Early Tumor Detection and Therapeutics Using an Advanced Magnetic Resonance Nano-Theranostic System

摘要

In this dissertation, I proposed an approach to conducting an in vivo nano-theranostic system of combined hyperthermia/MRI to simultaneously diagnose and treat cancer. The procedure involves injecting biocompatible magnetic nanoparticles that not only act as molecular beacons to enhance MRI contrast for early tumor detection but also destroy tumor cells when the particles are heated by exposing them to an applied magnetic field. However, the promising possibilities of this pre-clinical or clinical application can only be realized if: (i) A more sensitive MRI method is applied to enhance the imaging contrast between the difficult-to-detect early-stage tumor and the healthy tissue while significantly reduces the lengthy acquisition time required for high quality image reconstruction. (ii) The physical and magnetic properties of the nanoparticles are precisely controlled to optimize their heating efficiency, which is critical to focusing the energy onto tumor cells and avoiding damaging healthy tissue.;For the theranostic purpose of developing molecular diagnostics and targeted therapeutics, I performed theoretical calculations and conducted in vivo experiments to validate the applicability and efficacy of my proposed technique. The major research projects and the preliminary achievements during my five-year Ph.D. career under the supervision of Prof. Yung-Ya Lin include the following: (i) I established a novel model to evaluate the heating efficiency of magnetic nanoparticles for in vivo nano-theranostic hyperthermia in the presence of MRI, based on three major findings about the magnetic field's effect on the relaxation process, the aggregate formation of magnetic nanoparticles, and the nonlinear response of the magnetic susceptibility. (ii) To improve the heating efficiency of in vivo nano-theranostic hyperthermia in the clinical MRI environment, I proposed either using a high frequency-driven rotating magnetic field to heat small magnetic nanoparticles encapsulated along with therapeutic drugs inside thermosensitive liposomes, or else using a low frequency-driven linearly ramped alternating magnetic field combined with a built-in MRI gradient to trigger the Brownian relaxation mechanism. (iii) By taking advantage of an active feedback electronic device that was homebuilt to implement active-feedback pulse sequences to generate avalanching spin amplification, we showed both theoretically and experimentally that our new technique enhanced the imaging contrast at the tumor site fivefold, allowing the tumor to be successfully identified without intervention. (iv) I employed compressive sensing to extract all of the clinically important features of MR images by collecting only a small sample of the data. In comparison to the conventional T2-weighted imaging and compressive sensing reconstruction by Gaussian sampling, my newly proposed sensing matrix was able to reconstruct feedback-based images that had less sparsity, a higher correlation coefficient, and an improved contrast-to-noise ratio.;In the interest of the clinical application of this in vivo nano-theranostic system of combined hyperthermia/MRI, the results of my research offer a a novel methodology to perform fast and sensitive imaging for early tumor detection and a paradigm for designing magnetic nanoparticles to treat cancer efficiently through the hyperthermia in the MR environment.