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

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.

项目概要胰腺导管腺癌（PDAC）是一种臭名昭著的恶性肿瘤，但其生存率却很低。手术仍然是第一选择，因为大多数肿瘤仍然无法切除，并且对化疗和化疗具有高度抵抗力。迫切需要低重叠或非重叠的空间和时间局部治疗。毒性，例如光动力疗法 (PDT)，已证明 1) 它对化疗和药物的有效性耐药细胞，2) 尽管 PDAC 肿瘤中存在基质，但药物渗透增强，3) 减少 PDT 是一种基于光化学的方式，可优先产生光介导的局部细胞毒性。通过特定波长的激光激活光敏剂 (PS) 分子来靶向组织。7 最近临床研究还表明 PDT 可以有效减少 PDAC 肿瘤体积，从而使以前无法切除的肿瘤可切除。11–15 然而，在 PDAC 治疗中使用 PDT 的一个主要障碍是将 PS 特异性递送至肿瘤和基于肿瘤中 PS 积累的精确剂量测定在该提案中我们克服了这一问题。通过使用生物相容性液态金属纳米粒子（NP），即共晶，PDT 的这两个障碍镓和铟合金（EGaIn、75% Ga、25% In）纳米颗粒作为伴侣，在酸性肿瘤中分解 EGaIn NPs 可以轻松制造，并且可以向肿瘤位点提供高负载的 PS。由于其表面存在氧化镓皮4,5，因此化学和机械性能极其稳定可以用靶向配体和 PS 进行功能化，产生 EGaP（EGaIn + PS）。配体和 PS 负载的高表面积，但在近处也具有比血液更高的光学吸收红外（NIR）区域，使其有利于光声成像（PAI），一种深层组织成像方式基于光学吸收系数的 PAI 可以与无处不在的技术透明地集成。超声成像 (USPAI) 如之前 us1-4 所示，用于获取肿瘤的多参数 3D 信息同时测量体积、纳米颗粒摄取、血管密度、血管灌注和肿瘤氧合状态设计有效的 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，使用 EGaP 的 PDT 将产生更好的结果，并且可以通过以下 3 个具体目标： Aim-1：我们将综合、表征和评估 EGaP；Aim-2：我们将建立 EGaP 和 Aim-3 的药代动力学、生物分布和安全性特征；我们将评估 EGaP 在具有不同病理生理学的原位 PDAC 模型中的体内功效。与临床可转化的 USPAI 相结合将为 PDAC 提供一个新颖的治疗平台。 EGaP 的生物分布、使用光声成像技术评估药物摄取以及设计以患者特定方式进行的剂量测定可应用于广泛的实体瘤治疗。