Biodegradable liquid metal nanoagents for photoacoustic image-guided photodynamic therapy

项目摘要 胰腺导管腺癌(PDAC)是一种臭名昭著的恶性肿瘤，其存活率很低。 手术仍然是首选，因为大多数肿瘤仍然无法切除，而且对化疗和化疗具有高度耐药性. 放射疗法。迫切需要低重叠或无重叠的空间和时间局部治疗。 毒性，如光动力疗法(PDT)，它已经证明了1)它对化疗和药物治疗的有效性- 耐药细胞，2)尽管PDAC肿瘤中存在间质，但药物渗透性增强，以及3)减少 转移。PDT是一种基于光化学的方式，在局部给予优先的光介导的细胞毒作用。 通过特定波长的激光激活光敏剂(PS)分子来靶向组织。 临床研究还表明，PDT在缩小PDAC肿瘤体积方面有效，使以前无法切除的肿瘤成为可能。 11-15然而，PDT在PDAC治疗中使用的一个主要障碍是PS特定地输送到 肿瘤和基于PS在肿瘤中积累的准确剂量测定。在这项提案中，我们克服了 这两个障碍是通过使用生物相容的液态金属纳米颗粒(NPs)，即共晶 镓和铟(Egain，75%Ga，25%In)纳米颗粒作为伴侣的合金，在酸性肿瘤中分解 并将PS的高有效载荷输送到肿瘤部位。纳米粒子可以很容易地制造出来，并且是 由于其表面存在氧化镓皮肤，因此在化学和机械上非常稳定。 可以通过靶向配体和PS产生EGaP(Egain+PS)来功能化。这些NP不仅提供 高比表面积的配体和负载PS，但在近红外光谱中也比血液有更高的光吸收 红外(NIR)区域，使其有利于光声成像(PAI)，这是一种深层组织成像方式 基于光吸收系数。PAI可以透明地与无处不在的 超声成像(USPAI)，如先前的US1-4所示，以获得关于肿瘤的多参数三维信息 体积、纳米颗粒摄取、血管密度、血管灌注量和肿瘤氧合状态 用于设计有效的光动力疗法剂量。这个项目的总体假设是光声图像制导 在PDAC模型中，与被动PDT相比，带有EGaP的PDT将产生更好的结果，并将通过 以下三个具体目标：目标-1：我们将合成，表征和评价体外治疗效果 EGaPs；Aim-2：我们将建立EGaPs的药代动力学、生物分布和安全性概况；以及Aim-3： 我们将在不同病理生理学的原位PDAC模型中评估EGaPs的体内疗效。EGaP 与临床可翻译的USPAI相结合将为PDAC提供一个新的治疗平台。关于以下方面的见解 EGaP的生物分布，使用光声成像技术评价药物摄取，以及设计 以患者特有的方式进行的剂量测定可应用于广泛的实体肿瘤治疗。

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a notorious malignancy with no change to the dismal survival rate. Surgery is still the first option where most tumors are still unresctable and also highly resistant to chemo and radiotherapies. There is dire need for spatially and temporally localized therapies with low or non-overlapping toxicity such as photodynamic therapy (PDT) which has demonstrated 1) its effectiveness on chemo- and drug- resistant cells, 2) Enhanced drug penetration despite the stroma present in PDAC tumors and 3) decreased metastasis. PDT is a photochemistry-based modality that imparts preferential light-mediated cytotoxicity locally to target tissues via activation of a photosensitizer (PS) molecule by laser light of specific wavelength.7 Recent clinical studies also show PDT efficacy in reducing PDAC tumor volume, making previously unresectable tumors resectable.11–15 However,a major roadblock for PDT use in PDAC treatment is specific delivery of the PS to the tumor and accurate dosimetry that is based on PS accumulation in the tumor. In this proposal we overcome these two roadblocks for PDT via the use of biocompatible liquid metal nanoparticles (NPs), namely the eutectic alloy of gallium and indium (EGaIn, 75% Ga, 25% In) NPs as chaperones, breakdown in acidic tumor environment and deliver high payloads of PS to tumor sites. EGaIn NPs can be fabricated with ease and are extremely chemically and mechanically stable due to the presence of a gallium oxide skin on its surface4,5 which can be functionalized with targeting ligands and PS creating EGaPs (EGaIn + PS). These NPs not only provide high surface area for ligands and PS loading but also have higher optical absorption than blood in the near- infrared (NIR) region, making them conducive for photoacoustic imaging (PAI), a deep tissue imaging modality based on optical absorption coefficient. PAI can be transparently integrated with ubiquitously available ultrasound imaging (USPAI) as shown by us1-4 previously to obtain multi-parametric 3D information on tumor volume, nanoparticle uptake, vascular density, vascular perfusion and tumor oxygenation status simultaneously for designing an effective PDT dose. The overall hypothesis of this project is that photoacoustic image-guided PDT with EGaPs will yield superior results compared to passive PDT in PDAC models and will be achieved with the following 3 specific aims: Aim-1: We will synthesize, characterize and evaluate in vitro treatment efficacy of EGaPs; Aim-2: We will establish the pharmacokinetics, biodistribution and safety profile of EGaPs; and Aim-3: we will evaluate in vivo efficacy of EGaPs in orthotopic PDAC models with different pathophysiology. EGaPs integrated with clinically translatable USPAI will provide a novel treatment platform for PDAC. The insights on biodistribution of EGaPs, evaluation of drug uptake using photoacoustic imaging techniques, and design of dosimetry in a patient specific manner can be applied to broad range of solid tumor treatments.