We develop magnetic resonance (MR) methods for real-time measurement of tissue microstructure and membrane permeability of live and fixed excised neonatal mouse spinal cords. Diffusion and exchange MR measurements are performed using the strong static gradient produced by a single-sided permanent magnet. Using tissue delipidation methods, we show that water diffusion is restricted solely by lipid membranes. Most of the diffusion signal can be assigned to water in tissue which is far from membranes. The remaining 25% can be assigned to water restricted on length scales of roughly a micron or less, near or within membrane structures at the cellular, organelle, and vesicle levels. Diffusion exchange spectroscopy measures water exchanging between membrane structures and free environments at 100 s-1.

Nanoparticle radiosensitization has been well demonstrated to enhance effects of radiotherapy, motivated to improve therapeutic ratios and decrease morbidity in cancer treatment. A significant challenge exists in optimizing formulations and translation due to insufficient knowledge of the associated mechanisms which have historically been limited to physical concepts. Here we investigated a concept for the role of biological mechanisms. The mere presence of gold nanoparticles led to a down regulation of thymidylate synthase, important for DNA damage repair in the radioresistant S phase cells. By developing a cross-correlative methodology to reveal probabilistic gold nanoparticle uptake by cell sub-populations and the associated sensitization as a function of the uptake, a number of revealing observations have been achieved. Surprisingly, for low numbers of nanoparticles a desensitization action was observed. Sensitization was discovered to preferentially impact S phase cells where impairment of the DNA damage response by the homologous recombination pathway dominates. This small but radioresistant cell population correlates with much greater proliferative ability. Thus a paradigm is presented whereby enhanced DNA damage is not necessarily due to an increase in the number of DNA Double Strand Breaks (DSBs) created, but can be from a nanoparticle-induced impairment of the damage response by down regulating repair proteins such as thymidylate synthase.