Biodegradable liquid metal nanoagents for photoacoustic image-guided photodynamic therapy

用于光声图像引导光动力治疗的可生物降解液态金属纳米剂

基本信息

批准号：
10453150
负责人：
Srivalleesha Mallidi
金额：
$ 22.59万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-04 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453150
关键词：
3-Dimensional Adherent Culture Aftercare Area Biochemical Biodistribution Blood Blood Vessels Cause of Death Cell Death Cell Line Cells Cetuximab Chemicals Clinical Research Combined Modality Therapy Custom Diagnosis Disease Dose Drug Delivery Systems Drug Evaluation Drug Kinetics Drug resistance Effectiveness Environment Epidermal Growth Factor Receptor FDA approved Formulation Functional disorder Hyaluronic Acid Hypoxia Image Imaging Techniques In Vitro Indium Lasers Ligands Light Liquid substance Local Therapy Malignant Neoplasms Mechanics Mediating Metals Methods Modality Modeling Molecular Chaperones Monitor Mus Nano delivery Necrosis Neoplasm Metastasis Operative Surgical Procedures Optics Organ PUVA Photochemotherapy Pancreatic Ductal Adenocarcinoma Patients Penetration Perfusion Pharmaceutical Preparations Photochemistry Photosensitizing Agents Procedures Publishing Radiation therapy Recurrence Resectable Resistance Safety Site Skin Solid Neoplasm Surface Survival Rate Tissue imaging Tissues Toxic effect Treatment Efficacy Treatment Protocols Treatment outcome Tumor Oxygenation Tumor Tissue Tumor Volume Tumor Weights Ultrasonography Unresectable absorption base biomaterial compatibility chemotherapy clinical translation clinically translatable contrast imaging cytotoxicity density design dosimetry effective therapy gallium alloy gallium oxide gemcitabine image guided imaging modality improved in vivo in vivo Model in vivo evaluation insight mouse model nanofabrication nanoparticle novel optical imaging overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model photoacoustic imaging side effect standard of care treatment response tumor uptake

3-Dimensional Adherent Culture Aftercare Area Biochemical Biodistribution Blood Blood Vessels Cause of Death Cell Death Cell Line Cells Cetuximab Chemicals Clinical Research Combined Modality Therapy Custom Diagnosis Disease Dose Drug Delivery Systems Drug Evaluation Drug Kinetics Drug resistance Effectiveness Environment Epidermal Growth Factor Receptor FDA approved Formulation Functional disorder Hyaluronic Acid Hypoxia Image Imaging Techniques In Vitro Indium Lasers Ligands Light Liquid substance Local Therapy Malignant Neoplasms Mechanics Mediating Metals Methods Modality Modeling Molecular Chaperones Monitor Mus Nano delivery Necrosis Neoplasm Metastasis Operative Surgical Procedures Optics Organ PUVA Photochemotherapy Pancreatic Ductal Adenocarcinoma Patients Penetration Perfusion Pharmaceutical Preparations Photochemistry Photosensitizing Agents Procedures Publishing Radiation therapy Recurrence Resectable Resistance Safety Site Skin Solid Neoplasm Surface Survival Rate Tissue imaging Tissues Toxic effect Treatment Efficacy Treatment Protocols Treatment outcome Tumor Oxygenation Tumor Tissue Tumor Volume Tumor Weights Ultrasonography Unresectable absorption base biomaterial compatibility chemotherapy clinical translation clinically translatable contrast imaging cytotoxicity density design dosimetry effective therapy gallium alloy gallium oxide gemcitabine image guided imaging modality improved in vivo in vivo Model in vivo evaluation insight mouse model nanofabrication nanoparticle novel optical imaging overexpression pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model photoacoustic imaging side effect standard of care treatment response tumor uptake

展开

项目摘要

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.

项目摘要胰腺导管腺癌（PDAC）是臭名昭著的恶性肿瘤，没有变化的生存率改变。手术仍然是大多数肿瘤仍然无法分辨，并且对化学疗法和高度耐药性的第一个选择放射疗法。迫切需要在空间和临时局部疗法中，具有低或非重叠的疗法毒性，例如光动力疗法（PDT），它证明了其对化学和药物的有效性抗性细胞，2）增强了药物穿透目的地，PDAC肿瘤中存在的基质和3）精制转移。 PDT是一种基于光化学的模态，无法在本地优先使用光介导的细胞毒性通过激光通过特定波长激活光敏剂（PS）分子来靶向时间。7最近临床研究还表明，PDT减少PDAC肿瘤体积的效率，使以前无法切除的肿瘤可切除。11–15然而，PDT在PDAC处理中使用的主要障碍是将PS的特定递送到基于肿瘤中PS的积累的肿瘤和精确剂量测定法。在这个建议中，我们克服了通过使用生物相容性的液体金属纳米颗粒（NP），这两个障碍物用于PDT，即Eutectic 甘露和粘合剂合金（例如75％Ga，25％）作为伴侣，酸性肿瘤分解环境并向肿瘤部位提供高效的PS。 Egain NP可以轻松制造，并且由于其表面上存在氧化；可以通过靶向配体和PS创建EGAP（EGAIN + PS）功能化。这些NP不仅提供配体和PS负荷的高表面积，但在接近 - 红外（NIR）区域，使它们成为光声成像（PAI）的导电，深层组织成像方式基于光学滥用系数。 PAI可以与普遍存在的可用超声成像（USPAI）如前所述，以获取有关肿瘤的多参数3D信息简单用于设计有效的PDT剂量。该项目的总体假设是光声图像引导与PDAC模型中的被动PDT相比以下3个特定目标：AIM-1：我们将合成，表征和评估体外治疗效率的 egaps; AIM-2：我们将建立EGAP的药代动力学，生物分布和安全性；和AIM-3：我们将评估具有不同病理生理学的原位PDAC模型中的EGAP的体内效率。 egaps 与临床上可翻译的USPAI集成将为PDAC提供新颖的治疗平台。见解 EGAP的生物分布，使用光声成像技术评估药物吸收以及设计以患者为特定方式的剂量法可以应用于广泛的实体瘤治疗。