Nanoparticle-mediated Histotripsy (NMH) for Noninvasive and Targeted Ablation of Metastatic Breast Cancer

纳米颗粒介导的组织解剖 (NMH) 用于转移性乳腺癌的无创和靶向消融

• 批准号: 10376030
• 负责人: Eli Vlaisavljevich
• 金额: $ 18.47万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376030
• 关键词: 3-Dimensional; 4T1; Ablation; Acoustics; Address; Binding; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cancer Patient; Cell Culture System; Cessation of life; Clinical Data; Coupled; Custom; Development; Diagnosis; Diffusion; Disease; Engineering; Feedback; Foundations; Image; In Vitro; Life; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic breast cancer; Methods; Microscopy; Neoplasm Metastasis; Nodule; Particle Size; Patients; Physiologic pulse; Primary Neoplasm; Pulse Pressure; Specificity; Speed; Structure; System; Techniques; Testing; Thermal Ablation Therapy; Time; Tissue Engineering; Tissues; Transducers; Woman; Work; biomaterial compatibility; cancer therapy; image guided; improved; in vitro testing; in vivo; malignant breast neoplasm; mortality; mouse model; nanoDroplet; nanoparticle; neoplastic cell; new technology; novel; orthotopic breast cancer; particle; perfluorohexane; pre-clinical; pressure; real-time images; response; standard of care; treatment strategy; tumor; tumor ablation; tumor microenvironment; ultrasound; ultrasound ablation

PROJECT SUMMARY Breast cancer is the most common malignancy among women, with almost 1.7 million patients diagnosed annually. Although promising treatment options are currently available, metastatic disease remains a significant challenge. Indeed, the vast majority of breast cancer deaths are a direct consequence of metastasis and no cure is available once metastatic disease has developed. Thus, new treatment strategies are needed to eliminate mortality associated with metastatic breast cancer. This proposal is focused on the development of nanoparticle-mediated histotripsy (NMH) as a non-invasive and targeted ablation method for the treatment of multi-focal breast tumors. Histotripsy is a non-invasive, non-ionizing, and non-thermal ultrasound ablation method that destroys tissue through the precise control of acoustic cavitation generated by high- pressure (>25-30 MPa) pulses. Histotripsy does not have the limitations of thermal ablation and can produce consistent ablation, even in near vessels. Additional benefits of histotripsy include high precision and real-time imaging guidance. However, although histotripsy shows promise as an improved ablation method for the treatment of primary tumors, this treatment method requires high ultrasound pressures and remains limited to tumors that can be identified and imaged prior to treatment, which is often not feasible in metastatic breast cancer patients with multiple tumor nodules. To address this need, our team recently invented NMH as a targeted ablation approach for treating multi-focal tumors by combining perfluorohexane (PFH) nanoparticles with histotripsy. NMH takes advantage of the significantly reduced cavitation threshold of these particles, allowing for histotripsy to be selectively generated only in regions containing the particles. In this proposal, we develop NMH for the selective ablation of metastatic breast tumors. In Aim 1 we engineer and characterize PFH “nanocones” with a smaller size (~50nm), higher stability, and functionalized targeting capabilities compared to our previously tested particles. Aim 2 will test the in vitro feasibility of these PFH “nanocones” for targeting and selectively ablating breast cancer cells in a tissue engineered 3D breast cancer model. Aim 3 will investigate the in vivo feasibility of NMH for the targeted ablation of metastatic breast tumors in an orthotopic mouse model. Together, these studies are expected to demonstrate the feasibility of NMH for multi-focal tumor ablation, which is essential to establishing the potential of this new technology. If successful, this work will lay the foundation for NMH as a targeted multi-focal cancer therapy capable of significantly improving the standard of care for cancer patients by increasing targeting specificity and treating tumors too small to detect by imaging.

