Assessing Effective Transvascular Particle Delivery to the Brain Parenchyma: A Challenge to Neuroradiology

With the increased discussion over issues surrounding genetic manipulation of cells, neurotissue regeneration, and potential therapeutic models designed to alter cell growth and lines, a timely article by Muldoon et al appears in this issue of the American Journal of Neuroradiology (page 217). Questions basic to the future of neuroradiology and its role in the cellular treatment and imaging of a variety of CNS diseases are twofold. Will the transvascular delivery of minute, viral-sized particles effectively cross all cellular barriers within the brain, and will imaging protocols be developed that can help one accurately assess the efficacy of transvascular delivery of such particles to their desired cellular locations?

Muldoon et al have demonstrated with their rodent model that current MR imaging techniques cannot adequately reveal the precise particle distribution of therapeutic agents after transvascular delivery to the brain. Signal changes on MR images revealing iron-containing compound leakage through an intentionally disrupted blood-brain barrier (BBB) only gives gross anatomic information. These signal changes give little indication of what is happening where it counts, i.e. at the microscopic cellular level. The authors indicate that two physiologic barriers impede even distribution across the BBB: the well known tight vascular endothelial junctions of the BBB, and a basal membrane barrier. An important premise of this article asserts that when an agent crosses the BBB, it may not permeate the entire brain because of this second level of impairment to free diffusion. Because the two experimental materials, Feridex and MION, are of similar size, the authors discount particle size as a major factor for their observation of unequal particle distribution within the brain. Rather, they theorize that differences either in opsonization (susceptibility to phagocytosis) or in the electrostatic charge caused by dextran coating could account for their findings. Whatever the explanation, the implications these results have for the means of particle delivery and the subsequent imaging assessment of its effect are significant.

To develop imaging methods that can help one discriminate between effective and ineffective agents (“stealth” and “non-stealth,” as the authors put it) will be a difficult challenge for neuroradiology; however, possible strategies could be developed. The use of MR systems with field strengths far greater than currently employed high-field magnets might allow a better understanding of the distribution of particles by achieving high spatial resolution (i.e., 20–40 micron in-plane resolution). This, in concert with appropriate contrast-labeled particles and rapid time-resolved high-resolution MR, might help determine whether particles are distributed evenly throughout the brain parenchyma or have accumulated heterogeneously at or near brain capillaries. Regardless of the outcome, this article not only challenges the “conventional wisdom” relative to the BBB, but offers a distinct challenge for highly detailed MR imaging.