We have analyzed bionanoparticles that are designed for labeling cells and then imaging those cells in animal models by in vivo magnetic resonance imaging. These nanocomplexes, comprising three FDA-approved drugs (heparin, protamine and ferumoxytol), can be taken up into human cell lines, and detected when implanted into rodents. The major component of the ferumoxytol component is superparamagetic iron oxide nanoparticle (SPIONP), which provides MRI contrast for diagnostic imaging. We have performed electron tomography and energy-filtered transmission electron microscopy (EFTEM) to determine the distribution of the three constituents within the individual nanocomplexes using element-specific signals. The protamine component was imaged with the nitrogen signal, the heparin component with the sulfur signal, and the surrounding shell of ferumoxytol with the iron signal. Electron tomography was also employed to visualize the three-dimensional organization of the ferumoxytol nanoparticles within the approximately 200-nm diameter nanocomplexes. Our analysis showed that the nanocomplexes contained a homogeneous soft core consisting of approximately a 1:1 mass ratio of protamine and heparin, consistent with a balancing of the positive charge on protamine with the negative charge on heparin. Electron microscopy has enabled us to characterize another SPIONP that is combined with a nano-drug formulation consisting of the anti-cancer drug doxorubicin loaded into a polyethyleneimine-coating on the iron oxide nanoparticles, forming a theranostic nanocomplex. Magnetic nanocrystals like SPIONPs have been developed mainly as MRI contrast agents and as magnetic labels for tracking stem cells. However, with this design, the SPIONPs can function as drug delivery vehicles to reach tumor sites and image those sites through magnetic contrast. We have also characterized monodisperse manganese oxide nanoparticles that had been solubilized by coating with polyaspartic acid. These particles show much higher R1 relaxivity in MRI because the polyaspartic acid layer is more hydrophilic and compact than other more commonly used coatings such as PEGylated phospholipid, which facilitates more efficient water-manganese interactions. In particular, nanoparticles with a core size of 10 nm exhibited greater enhancement in MRI contrast than did ones with larger core sizes.

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National Institute of Biomedical Imaging and Bioengineering
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Bryant Jr, L Henry; Kim, Saejeong J; Hobson, Matthew et al. (2016) Physicochemical Characterization of Ferumoxytol, Heparin and Protamine Nanocomplexes for improved magnetic labeling of stem cells. Nanomedicine :
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