Among available therapeutic methods in cancer treatment, magnetic nanoparticle hyperthermia emerges as a highly promising approach due to its simple implementation, low cost, and few complications. In this process, magnetic particles delivered to tissue or blood vessels induce heating when exposed to alternating magnetic fields. This localized heat generation leads to thermal damage to the tumor. The employment of nano-sized particles enables adequate amount of heat to be generated within tumor tissue without necessitating heat penetration through the skin surface, thus eliminating the consequent side effects of excessive collateral thermal damage. Although the versatility of magnetic nanoparticle hyperthermia in treating deep-seated/irregular shaped tumors is unsurpassed by traditional non-invasive heating approaches, this method is severely limited by the lack of controlling the temperature elevations during the process. The non-homogeneous temperature distribution and inadequate temperature elevation in tumor tissue may lead to inadequacy in killing tumor cells and/or damage to healthy tissue. Multiple-site injection of nanoparticles has great potential for achieving a desired temperature elevation throughout the entire tumor region, but requires optimized injection strategy including injection sites, injection amount, and injection rate. Therefore, in the proposed study an in vivo experimental study of magnetic nanoparticle hyperthermia on tumors implanted on mice and a multi-scale computational study of nanoparticle transport in biological tissue will be performed with the aims of advancing understanding of nanofluid transport in tumor and quantifying the heating patterns induced by these nanoparticles under various therapeutic conditions. The ultimate outcome of this project is the development of a global methodology for designing individualized treatment protocol for irregular shaped tumors. Intellectual Merit: The findings of this study will (1) significantly advance understanding of nanoparticle transport in tissue and magnetic nanoparticle-induced heating pattern in hyperthermia treatment of cancer; (2) provide a platform on which the effect of particle properties, tissue microstructures, and injection strategy on the migration of particles and heating patterns in tumors can be tested; (3) establish a database describing the dependence of thermally affected region on injection parameters; and (4) develop of an optimized treatment strategy using multi-site injection. The capability of quantifying the induced heating pattern by nanoparticles in tumors is an important advance that moves the treatment planning from an almost empirical trial-and-error approach to a science-based engineering methodology. Broader Impact: The proposed study will be integrated into our seminar series and curricula for disseminating bio-nanotechnology as well as educating and training students in an interdisciplinary setting. Both PIs have established track records of commitment for promoting underrepresented minority students in STEM fields. The funding will provide our students from diverse backgrounds with ample research opportunities to engage in experiential training. Transformative essence: This study will lead to a global methodology for designing an optimized, patient-specific treatment protocol for magnetic nanoparticle hyperthermia with maximum treatment outcomes in clinical applications. The success of magnetic nanoparticle hyperthermia will offer cancer patients a low cost treatment method that has high tumor cell-killing potential and minimal complications. In addition, the study of nanoparticle migration in tissue will benefit the study of nanotoxicology and site-specific drug delivery using nanomaterials. This project is jointly funded by the Thermal Transport Processes (TTP) Program, the Biomedical Engineering (BME) Program, and the Fluid Dynamics (FD) Program, all of the Chemical, Bioengineering, Environmental, and Transport Systems (CBET) Division within the Directorate for Engineering (ENG).
Cancer-related illness is the second leading cause of death in many industrialized countries. Although traditional treatment, such as chemotherapy, radiation and surgical intervention, have increased the five-year survival rate in cancer patients, neither may be able to eliminate all cancerous tissue due to the irregular shape of tumors. Magnetic nanoparticle hyperthermia has emerged as a highly promising treatment due to its simple implementation, high tumor cell-killing potential, low cost, and minimal complications. In this approach, magnetic nanoparticles delivered to tissue or blood vessels induce heating when exposed to alternating magnetic fields. This heating leads to localized thermal damage to the tumor. The objective of the treatment is to maximize thermal damage to tumor cells while sparing the surrounding healthy tissue through optimized injection strategies and heating protocols. To achieve this goal, it is essential to acquire knowledge of nanoparticle distribution in tumors, advance the understanding of nanofluid and nanoparticle transport in tumors during an infusion process, and develop a global methodology for designing individualized treatment protocol for irregular-shaped tumors. With the support from the National Science Foundation, we have performed theoretical and experimental studies of magnetic nanoparticle hyperthermia in implanted tumors. The research endeavor of this project has been focused on microCT imaging of nanoparticle distribution in tissue-equivalent gels and tumors, quantification of heating pattern during in vivo heating experiments, simulation of nanoparticle interaction and transport in deformable tumors using multiscale and multiphysics modeling approaches, and laser photothermal therapy with gold nanorods. The direct quantification of the nanoparticle concentration distribution in opaque tissues has presented a formidable challenge in the past decade. The experiment studies of microCT imaging of tissue-equivalent gels and tumors have demonstrated the feasibility of using this technique to visualize the dispersion of nanofluid in biological tissues. MicroCT scan is able to provide typical pseudo three-dimensional images of the density variations in the vicinity of the injection site. Moreover, our study confirms that the pixel index number of the microCT image can be interpreted as indicator of the concentration distribution of the nanoparticles in tumors. This discovery shows the potential of microCT as an efficient tool to quantify the nanoparticle concentration distribution. The in vivo experiment of nanoparticle-induced temperature elevation in tumors shows the feasibility of elevating tumor temperatures higher than 50°C using very small amounts of ferrofluid with a relatively low magnetic field. Temperature mapping in implanted prostatic tumors during magnetic nanoparticle hyperthermia shows a bell-shaped temperature profiles in the vicinity of the injection site at steady state. The maximum temperature occurs at the vicinity of the injection site. A multiscale theoretical model has been developed for predicting the flow pattern, tissue deformation, the formation of backflow, and nanoparticle concentration in the tumor after injection. Nanoparticle deposition on the cellular structure is found to cause accumulation of the particles near the injection site and substantially reduce the penetration depth of the particle in the tumor. The simulation results suggest that a slow injection rate and small needle diameter lead to a more confined nanofluid distribution near the injection site. An algorithm to optimize the heat absorption distribution for multi-site injections in magnetic nanoparticle hyperthermia has also been developed for large and irregular-shaped tumors where a single injection is not sufficient to cover the entire tumor with nanofluid. The optimization process provides the clinician with information such as the injection site and Specific Adsorption Rate (SAR) distribution at each site. The optimization algorithm designed in this study significantly improves the treatment outcome especially when the tumor is deep seated and irregular in shape. In addition to magnetic nanoparticle hyperthermia, we also conducted in vivo experimental study of laser photothermal therapy using gold nanorods. The feasibility of detecting 250 OD gold nanorod solution injected to the tumors has been demonstrated via a high resolution microCT imaging system. Compared to other nanostructures, the gold nanorods used in this study do not accumulate at the injection site, but exhibit a relatively uniform deposition of the nanorods in the tumors observed by the microCT scans. It has been shown that the laser heating of 15 minutes on the tumor tissue containing gold nanorods is effective to cause irreversible thermal damage to the tumors with a low laser irradiance on the tumor surface (1.6 W/cm2). We observed an average tumor shrinkage to less than 7% of its original volume within 25 days after the heating treatment. On the contrast, the tumors without heating continue to grow and double their sizes within 18 days. The histological analyses also show tumor necrosis/apoptosis events surrounding the tumor center. However, thermal damage to the tumor is not uniform with possibly recoverable damage at the tumor periphery. Nevertheless, the results in this study have indicated effectiveness of the heating protocols and are consistent with thermal damage assessment estimated by the measured temperature history.
