current leads, that show peak emission at 1700 – 2000 nm, package them into LDBCs, and coat the nanoparticles with ILs. We will measure their photophysical properties and confirm the preference that ILs confer to murine and human blood components as potential cargo carriers. (Aim 2) We will assess the safety (subacute, acute, subchronic, reproductive, mutagenic) and biodistribution of up to 5 leading formulations in rats, and capture high-resolution live brain imaging. (Aim 3) Lead candidates (based on CNS distribution and photophysical properties) will be assessed in vitro and in vivo in a xenografted glioblastoma rat model.

项目摘要/摘要 目前有有限的治疗方法可用于治疗不可接受的脑癌，没有 这有意义地延长了患者的寿命。成像这些弥漫性肿瘤也是一个挑战， 当前的荧光问题在具有高生物背景荧光的波长中散发出来。 该建议描述了在近红外II中发出的新型染料分子的发展 （NIR-II）/短波红外（SWIR）区域（1000 - 2000 nm）。在NIR-II/SWIR地区， 在更长的波长下发现较高的分辨率图像。没有小的分子发射器具有峰值 1400 nm以上的发射，只有一个已知的分子的峰值发射> 1250 nm。我们有 初步合成具有发射最大值的两种荧光材料 预计在〜1700 nm和> 1900 nm。这些染料提供了进一步看到Swir的能力 区域比任何其他报道的有机小分子，其中图像分辨率最高。 此外，我们提议合成具有较短波长发射的材料 材料> 2000 nm，其中成像深度和对比度都被建议不断改进 基于当前的文献。为了有效地将染料分子传递到大脑中，我们 必须将它们封装成纳米载体。线性树枝状聚合物（LDBC） 代表了药物输送车的高度功能化材料。它的双线性/树突状 大自然使其在封装各种分子方面非常出色。我们使用生物相容性离子 液体（IL），由不对称阳离子和阴离子组成的熔融盐，以“调整”的亲和力 纳米颗粒到不同的细胞类型。使用此策略，我们开发了一个促进的IL 红细胞上的纳米颗粒“搭便车”以将其输送到大脑中，并实现细胞选择性 小胶质细胞的靶向后，一旦输送到中央车厢。大鼠的初步数据 证明约48％的注射纳米颗粒在6小时内积聚在大脑中，有利 改善当前纳米颗粒输送策略。为此，我们将（AIM 1）生成 除我们当前的潜在客户外，新型NIR-II候选人的库还显示 1700 - 2000 nm，将它们包装成马利亚国外，并用ILS将纳米颗粒涂上。我们将衡量 它们的光物理特性，并确认ILS赋予鼠和人类的偏好 血液成分作为潜在的货物载体。 （AIM 2）我们将评估安全性（亚急性，急性， 亚慢性，生殖，诱变）和大鼠多达5个主要公式的生物分布， 并捕获高分辨率的活脑成像。 （AIM 3）主要候选人（基于CNS 分布和光物理特性）将在异种移植中评估体外和体内 胶质母细胞瘤大鼠模型。