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

项目总结/摘要 目前有有限的治疗方法可用于治疗不可手术的脑癌， 有意义地延长病人的寿命。对这些弥漫性肿瘤进行成像也是一个挑战， 并且当前的荧光探针发射具有高生物背景荧光的波长。 该提案描述了新型染料分子的发展，在近红外II发射 （NIR-II）/短波红外（SWIR）区域（1000 - 2000 nm）。在NIR-II/SWIR区域内， 在较长的波长下发现较高分辨率的图像。没有小分子发射体具有峰值 发射超过1400 nm，并且只有一种已知分子具有>1250 nm的峰值发射。我们有 初步合成了两种具有保守发射峰的荧光材料 在约1700 nm和>1900 nm处投影。这些染料提供了进一步观察短波红外线的能力 区域比任何其他报告的有机小分子，其中图像分辨率最高。 此外，我们提出了合成具有比这些更短波长发射的材料， >2000 nm的材料，其中成像深度和对比度都被建议持续改进 根据目前的文献。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。线性-树枝状嵌段共聚物 代表用于药物递送载体的高度官能化的材料。其双重线性/树枝状 大自然使其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（IL），由不对称阳离子和阴离子组成的熔融盐，以“调节" 纳米粒子对不同类型的细胞。使用这种策略，我们开发了一种IL， 纳米颗粒在红细胞上“搭便车”，将它们运送到大脑，并实现细胞选择性 一旦递送到中央室，就靶向小胶质细胞。大鼠的初步数据 显示约48%的注射纳米颗粒在6小时内在大脑中积累，这是一个巨大的 对当前纳米颗粒递送策略的改进。为此，我们将（目标1）生成 一个新的NIR-II候选库，除了我们目前的线索，显示峰值发射在 1700 - 2000 nm，将它们封装到LDBC中，并用离子液体涂覆纳米颗粒。我们将测量 它们的生物物理性质，并确认IL赋予小鼠和人类的偏好 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、致突变）和多达5种主要制剂在大鼠中的生物分布， 并捕捉高分辨率的实时脑成像。(Aim 3）主要候选人（基于CNS 分布和生物物理性质）将在异种移植的小鼠中进行体外和体内评估。 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.