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

项目摘要/摘要 目前可用于治疗不可手术的脑癌的治疗方法有限，而且还没有 这有意义地延长了患者的寿命。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较高的生物背景荧光。 本提案描述了在近红外II中发射的新型染料分子的发展。 (NIR-II)/短波红外(SWIR)区(1000-2000 nm)。在NIR-II/SWIR区域内， 更高分辨率的图像在更长的波长上被发现。没有小分子发射体有峰值 超过1400 nm的发射，只有一个已知分子有峰值发射&gt；1250 nm。我们有 保守地合成了两种具有最大发射峰的荧光材料 投影在~1700 nm和&gt；1900 nm处。这些染料提供了进一步观察SWIR的能力 图像分辨率最高的任何其他有机小分子的区域。 此外，我们还建议合成发射波长比这些更短的材料。 建议继续提高成像深度和对比度的材料&gt；2000 nm 基于当前的文献。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。线状树枝状嵌段共聚物(LDBC) 是一种用于药物输送载体的高度功能化材料。它的对偶线性/树枝状结构 大自然使它在封装各种分子方面表现出色。我们使用生物相容的离子 液体(ILS)，由不对称阳离子和阴离子组成的熔融盐类，用于调节 不同细胞类型的纳米粒子。使用这一策略，我们开发了一种IL，以促进 纳米颗粒在红细胞上搭便车，将其运送到大脑，实现细胞选择性 一旦小胶质细胞被送到中央隔室，靶向就会发生。大鼠的初步数据 证明注射的纳米颗粒中约48%在6小时内在大脑中积累，这是一个巨大的 对目前纳米颗粒输送策略的改进。为此，我们将(目标1)生成 除了我们目前的引线外，还有一个新的NIR-II候选库，显示出峰值发射在 1700-2000 nm，将其封装成LDBC，并用ILS包覆纳米颗粒。我们将衡量 它们的光物理性质，并证实了ILS对小鼠和人类的偏好 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、 亚慢性、生殖性、致突变性)和最多5种主要配方在大鼠体内的生物分布， 并捕捉到高分辨率的实时大脑成像。(目标3)主要候选人(根据CNS 分布和光物理性质)将在体外和体内异种移植 胶质母细胞瘤大鼠模型。

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.