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

在美国，每年有超过50万人死于癌症。虽然使用先进的外科技术、放射治疗和新的药物在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方法。近年来，纳米颗粒，即直径在几十纳米量级的颗粒，被探索为一种治疗癌症的新介质。纳米粒子可以由各种生物兼容材料构建，并可以中空，这样它们就可以装载药物。生物标志物可以被放置在它们的表面，这样纳米颗粒就可以特定地靶向肿瘤，然后释放药物。因此，基于纳米颗粒的疗法有可能减少许多抗癌药物伴随的令人衰弱的副作用，并增加它们杀死癌细胞的效力。然而，关于纳米颗粒是如何离开血管并在肿瘤中积累的，人们知之甚少。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纳米颗粒在肿瘤中的积聚。人们正在研究纳米颗粒在人类前列腺癌小鼠模型中的传输和分布，并通过微型计算机断层扫描(MicroCT)成像对纳米颗粒在肿瘤内的积聚进行量化。利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是如何从血管进入肿瘤组织的。计算模型将帮助研究人员预测温度升高在不同大小和形状的肿瘤中可能如何发挥作用。除了培训研究生和本科生外，研究人员还在马里兰大学巴尔的摩县分校开展STEM外联活动，并参与STEM联盟项目WISE(科学与工程女性)、WSAS(女性认真对待科学)和SEED(针对经济困难高中生的暑期项目)。他们正在开发一种基于网络的、用户友好的界面，供科学界使用，以说明纳米颗粒在肿瘤中的扩散过程。虽然纳米技术的进步通过将治疗药物连接到纳米载体上以靶向传递到肿瘤中，同时降低了全身毒性，从而使癌症治疗发生了革命性的变化，但纳米结构从肿瘤毛细血管到肿瘤间质空间的转移和扩散到整个肿瘤区域仍然很难实现。实现这一目标的障碍在很大程度上是由于毛细血管中的小孔和肿瘤的高间质压力导致的大流动阻力。该项目的目标是通过使用温和热疗来促进纳米结构向肿瘤的传输，从而克服这两个障碍。本研究项目的三个部分包括1)进行体内实验研究，以评估全身和局部亚温对小鼠前列腺癌移植瘤纳米载体沉积的影响，并测量实验期间的温度、肿瘤间质压力和局部血液灌注率；2)使用MicroCT对实验后切除的所有肿瘤进行扫描，以量化三维纳米颗粒在肿瘤中的分布和总沉降量；以及3)建立三维理论模型，以实验测量的参数为输入，定量纳米颗粒在肿瘤毛细血管中的传输和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以用来检验多尺度模型的假设和简化，提取传输特性和分布，并最终提高对具有异质多孔结构的肿瘤中纳米颗粒输送的理解。

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.