项目摘要 乳腺癌是女性最常见的恶性肿瘤，近170万患者被诊断出 尽管目前可提供有希望的治疗选择，但转移性疾病仍然是重要的 挑战。确实，绝大多数乳腺癌死亡是转移的直接结果，无法治愈 一旦发生转移性疾病就可以使用。这是需要新的治疗策略来消除 与转移性乳腺癌相关的死亡率。该提议的重点是发展 纳米粒子介导的组织疗法（NMH）作为一种非侵入性和靶向消融方法 多焦腹肿瘤的治疗。组织疗法是一种非侵入性，非离子化和非热超声 消融方法通过高 - 压力（> 25-30 MPa）脉冲。组织疗法没有热消融的局限性，可以产生 一致的消融，即使在附近的船只中也是如此。组织疗法的其他好处包括高精度和实时 成像指导。但是，尽管组织疗法显示出有望作为改进的消融方法 治疗原发性肿瘤，这种治疗方法需要高超声压力，并且仍限于 可以在治疗前鉴定和成像的肿瘤，这通常在转移性乳腺癌中是不可行的 患有多个肿瘤结节的患者。为了满足这一需求，我们的团队最近发明了NMH作为目标 通过结合全氟己烷（PFH）纳米颗粒来治疗多焦点肿瘤的消融方法 与组织疗法。 NMH利用这些颗粒的空化阈值显着降低 仅在包含颗粒的区域中选择性地生成组织疗法。在这个建议中，我们 为转移性乳腺肿瘤的选择性消融开发NMH。在AIM 1中，我们设计并表征PFH 尺寸较小（〜50nm），稳定性较高和靶向靶向功能的“纳米酮”与 我们先前测试的颗粒。 AIM 2将测试这些PFH“纳米酮”的体外可行性用于靶向和 在组织设计的3D乳腺癌模型中，有选择地烧烤乳腺癌细胞。 AIM 3将调查 NMH在正质小鼠模型中靶向乳腺肿瘤的靶向消融的体内可行性。 总之，这些研究预计将证明NMH对多焦点肿瘤消融的可行性，这 对于确定这项新技术的潜力至关重要。如果成功，这项工作将为 NMH作为靶向的多核癌疗法，能够显着改善癌症的护理标准 通过增加靶向特异性并治疗太小而无法通过成像检测的患者。

项目成果

Experimental and Computational Investigation of Clustering Behavior of Cyclodextrin-Perfluorocarbon Inclusion Complexes as Effective Histotripsy Agents.

环糊精-全氟化碳包合物作为有效组织解剖剂的聚类行为的实验和计算研究。

• DOI: 10.1021/acs.molpharmaceut.2c00268
• 发表时间: 2022
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Kaymaz,Betül;Mustafa,Waleed;Hall,Sarah;Vlaisavljevich,Eli;Sensoy,Ozge;YukselDurmaz,Yasemin
• 通讯作者: YukselDurmaz,Yasemin

Bubble Cloud Behavior and Ablation Capacity for Histotripsy Generated from Intrinsic or Artificial Cavitation Nuclei.

• DOI: 10.1016/j.ultrasmedbio.2020.10.020
• 发表时间: 2021-03
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Edsall C;Khan ZM;Mancia L;Hall S;Mustafa W;Johnsen E;Klibanov AL;Durmaz YY;Vlaisavljevich E
• 通讯作者: Vlaisavljevich E

Successful In Situ Targeting of Pancreatic Tumors in a Novel Orthotopic Porcine Model Using Histotripsy.

• DOI: 10.1016/j.ultrasmedbio.2023.07.013
• 发表时间: 2023-11
• 期刊: ULTRASOUND IN MEDICINE AND BIOLOGY
• 影响因子: 2.9
• 作者: Imran, Khan Mohammad;Gannon, Jessica;Morrison, Holly A.;Tupik, Juselyn D.;Tintera, Benjamin;Nagai-Singer, Margaret A.;Ivester, Hannah;Madanick, Justin Markov;Hendricks-Wenger, Alissa;Uh, Kyungjun;Luyimbazi, David T.;Edwards, Michael;Coutermarsh-Ott, Sheryl;Eden, Kristin;Byron, Christopher;Clark-Deener, Sherrie;Lee, Kiho;Vlaisavljevich, Eli;Allen, Irving C.
• 通讯作者: Allen, Irving C.