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

• 批准号: 10583512
• 负责人: Srivalleesha Mallidi
• 金额: $ 17.28万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583512
• 关键词: 3-Dimensional; Adherent Culture; Aftercare; Area; Biochemical; Biodistribution; Blood; Blood Vessels; Cause of Death; Cell Death; Cell Line; Cells; Cetuximab; Chemicals; Chemoresistance; Clinical Research; Combined Modality Therapy; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Evaluation; Drug Kinetics; Drug resistance; Effectiveness; Environment; Epidermal Growth Factor Receptor; FDA approved; Formulation; Fostering; 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; Nanodelivery; Necrosis; Neoplasm Metastasis; Operative Surgical Procedures; Optics; Organ; PUVA Photochemotherapy; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Photochemistry; Photosensitizing Agents; Procedures; Proliferating; Publishing; Radiation therapy; Recurrence; Resectable; Resistance; Safety; Site; Skin; Solid Neoplasm; Surface; Survival Rate; Therapeutic; Tissue imaging; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tumor Oxygenation; Tumor Tissue; Tumor Volume; Tumor Weights; Ultrasonography; Unresectable; absorption; biomaterial compatibility; chemotherapy; clinical translation; 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; ineffective therapies; insight; mouse model; nano; 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

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）是一种恶名昭彰的恶性肿瘤，其生存率一直很低. 手术仍然是第一选择，大多数肿瘤仍然是不可撤销的，也高度耐化疗， 放射治疗迫切需要具有低重叠或非重叠的空间和时间局部化治疗。 毒性，如光动力疗法（PDT），其已证明1）其对化疗和药物治疗的有效性， 2）尽管PDAC肿瘤中存在基质，但药物渗透增强，以及3）药物渗透减少， 转移PDT是一种基于光化学的方式，其在局部赋予优先的光介导的细胞毒性。 通过特定波长的激光激活光敏剂（PS）分子，将其作用于靶组织。 临床研究也显示PDT在减小PDAC肿瘤体积，使以前不能切除的肿瘤 可切除的。11 -15然而，PDT在PDAC治疗中使用的一个主要障碍是将PS具体输送到 肿瘤和准确的剂量测定，这是基于PS在肿瘤中的积累。在这份提案中，我们克服了 通过使用生物相容性液态金属纳米颗粒（NPs），即共晶纳米颗粒， 镓铟合金（EGaIn，75% Ga，25% In）纳米颗粒作为伴侣，在酸性肿瘤中分解 环境和提供高有效载荷的PS到肿瘤部位。EGaIn纳米颗粒可以容易地制造， 由于在其表面上存在氧化镓皮，因此具有极高的化学和机械稳定性4，5， 可以用靶向配体和PS官能化，产生EGaP（EGaIn + PS）。这些NP不仅提供 配体和PS负载的高表面积，而且在近红外线中具有比血液更高的光吸收。 红外（NIR）区域，使其有利于光声成像（派），一种深层组织成像模式 基于光吸收系数。派可以透明地与无处不在的 超声成像（USPAI），如US 1 -4所示，以获得肿瘤的多参数3D信息 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。本项目的总体假设是，光声图像引导 与PDAC模型中的被动PDT相比，使用EGaPs的PDT将产生上级结果，并且将通过以下方式实现： 以下3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：我们将确定EGaPs的药代动力学、生物分布和安全性特征; Aim-3： 我们将评估EGaPs在具有不同病理生理学的原位PDAC模型中的体内功效。EGAP 与临床上可翻译的USPAI相结合将为PDAC提供一种新的治疗平台。关于的见解 EGaPs的生物分布，使用光声成像技术评价药物摄取，以及设计 以患者特异性方式的剂量测定可应用于宽范围的实体瘤治疗。

项目成果

Investigation of silk as a phantom material for ultrasound and photoacoustic imaging.

• DOI: 10.1016/j.pacs.2022.100416
• 发表时间: 2022-12
• 期刊: PHOTOACOUSTICS
• 影响因子: 7.9
• 作者: Nguyen, Christopher D.;Edwards, Skye A.;Iorizzo, Tyler W.;Longo, Brooke N.;Yaroslavsky, Anna N.;Kaplan, David L.;Mallidi, Srivalleesha
• 通讯作者: Mallidi, Srivalleesha

3D Ultrasound-Guided Photoacoustic Imaging to Monitor the Effects of Suboptimal Tyrosine Kinase Inhibitor Therapy in Pancreatic Tumors.

• DOI: 10.3389/fonc.2022.915319
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Claus, Abigail;Sweeney, Allison;Sankepalle, Deeksha M.;Li, Brian;Wong, Daniel;Xavierselvan, Marvin;Mallidi, Srivalleesha
• 通讯作者: Mallidi, Srivalleesha