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

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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.