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.

摘要：光声成像（PAI）是一种有前景的非电离、低成本、高效率的成像方式。 在适合高通量临床前的平台中进行对比度和高时空分辨率成像 然而，分子 PAI 的广泛使用受到严重限制。 经验证的造影剂的可用性。目前可用的造影剂要么没有足够的。 PAI 所需的脉冲照明下的光稳定性，缺乏足够的 PAI 信号生成能力 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着重叠，这会减少 为了解决这些限制，提出了一种新型 PAI 造影剂： 基于相变全氟化碳 (PFC) 纳米液滴 (ND) 这些试剂基于液体。 PFC 核心和染料或纳米颗粒形式的光吸收“熔丝”，用 ND 进行照明。 脉冲激光触发由吸光发色团加热的 PFC 核心从液体到气体的转变，从而产生 因此，这些试剂通常被称为激光激活 ND（LAND）。 此外，激光激发后，PFC 微泡可以重新凝结成纳米液滴形式， 它可以允许多重激发以及动态成像对比度和超分辨率 PAI 的可能性。 然而，多个研究小组对这种令人兴奋的造影剂设计的评估揭示了一个关键问题 局限性 – 常用的染料分子或纳米颗粒不溶于全氟化碳或不与全氟化碳混合。 因此，当前的 LAND 在外壳中包含其“保险丝”（即染料吸收剂），其负载效率和 染料的分布变化很大，具体取决于 LAND 涂层和染料化学物质的具体情况 重要的是，除了与 LAND 的不可重复性和注射保质期相关的限制之外。 由于染料分子从 LAND 壳中泄漏，最近对相变 ND 的研究表明 这些数据强调了从核心内部加热 LAND 来实现有效的液体到气体转换的优势。 ND 核心内部加热对于激活 LAND 的重要性，这是无法有效实现的 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口（NIR-I 和 NIR-II）中具有吸光度的氟化染料。 假设氟化染料将溶解在 PFC 核心内部，从而产生高度可重复的、 稳定的 LAND 配方，大大提高了激光激活效率，以反映 LAND 的这些进步。 在配方中，我们将掺杂氟化染料的 PFC ND 称为增强型 LAND (eLAND)。 增加 PFC 核心内均匀分布的氟化染料的浓度将显着改善 我们的估计表明，激活功效的提高可能与此相关。 eLAND 的 PAI 深度灵敏度显着提高（厘米级）； 深度渗透可能会改变分子 PAI 在临床前和临床环境中的游戏规则。