Mild hyperthermia to enhance delivery of therapeutic nanocarriers in tumors: imaging, in vivo study, and simulation

轻度热疗可增强肿瘤中治疗性纳米载体的递送：成像、体内研究和模拟

• 批准号: 1705538
• 负责人: Liang Zhu
• 金额: $ 33.01万
• 依托单位: University of Maryland Baltimore County
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1705538&HistoricalAwards=false
• 关键词: Mild; hyperthermia; enhance; delivery; therapeutic

In the United States, more than one-half million people die from cancer each year. Although considerable progress has been made in the fight against some forms of the disease using advanced surgical techniques, radiation, and new classes of drugs, effective treatments are still needed. In recent years nanoparticles, particles with a diameter on the order of several tens of nanometers, have been explored as a new medium for cancer treatment. Nanoparticles can be constructed from a variety of biocompatible materials and can be made hollow so that they can be loaded with drugs. Biomarkers can be placed on their surfaces so that the nanoparticles can specifically target a tumor and then release the drugs. Nanoparticle-based therapies, therefore, have the potential to reduce the debilitating side effects that accompany many cancer drugs and to increase their potency in killing cancer cells. However, little is understood about of how nanoparticles exit blood vessels and accumulate in tumors. In this project, researchers are exploring the use of local, mild heating to increase the accumulation of nanoparticles in a tumor. The transport and distribution of nanoparticles in a mouse model of human prostate cancer is being studied, and the accumulation of nanoparticles inside the tumor is being quantified via micro-computed tomography (microCT) imaging. Using the measurements obtained from actual tumors, a computational model is being developed to explain how the nanoparticles get out of the blood vessels and into the tumor tissue. The computational model will help researchers predict how increased temperature might work in tumors of different sizes and shapes. In addition to training graduate student and undergraduate students, the researchers are engaging in STEM outreach activities at the University of Maryland Baltimore County and STEM alliance programs WISE (Women in Science and Engineering), WSAS (Women Serious about Science), and SEED (summer program for economically disadvantaged high school students). They are developing a web-based, user-friendly interface for use by the scientific community to illustrate the nanoparticle spreading process in tumors. Though advancements in nanotechnology have revolutionized cancer treatment by conjugating therapeutic drugs onto nanocarriers for targeted delivery into tumors while reducing systemic toxicity, nanostructure transport from tumor capillaries to tumor interstitial space and diffusion to the entire tumor region is still difficult to achieve. Barriers to accomplishing this goal are largely due to the large flow resistance caused by small pores in the capillary and high interstitial pressure in tumors. The goal of this project is to overcome these two barriers by using mild hyperthermia to facilitate nanostructure transport to tumors. The three parts of this research project involve 1) performing in vivo experimental studies to evaluate the effects of whole body and local mild hyperthermia on the deposition of nanocarriers in human prostate cancer xenograft tumors in mice, and to measure temperatures, tumor interstitial pressure, and local blood perfusion rate during experiments; 2) using microCT to scan all the tumors resected after the experiments to quantify both the 3-D nanoparticle distribution and the total amount of nanoparticle deposition in the tumors; and 3) developing a 3-D theoretical model to quantify nanoparticle transport across tumor capillaries and nanoparticle diffusion and advection in the tumor interstitial tissue space, using experimentally measured parameters as inputs. In the long term, it is anticipated that the experimental data and computer models can be used to test assumptions and simplifications of multi-scale modeling, to extract transport properties and distribution, and to ultimately advance understanding of nanoparticle delivery in tumors with heterogeneous porous structures.

