Imaging and nanomedicine for diagnosis and therapy in the central nervous system: report of the eleventh annual Blood-Brain Barrier Disruption Consortium meeting

Abstract

The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. The Eleventh Annual Blood-Brain Barrier Disruption Consortium Meeting was convened to discuss recent advances and future directions in imaging and nanomedicine. Two sessions, one on Cell and Molecular Imaging in the CNS and another on Nanotechnology, Nanobiology, and Nanomedicine, were held March 17-18, 2005, in Portland, Ore. CNS imaging presentations targeted differentiating tumor, neural lesions, and necrosis from healthy brain tissue; methods of delivery of imaging agents across the BBB; and new iron oxide-based nanoparticle contrast agents for MR imaging. Nanobiology presentations covered the development of new nanotechnology and its use in imaging, diagnosis, and therapy in the CNS. Discussions at this meeting stressed the role of biotechnology in the convergence of CNS imaging and nanomedicine and are summarized in this article.

Fig 1.

Imaging intratumor injection. Nude rats with 7-day intracerebral small cell lung carcinoma xenografts were scanned by MR imaging 1 day before and 1 hour after intratumor injection of either gadolinium (top) or ferumoxtran-10 (bottom) contrast agents. Axial T1-weighted MR images were obtained at 3T by using a custom rat head coil. One day after contrast injection, coronal 100-μm rat brain sections were evaluated for histology by hematoxylin staining. Delivery of the USPIO is highly heterogeneous throughout the tumor and brain around the tumor, in contrast to the more homogeneous distribution of gadolinium.

Fig 2.

T1-weighted MR imaging in a patient with recurrence of a low-grade astrocytoma. The patient had stable disease after previous craniotomy (A) but showed recurrence on gadolinium images in March 2005 (B). The patient received ferumoxtran-10, and 24 hours later underwent preoperative MR imaging (C) as well as MR imaging with the 0.15T intraoperative scanner before (D) and during (E) craniotomy. Postoperative MR imaging (F) correlated with the residual areas of enhancing tumor seen on intraoperative MR imaging. High signal intensity in the tumor cavity, not present on intraoperative MR imaging, demonstrates the problem of differentiating residual enhancing tumor from blood products. Because the ferumoxtran-10 persists for 4–7 days, the postoperative MR images were exactly the same with or without the addition of gadolinium.

Fig 3.

Examples of Prussian blue–stained histopathology of mouse Sca1+ hematopoietic stem cells labeled with ferumoxides/poly-l-lysine (A), human CD 34 AC 133 hematopoietic stem cells labeled with ferumoxides/protamine sulfate (B), and human mesenchymal stem cells labeled with ferumoxides/protamine sulfate (C). Both mouse and human hematopoietic stem cells have been used as endothelial precursor cells (Bar = 20 μm).

Fig 3.

Examples of Prussian blue–stained histopathology of mouse Sca1+ hematopoietic stem cells labeled with ferumoxides/poly-l-lysine (A), human CD 34 AC 133 hematopoietic stem cells labeled with ferumoxides/protamine sulfate (B), and human mesenchymal stem cells labeled with ferumoxides/protamine sulfate (C). Both mouse and human hematopoietic stem cells have been used as endothelial precursor cells (Bar = 20 μm).

Fig 4.

Axial T2*-weighted gradient-echo MR imaging (TR/TE, 450/4.2 ms, with resolution at 500 × 80 x 70 μm) at 7T performed 10 days after implantation of RT2 rat glioma into the brain of a mouse that received a tail vein infusion of 500,000 killed ferumoxides/poly-l-lysine–labeled Sca1+ endothelial precursor cells (A) or live 500,000 ferumoxides/poly-l-lysine–labeled Sca1+ endothelial precursor cells (B) 2 days before implantation of tumor. The hypointense ring (arrow) surrounding the tumor is clearly visible on the animal receiving magnetically labeled endothelial precursor cells and represents the incorporation of these cells into ongoing vasculogenesis and neovasculature of the growing tumor. Killed labeled cells served as a control and did not migrate to the tumor. MR imaging courtesy of Stasia A. Anderson, MD.

Fig 5.

High-resolution transmission electron micrographs of the oxide-coated iron clusters with the diameters approximately 3–85 nm, prepared on carbon microgrids (A-D). The size-dependent-specific magnetic moments of iron oxide–coated iron nanoclusters are shown in panel E.