Development of fluorinated dyes for deeper tissue photoacoustic imaging with phase changing nanodroplets

开发用于相变纳米液滴更深组织光声成像的氟化染料

• 批准号: 10439866
• 负责人: Richard R Bouchard
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439866
• 关键词: Address; Adopted; Anatomy; Animal Model; Antibodies; Back; Biodistribution; Breast Cancer Cell; Breast Cancer Model; Cell Culture Techniques; Chelating Agents; Chemical Structure; Clinical; Clinical Trials; Contrast Media; Data; Development; Diagnosis; Dyes; Embryo; Epidermal Growth Factor Receptor; Evaluation; Extravasation; Fluorocarbons; Formulation; Gases; Generations; Heating; Hemoglobin; Image; Ions; Lasers; Life; Light; Lighting; Lipids; Liquid substance; Magnetic Resonance Imaging; Microbubbles; Modality; Molecular; Monitor; Optics; Pathology; Penetration; Peripheral; Phase Transition; Physiologic pulse; Prognosis; Protocols documentation; Publishing; Reproducibility; Research; Resolution; Signal Transduction; System; Technology; Thermodynamics; Thick; Tissues; Toxic effect; Visualization; base; chromophore; clinical application; contrast imaging; cost; cyanine; design; detection limit; early detection biomarkers; imaging approach; improved; in vivo; molecular imaging; molecular marker; mouse model; nanoDroplet; nanoparticle; personalized medicine; phantom model; phase change; photoacoustic imaging; pre-clinical; preclinical imaging; preclinical study; spatiotemporal; tool; triple-negative invasive breast carcinoma

Abstract. Photoacoustic imaging (PAI) is a promising modality that is non-ionizing, low-cost, and offers high- contrast and high-spatiotemporal-resolution imaging in a platform that is amenable for high-throughput preclinical use and for specific clinical applications. However, widespread use of molecular PAI is severely limited by availability of validated contrast agents. Currently available contrast agents either do not have adequate photostability under the pulsed illumination that is required for PAI, lack sufficient PAI-signal-generation ability for deep imaging, or their absorbance spectra significantly overlap with those of hemoglobin, which reduces imaging sensitivity. In order to address these limitations, a new class of PAI contrast agents was proposed that is based on phase-changing perfluorocarbon (PFC) nanodroplets (NDs). These agents are based on a liquid PFC core and a light-absorbing “fuse” in the form of a dye or a nanoparticle. Illumination of these NDs with a pulsed laser triggers liquid-to-gas transition of the PFC core heated by light-absorbing chromophores that results in a very strong PAI signal. Therefore, these agents are often referred to as Laser-Activated NDs (LANDs). Furthermore, after laser excitation PFC microbubbles can re-condense back into their liquid nanodroplet form, which can allow multiple excitations and the possibility for dynamic imaging contrast and super-resolution PAI. However, evaluation of this exciting contrast agent design by multiple research groups revealed one critical limitation – commonly used dye molecules or nanoparticles are not soluble or mixable with perfluorocarbons. Therefore, current LANDs contain their “fuses” (i.e., dye absorbers) in the shell with a loading efficiency and distribution of the dyes that is highly variable depending on specifics of a LAND's coating and a dye's chemical structure. Importantly, in addition to the limitations associated with irreproducibility and a shot shelf-life of LANDs due to leakage of dye molecules from a LAND's shell, recent studies of phase-changing NDs showed the advantage of heating LANDs from within the core for an effective liquid-to-gas transition. These data underline the importance of heating inside an ND's core for activation of LANDs that cannot be effectively achieved with peripherally located chromophores. Here we propose to address weaknesses of the prior research by developing fluorinated dyes with absorbance in the first and second near-infrared tissue windows (NIR-I and NIR-II). Our hypothesis is that the fluorinated dyes will be soluble inside the PFC core, thus resulting in highly reproducible, stable LAND formulations with greatly improved laser activation efficacy. To reflect these advancements in LAND formulation, we refer to PFC NDs doped with fluorinated dyes as enhanced LANDs (eLANDs). We posit that an increase in concentration of uniformly distributed fluorinated dyes inside the PFC core will dramatically improve efficacy of eLAND's activation. Our estimates show that this gain in activation efficacy could be associated with a highly significant (on the order of centimeters) increase in depth sensitivity of PAI with eLANDs; such increase in depth penetration could be a game changer in molecular PAI in pre-clinical and clinical settings.

抽象的。光声成像（PAI）是一种非离子化，低成本的承诺方式，并提供高级 在一个适合高通量临床前的平台中，对比度和高速分辨率成像 使用并用于特定的临床应用。但是，分子PAI的宽度使用受到严重限制 可用性验证造影剂。目前可用的对比代理是否没有足够的 PAI所需的脉冲照明下的光稳定性，缺乏足够的PAI信号能力 对于深层成像或它们的吸光度光谱与血红蛋白的吸收光谱显着重叠，这会减少 成像灵敏度。为了解决这些限制，提出了一类新的PAI对比代理 基于相变的全氟化碳（PFC）纳米光（NDS）。这些试剂基于液体 PFC核心和以染料或纳米颗粒形式的浅色“保险丝”。用 脉冲激光触发PFC核心的液体到气体转变，该核心通过吸收浅色发色团加热 在非常强的PAI信号中。因此，这些药物通常被称为激光激活的ND（土地）。 此外，激光兴奋后PFC微泡可以重新调节其液体纳米圆形形式， 这可以允许多种兴奋以及动态成像对比度和超分辨率PAI的可能性。 但是，多个研究小组对这种令人兴奋的对比代理设计的评估揭示了一个关键 限制 - 常用的染料分子或纳米颗粒不是固体或与全氟化合物混合的。 因此，当前土地以载荷效率和 根据土地涂层的细节和染料化学品的细节，染料的分布高度可变 结构。重要的是，除了与不可夸大性和土地生命相关的限制外 由于染料分子从土地壳中泄漏，最近对变相的NDS的研究表明 从核心内部的加热土地的优势进行有效的液体到气体过渡。这些数据强调 在ND的核心内部加热对于激活无法有效实现的土地的重要性 位于外围的发色团。在这里，我们建议通过开发来解决先前研究的弱点 在第一和第二近红外组织窗（NIR-I和NIR-II）中吸收氟化染料。我们的 假设是氟化染料将在PFC核心内部固体，从而导致高度繁殖， 稳定的土地配方大大提高了激光激活效率。反映这些在土地上的进步 形成，我们将用氟化染料掺杂的PFC NDS称为增强的土地（Elands）。我们指出一个 PFC核心内部均匀分布的氟化染料的浓度增加将显着改善 Eland激活的效率。我们的估计表明，激活效率的增益可能与 高度显着的（在厘米的顺序上）会增加PAI与Elands的深度敏感性；这样的增加 在临床前和临床环境中，深度渗透可能是分子PAI的游戏规则改变者。