在美国，每年有超过150万人死于癌症。虽然在使用先进的外科技术、放射和新型药物对抗某些形式的疾病方面取得了相当大的进展，但仍然需要有效的治疗。 近年来，纳米颗粒，直径在几十纳米量级的颗粒，已经被探索作为癌症治疗的新介质。纳米颗粒可以由各种生物相容性材料构成，并且可以制成中空的，使得它们可以装载药物。 生物标志物可以放置在它们的表面，这样纳米颗粒就可以特异性地靶向肿瘤，然后释放药物。 因此，基于纳米颗粒的疗法有可能减少许多癌症药物伴随的使人衰弱的副作用，并增加其杀死癌细胞的效力。 然而，人们对纳米颗粒如何离开血管并在肿瘤中积累知之甚少。 在这个项目中，研究人员正在探索使用局部温和加热来增加肿瘤中纳米颗粒的积累。 正在研究纳米颗粒在人类前列腺癌小鼠模型中的运输和分布，并且正在通过微计算机断层扫描（microCT）成像量化肿瘤内纳米颗粒的积累。使用从实际肿瘤中获得的测量结果，正在开发一个计算模型来解释纳米颗粒如何从血管中进入肿瘤组织。 计算模型将帮助研究人员预测温度升高如何在不同大小和形状的肿瘤中起作用。 除了培训研究生和本科生外，研究人员还在马里兰州巴尔的摩县大学和STEM联盟计划WISE（科学与工程女性），WSAS（女性认真对待科学）和SEED（经济困难高中生暑期计划）开展STEM推广活动。 他们正在开发一个基于网络的用户友好界面，供科学界使用，以说明纳米粒子在肿瘤中的扩散过程。虽然纳米技术的进步已经通过将治疗药物缀合到纳米载体上用于靶向递送到肿瘤中而彻底改变了癌症治疗，同时降低了全身毒性，但是从肿瘤毛细血管到肿瘤间质空间的纳米结构运输和扩散到整个肿瘤区域仍然难以实现。 实现这一目标的障碍主要是由于毛细血管中的小孔和肿瘤中的高间质压力引起的大流动阻力。该项目的目标是通过使用轻度高温来克服这两个障碍，以促进纳米结构运输到肿瘤。本研究项目的三个部分包括：1）进行体内实验研究，评估全身和局部轻度高温对小鼠人前列腺癌异种移植瘤中纳米载体沉积的影响，并在实验过程中测量温度、肿瘤间质压和局部血液灌注率; 2）使用microCT扫描实验后切除的所有肿瘤，以量化肿瘤中的3-D纳米颗粒分布和纳米颗粒沉积的总量;以及3）使用实验测量的参数作为输入，开发3-D理论模型以量化纳米颗粒穿过肿瘤毛细血管的运输以及纳米颗粒在肿瘤间质组织空间中的扩散和平流。从长远来看，预计实验数据和计算机模型可用于测试多尺度建模的假设和简化，提取传输特性和分布，并最终推进对具有异质多孔结构的肿瘤中纳米颗粒递送的理解。

项目成果

Thermal Analysis of Calcium–Magnesium–Alumino–Silicate Infiltration Dynamics in Thermal Barrier Coatings

• DOI: 10.2514/1.t6171
• 发表时间: 2021-02
• 期刊: Journal of Thermophysics and Heat Transfer
• 影响因子: 2.1
• 作者: Timothy W. Munuhe;Liang Zhu;Ronghui Ma

Effect of Surface Topography on Particle Deposition from Liquid Suspensions in Channel Flow

• DOI: 10.3390/fluids5010008
• 发表时间: 2020-01
• 期刊: Fluids
• 影响因子: 1.9
• 作者: M. Zaw;Liang Zhu;Ronghui Ma

Heating Protocol Design Affected by Nanoparticle Redistribution and Thermal Damage Model in Magnetic Nanoparticle Hyperthermia for Cancer Treatment

• DOI: 10.1115/1.4046967
• 发表时间: 2020-07-01
• 期刊: JOURNAL OF HEAT TRANSFER-TRANSACTIONS OF THE ASME
• 作者: Singh, Manpreet;Gu, Qimei;Zhu, Liang
• 通讯作者: Zhu, Liang

Enhanced nanoparticle deposition in pc3 tumors by mild whole body hyperthermia – a theoretical simulation

通过轻度全身热疗增强 pc3 肿瘤中的纳米颗粒沉积 — 理论模拟

• 发表时间: 2020
• 期刊: Bioengineering and Biotransport Conference Proceeding
• 作者: Singh, M.

Nanoparticle Redistribution in PC3 Tumors Induced by Local Heating in Magnetic Nanoparticle Hyperthermia: In Vivo Experimental Study

• DOI: 10.1115/1.4042298
• 发表时间: 2019-03-01
• 期刊: JOURNAL OF HEAT TRANSFER-TRANSACTIONS OF THE ASME
• 作者: Gu, Qimei;Joglekar, Tejashree;Zhu, Liang
• 通讯作者: Zhu, Liang