NIRT: Novel Magnetically and Thermally Responsive Nanoparticles for Cancer Treatment

In vitro and in vivo experiments in which cells arc in contact with magnetic nanoparticles and subjectcd to high frequency oscillating magnetic fields have shown that the particles may induce cell death. Owing to the intrinsic biocompatibility of superparamagnetic iron oxide nanoparticles, these observations have garnered considerable interest for the treatment of cancer, in which the nanoparticles could be directly injected into a cancer tumor or functionalized to sc1ectively target cancer cells. The subsequent application of an oscillating magnetic field would result in destruction of the cancer, without many of the deleterious side efTect common to radio- and chemotherapy. These observations have been tenned Magnetic Fluid Hyperthennia (MFH) or Magnetocytolysis, depending on whether a macroscopic temperature rise is observed. With the objective of improving our fundamental understanding of this phenomenon, the proposed research combines preparation of innovative magnetically and thennally active nanoparticles, experiments aimed at quantifying cell death and the physicochemical interaction between the nanoparticles and human cancer cells in vitro under controlled conditions, modeling and measurements of particle and energy transport in human cancer cells in vitro, and simulations of the interaction between polymers used to functionalize the particles and a mode1lipid bilayer. The nanoparticles to be developed and used are one example of an active nanostructure; through their coupling with an externally imposed magnetic field they can be made to translate or rotate, interacting with and affecting their nanoscale surroundings. Furthennore, we will decorate some of these particles with a thennoresponsive fluorescent tag, which will render them as "nanothennometers" allowing us to visualize, for the first time, the temperature cvolution inside a cell monolayer during MFH. The proposed education and outreach activities will expose K-12 students in Puerto Rico, New Jersey, and Kentucky to the potential of active nanostructures in cancer therapy, improve the education of Hispanic undergraduate and graduate students at UPRM, and provide strong mechanisms (through our collaborations) for recruiting of Hispanic students from UPRM to UKY and Rutgers and recruiting students from UKY and Rutgers to UPRM. Intellectual Merit: The proposed synthesis and fimctionalization work combines established techniques to obtain magnetic nanoparticles suitable for studying the mechanisms of cell death, their microscopic and macroscopic transport, and the temperature profiles within the cells. The combination of magnetic nanoparticles with thennoresponsive fluorescent tags is particularly innovative. The proposed work on elucidating and quantifying the mechanisms of cell death combines various complementary assays to unequivocally detennine how the magnetic nanoparticlcs kill the cclls. The proposed experiments and analysis on particle and energy transport during magnetocytolysis/MFH will provide the first measurements of magnetic nanoparticle penneability across an epithelial cell monolayer, the tirst measurements of temperature profiles within a cell monolayer during MFH, and insight into particle transport within and through the cells, coupled with microscopic and macroscopic analyses of these situations. Finally, the work on molecular modeling of membrane rupture and polymer-membrane interaction will serve to detennine if membrane rupture by the rotating nanoparticles is possible and serve to guide design of surface modi tiers to coat the particles in order to improve non-specific and specific binding to the cells. Broader Impact: Cancer is one of the leading causes of death in the USA. Current treatments involve extreme surgery and detrimental side effects due to chemotherapeutic agents or radiation. The proposed research will enable the development of an alternative cancer treatment which is minimally invasive. This interdisciplinary proposal will also support collaboration between young and senior faculty members in three institutions. Students, including underrepresented minorities, will have the opportunity to interact through videoconferencing and shared courses. Educational modules will be developed to introduce K-12 students to the potential of active nanostructures in the battle against cancer. By partnering with the Science on Wheels Educational Center and the UPRM-UW Partnership for Research and Education in Materials these modules will be widely disseminated in Puerto Rico. By partnering with the Rutgers/UPRM IGERT on nanophannaceuticals to ofTer innovative joint courses in all three institutions we will improve the education of Hispanic undergraduate and graduate students at UPRM, and provide strong mechanisms for recruiting among all thrce institutions. The proposed research addresses Fundamental Nanoscale Phenomena and Processes in Acti ve Nanostructures.