Abstract
Pathologic hyperpermeability exists in the spectrum of disease states, including neuro-ischemic, neuro-inflammatory and neuro-oncological. To-date the characterization of disease pathology with T 1 -weighted quantitative dynamic contrast-enhanced magnetic resonance imaging has relied on the study of modeled microvascular parameters such as diseased tissue transvascular flow rates of small molecule paramagnetic imaging agents with short plasma half-lives, based on which it is difficult to assess the specific nature of the disease state. Another type of T 1 -weighted quantitative dynamic contrast-enhanced magnetic resonance imaging involves the use of paramagnetic heavy metal-chelated dendrimer nanoparticles that possess longer plasma half-lives with pre-determined molar relaxivities to quantitatively image concentration of macromolecular contrast agent accumulation over time in hyperpermeable pathology such as solid tumor tissue with the important advantage of concomitantly treating the pathology, which, in recent years, has been shown to be possible with the use of optimally-sized theranostic dendrimer nanoparticles in the 7 to 10 nanometer size range that are functionalized biocompatibly with a small molecule therapeutic. In this focused review, this translational theranostic methodology for quantitative dynamic contrast-enhanced magnetic resonance imaging and the concomitant treatment of malignant solid tumors with optimally designed theranostic nanoparticles within the 7 to 10 nanometer size range is discussed in context of fine-tuning its suitability for the study and treatment of other disease states with pathologic hyperpermeability and without.
Highlights
Pathologic angiogenesis is a hallmark of hyperpermeable disease states of chromic hypoxia, solid malignancies, irrespective of type or grade, with there being a physiologic upper limit of pore size greater than that of normal healthy tissue blood capillaries with few exceptions [1,2,3]
The realization that nanoparticle-based formulations could serve as more efficient molecular forms for either the purpose of imaging, or alternatively, for the purpose of the treatment of disease states, is relatively longstanding in the field of translational nanoparticle science, whereby over the years a variety of functionalized nanoparticles over a spectrum of shapes, sizes and exterior biophysical properties have been investigated for their suitability for either imaging or therapeutic applications, but the majority have failed to meet the criterion of passive selectivity for hyperpermeable pathologies cum biocompatibility in the physiologic state
The translational quantitative dynamic contrast-enhanced magnetic resonance imaging (MRI) imaging methodology that has been applied, and is discussed utilizes the measure of the ability of a paramagnetic MRI imageable dendrimer functionalized with a small molecule therapeutic to contrast enhance water proton signal, its molar relaxivity (r1), with the realization that this measure, can be appropriately determined in vitro utilizing T1-weighted Spin-Echo and applied for the accurate determination of theranostic agent concentration in blood plasma and in the solid tumor tissue interstitium overtime on a voxel-by-voxel basis for an accurate noninvasive assessment of in vivo theranostic pharmacokinetics utilizing T1-weighted Gradient-Recall Echo
Summary
Pathologic angiogenesis is a hallmark of hyperpermeable disease states of chromic hypoxia, solid malignancies, irrespective of type or grade, with there being a physiologic upper limit of pore size greater than that of normal healthy tissue blood capillaries with few exceptions [1,2,3].
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