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.

项目概要/摘要 目前可用于治疗不可手术的脑癌的治疗方法有限，并且没有 有意义地延长患者的寿命。对这些弥漫性肿瘤进行成像也是一个挑战， 目前的荧光探针发射的波长具有高生物背景荧光。 该提案描述了发射近红外 II 光的新型染料分子的开发 (NIR-II)/短波红外 (SWIR) 区域 (1000 – 2000 nm)。在 NIR-II/SWIR 区域内， 在更长的波长处可以发现更高分辨率的图像。没有小分子发射器有峰值 发射超过 1400 nm，只有一种已知分子的峰值发射 >1250 nm。我们有 保守地初步合成了两种发射最大值的荧光材料 投影在 ~1700 nm 和 >1900 nm 处。这些染料能够进一步观察短波红外 (SWIR) 比任何其他报道的有机小分子区域图像分辨率最高。 此外，我们建议合成比这些发射波长更短的材料 >2000 nm 的材料，建议不断改进成像深度和对比度 根据现有文献。为了有效地将染料分子输送到大脑中，我们 必须将它们封装到纳米载体中。线性树枝状嵌段共聚物 (LDBC) 代表了一种用于药物输送载体的高度功能化材料。其双线性/树枝状 性质使其能够出色地封装各种分子。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盐，以“调整”亲和力 纳米颗粒针对不同的细胞类型。利用这一策略，我们开发了一个 IL 来促进 纳米粒子“搭便车”在红细胞上将其输送到大脑，并实现细胞选择性 一旦小胶质细胞被输送到中央室，就会靶向其。大鼠的初步数据 证明约 48% 的注射纳米粒子在 6 小时内积聚在大脑中，这是一个巨大的结果 改进当前的纳米粒子递送策略。为此，我们将（目标 1）生成 除了我们目前的先导化合物之外，还有一个新颖的 NIR-II 候选化合物库，这些化合物在 1700 – 2000 nm，将它们包装成 LDBC，并用 IL 涂覆纳米颗粒。我们将测量 它们的光物理特性并证实了 IL 赋予小鼠和人类的偏好 血液成分作为潜在的货物载体。 （目标 2）我们将评估安全性（亚急性、急性、 多达 5 种主要制剂在大鼠体内的亚慢性、生殖、致突变）和生物分布， 并捕获高分辨率的实时大脑成像。 （目标 3）主要候选人（基于 CNS 分布和光物理特性）将在异种移植中进行体外和体内评估 胶质母细胞瘤大鼠模型。