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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

基本信息

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
项目类别：
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

项目摘要

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中最常见的恶性肿瘤，有近170万患者被诊断每年。虽然目前有希望的治疗选择，但转移性疾病仍然是一个重要的问题。挑战.事实上，绝大多数乳腺癌死亡是转移的直接后果，无法治愈一旦发生转移性疾病，因此，需要新的治疗策略来消除与转移性乳腺癌相关的死亡率。该提案的重点是发展纳米粒子介导的组织摧毁术（NMH）作为一种非侵入性和靶向消融方法，治疗多灶性乳腺肿瘤。组织摧毁术是一种非侵入性、非电离、非热超声消融方法，通过精确控制由高- 压力（>25-30 MPa）脉冲。组织摧毁术没有热消融的局限性，一致消融，即使在近血管中。组织摧毁术的其他好处包括高精度和实时性成像制导然而，尽管组织摧毁术显示出作为用于肿瘤的改进的消融方法的前景，对于原发性肿瘤的治疗，这种治疗方法需要高超声压力，并且仍然限于可以在治疗前识别和成像的肿瘤，这在转移性乳腺癌中通常不可行多发性肿瘤结节患者。为了满足这一需求，我们的团队最近发明了NMH，通过组合全氟己烷（PFH）纳米颗粒治疗多病灶肿瘤的消融方法组织解剖学NMH利用这些颗粒的显著降低的空化阈值，允许仅在包含颗粒的区域中选择性地产生组织破坏。在本提案中，我们开发NMH用于转移性乳腺肿瘤的选择性消融。在目标1中，我们设计和表征PFH “纳米锥”具有更小的尺寸（~ 50 nm），更高的稳定性和功能化的靶向能力，我们之前测试过的粒子目标2将测试这些PFH“纳米锥”用于靶向和靶向的体外可行性。在组织工程3D乳腺癌模型中选择性消融乳腺癌细胞。目标3将调查在原位小鼠模型中NMH用于转移性乳腺肿瘤靶向消融的体内可行性。总之，这些研究有望证明NMH用于多灶肿瘤消融的可行性，是发挥这项新技术潜力的关键。如果成功，这项工作将为 NMH作为一种靶向多焦点癌症治疗，能够显著改善癌症的护理标准通过增加靶向特异性和治疗太小而无法通过成像检测的肿瘤来治疗患者。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.