Combined magnetophoresis and photodynamic therapy for the treatment of TNBC

磁泳与光动力联合治疗TNBC

• 批准号: 10586052
• 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/10586052
• 关键词: Abscopal effect; Adjuvant Therapy; Binding; Biomedical Engineering; Blood Vessels; Breast Cancer Treatment; Breast-Conserving Surgery; Cancer Cluster; Cell Line; Circulation; Contralateral; Custom; Diameter; Diffuse; Disease; Drug Kinetics; Encapsulated; Excision; Exhibits; Extravasation; Faculty; Formulation; Generations; Goals; Hematology; Histopathology; Immune response; Immunohistochemistry; Lasers; Location; Magnetic Resonance Imaging; Magnetic nanoparticles; 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; chemical property; chlorin; cytotoxicity; density; design; effective therapy; efficacy evaluation; imaging properties; improved; innovative technologies; intravenous administration; iron oxide nanoparticle; irradiation; lipophilicity; magnetic devices; 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没有反应 乳腺癌治疗。即使是积极的手术，即乳房切除术，也不能改善结果。事实上，患者 接受保乳手术 (BCS) 和放射治疗的乳腺癌特异性和整体表现更好 对于转移性和非转移性疾病，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隔效应。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远隔效应的治疗可以改善 目前的护理标准。其中一种选择是光动力疗法（PDT）。我们将利用间皮素靶向 光敏剂（PS）。我们之前发现间皮素在大多数 TNBC 中强烈表达 并且表达与总体生存率和疾病特异性生存率高度相关。 由于大多数 PS 是亲脂性的，因此它们通常被封装在纳米颗粒内以提高其溶解度并 促进全身递送。纳米粒子可被设计为携带高 PS 有效负载，延长 PS 循环 时间，改善肿瘤积累，并通过最大限度地减少健康组织中的 PS 摄取来减少脱靶光毒性。 然而，为了最大限度地发挥纳米颗粒的优势，必须开发新的纳米制剂 最大限度地减少活性氧产生的自猝灭。此外，新的战略必须 旨在帮助促进负载 PS 的纳米粒子渗透到肿瘤中。 最近，我们发现两亲性光敏剂 Chlorin e6 (Ce6) 能够形成稳定的水溶性 超顺磁性氧化铁纳米粒子（SPION）纳米团簇的涂层。由于独特的定位 在 SPION 表面上存在 Ce6 时，几乎没有观察到单线态氧产生的猝灭。这导致了 在 TNBC 小鼠模型中有效使用 Ce6 包覆的 SPION 纳米团簇 (CSN) 作为 PDT 剂， 从而显着减缓肿瘤生长。该提案的总体目标是通过以下方式改进这项工作： 将 CSN 与间皮素靶向和磁泳相结合，以提高特异性、积累、 CSN 在治疗 TNBC 中的渗透性和功效。将使用定制的磁力应用磁泳 装置可以径向 深刻地 从活体的任何位置分散 CSN。这项创新技术将 提高 CSN 达到预期目标的能力。该提案的具体目标是 目标 1. 合成并表征间皮素靶向的 Ce6 涂层的物理化学性质 SPION 纳米团簇 (CSN) 并表征第二代磁性器件；目标 2. 评估肿瘤 TNBC 小鼠模型中 CSN 的积累和渗透；目标 3. 评估药物的功效和毒性 在 TNBC 小鼠模型中使用 CSN 进行 PDT。

项目成果

Theranostic Phthalocyanine and Naphthalocyanine Nanoparticles for Photoacoustic Imaging and Photothermal Therapy of Tumors.

• DOI: 10.7150/ntno.88892
• 发表时间: 2024
• 期刊: Nanotheranostics
• 作者: Tian Y;Carrillo-Malani N;Feng K;Miller J;Busch TM;Sundaram KM;Cheng Z;Amirshaghaghi A;Tsourkas A
• 通讯作者: Tsourkas A