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)是一种很有前途的非电离、低成本、高分辨率的成像方式。 支持高通量临床前研究的平台中的对比度和高时空分辨率成像 用于特定的临床应用。然而，分子PAI的广泛使用受到以下因素的严重限制 有效造影剂的可用性。目前可用的造影剂要么没有足够的 PAI所需的脉冲光照下的光稳定性，缺乏足够的PAI信号产生能力 对于深度成像，或者它们的吸收光谱与血红蛋白的吸收光谱显著重叠，这降低了 成像灵敏度。为了解决这些限制，一种新的PAI造影剂被提出，它 是基于相变全氟碳(PFC)纳米液滴(NDS)。这些药剂是基于一种液体 PFC核心和以染料或纳米颗粒形式的光吸收“保险丝”。为这些NDS提供照明 脉冲激光触发由光吸收发色团加热的PFC堆芯的液-气转变，从而导致 在一个非常强烈的PAI信号中。因此，这些试剂通常被称为激光激活的NDS(LAND)。 此外，在激光激发后，PFC微泡可以重新凝聚成其液体纳米液滴的形式， 它可以允许多个激发，并有可能实现动态成像对比度和超分辨率PAI。 然而，多个研究小组对这一令人兴奋的造影剂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能溶解或与全氟碳化合物混合。 因此，电流平台在壳体中包含它们的“熔丝”(即染料吸收剂)，具有负载效率和 染料的分布根据土地涂层和染料的化学物质的具体情况而变化很大 结构。重要的是，除了与不可再生性和土地保质期短相关的限制外， 由于染料分子从陆地的外壳中泄漏，最近对相变NDS的研究表明 从核心内部加热的优势，实现了有效的液体到气体的转变。这些数据强调了 ND核心内部加热对于激活无法有效实现的地块的重要性 位于外围的发色团。在这里，我们建议通过开发以下方法来解决先前研究的弱点 在第一和第二近红外组织窗口中具有吸光度的氟化染料(NIR-I和NIR-II)。我们的 假设氟化染料将在PFC核心内溶解，从而产生高度可重复性， 稳定的LAND配方，极大地提高了激光激活效率。以反映土地上的这些进步 在配方中，我们将掺入氟化染料的PFC NDS称为增强LAND(ELAND)。我们假设一个 在PFC核心内均匀分布的含氟染料浓度的增加将显著改善 伊兰德激活的功效。我们的估计表明，这种激活效率的提高可能与 PAI对Elands的深度敏感度显著增加(约厘米)；这种增加 在临床前和临床环境中，深度渗透可能改变分子PAI的游戏规则。