Combined magnetophoresis and photodynamic therapy for the treatment of TNBC

磁泳与光动力联合治疗TNBC

• 批准号: 10297166
• 负责人: Andrew Tsourkas
• 金额: $ 44.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297166
• 关键词: Abscopal effect; Adjuvant; Binding; Biomedical Engineering; Blood Circulation; Blood Vessels; Breast Cancer Treatment; Breast-Conserving Surgery; Caliber; Cell Line; Contralateral; Custom; Devices; Diffuse; Disease; Drug Kinetics; Encapsulated; Excision; Exhibits; Extravasation; Faculty; Formulation; Generations; Goals; Hematology; Histopathology; Immune response; Immunohistochemistry; Intravenous; Lasers; Location; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Mastectomy; Modeling; Monitor; Neoplasm Metastasis; Nonmetastatic; Operative Surgical Procedures; Optics; PUVA Photochemotherapy; Patients; Penetration; Pennsylvania; Photosensitizing Agents; Phototoxicity; Primary Neoplasm; Production; Radial; Radiation; Radiation Oncology; Radiation therapy; Radiology Specialty; Reactive Oxygen Species; Recombinant Antibody; Singlet Oxygen; Site; Solid Neoplasm; Solubility; Specificity; Surface; Testing; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Tumor Antigens; Universities; Water; Work; amphiphilicity; base; chemical property; chlorin; cytotoxicity; density; design; effective therapy; efficacy evaluation; imaging properties; improved; innovative technologies; iron oxide nanoparticle; irradiation; lipophilicity; magnetic field; malignant breast neoplasm; member; mesothelin; mouse model; nanocluster; nanoformulation; nanoparticle; neoplastic cell; novel; standard of care; superparamagnetism; triple-negative invasive breast carcinoma; tumor; tumor growth; uptake

Triple negative breast cancer (TNBC) does not respond to some of the most effective therapies available for breast cancer treatment. Even aggressive surgery, i.e. mastectomy, does not improve outcome. In fact, patients receiving breast conserving surgery (BCS) and radiation therapy exhibit better breast cancer specific and overall survival than patients that undergo a mastectomy, for both metastatic and non-metastatic disease. This is thought to be due to the radiation-induced abscopal effect. Therefore, we hypothesize that and adjuvant treatment that can both improve local regional control during BCS and enhance the abscopal effect could improve the current standard of care. One such option is photodynamic therapy (PDT). We will utilize mesothelin-targeted photosensitizers (PS). We have previously found that mesothelin is strongly expressed in the majority of TNBCs and expression is highly associated with both overall and disease-specific survival. Since most PS are lipophilic, they are often encapsulated within nanoparticles to improve their solubility and to facilitate systemic delivery. Nanoparticles can be designed to carry high PS payloads, extend the PS circulation time, improve tumor accumulation, and reduce off-target phototoxicity by minimizing PS uptake in healthy tissue. However, in order to maximize the benefit of nanoparticles, new nanoformulations must be developed that minimize the self-quenching of reactive oxygen species generation. Moreover, new strategies must be established to help facilitate the penetration of PS-loaded nanoparticles into tumors. Recently, we found that the amphiphilic photosensitizer Chlorin e6 (Ce6) was able to form a stable, water-soluble coating on nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs). Due to the unique orientation of Ce6 on the SPION surface, little to no quenching of singlet oxygen production was observed. This led to the effective use of the Ce6-coated SPION nanoclusters (CSNs) as a PDT agent in a murine model of TNBC, leading to a significant slowing of tumor growth. The overall goal of this proposal is to improve upon this work by combining CSNs with mesothelin-targeting and magnetophoresis to improve the specificity, accumulation, penetration, and efficacy of CSNs in treating TNBC. Magnetophoresis will be applied using a custom magnetic device that can radially profoundly disperse CSNs from any location in a living subject. This innovative technology will improve the ability of CSNs to reach their intended targets.The specific aims for this proposal are as follows: Aim 1. Synthesize and characterize the physical-chemical properties of mesothelin-targeted, Ce6-coated SPION nanoclusters (CSNs) and characterize a 2nd generation magnetic device; Aim 2. Evaluate the tumor accumulation and penetration of CSNs in a murine model of TNBC; Aim 3. Evaluate the efficacy and toxicity of PDT with CSNs in a murine model of TNBC.

三阴性乳腺癌(TNBC)对一些最有效的治疗方法不起作用 乳腺癌的治疗。即使是激进的手术，如乳房切除术，也不能改善结果。事实上，患者 接受保乳手术(BCS)和放射治疗显示出更好的乳腺癌特异性和全面性 在转移性和非转移性疾病方面，生存率均高于接受乳房切除术的患者。这是 被认为是由于辐射引起的远景效应。因此，我们假设和佐剂 既能改善BCS期间的局部区域控制，又能增强非局部性效应的治疗方法可以得到改善 目前的护理标准。光动力疗法(PDT)就是这样一种选择。我们将利用以间充气蛋白为靶点的 光敏剂(PS)。我们之前已经发现，在大多数TNBCs中都有间充质蛋白的强烈表达 而且，表达与总体和疾病特异性生存高度相关。 由于大多数PS是亲脂性的，它们通常被包裹在纳米颗粒中以改善其溶解性并 促进系统性交付。纳米颗粒可以设计成携带高PS有效载荷，扩展PS循环 时间，改善肿瘤蓄积，并通过最小化PS在健康组织中的摄取来减少偏离靶点的光毒性。 然而，为了最大限度地利用纳米颗粒，必须开发新的纳米配方 最大限度地减少活性氧生成的自猝灭。此外，新的战略必须是 建立的目的是帮助PS负载的纳米颗粒渗透到肿瘤中。 最近，我们发现两亲性光敏剂三氯乙烷(Ce6)能够形成稳定的、水溶性的 包覆在纳米团簇上的超顺磁性氧化铁纳米颗粒(SPION)。由于独特的方位 在Spion表面，Ce6对单线态氧的产生几乎没有猝灭作用。这导致了 Ce6包被的Spion纳米簇(CSNS)作为PDT试剂在TNBC小鼠模型中的有效使用，领先 显著减缓了肿瘤的生长。这项提案的总体目标是通过以下方式改进这项工作 将CSNS与间甲硫蛋白靶向和磁渗透相结合，以提高特异性，蓄积性， CSNS对TNBC的渗透性和疗效。将使用自定义磁铁应用磁渗透 一种可以径向 深刻地 从活着的受试者体内的任何位置驱散CSN。这项创新技术将 提高社区服务中心达致预期目标的能力。这项建议的具体目标如下 目的：1.合成和表征Ce6包覆的介孔蛋白的物理化学性质 Spion纳米团簇(CSN)和第二代磁性设备的特征；目的2.评估肿瘤 CSNS在TNBC小鼠模型中的蓄积和渗透；目的3.评价CSNS的疗效和毒性 在TNBC小鼠模型中应用CSNS的光动力疗法。