Metal nanoshells are a class of nanoparticles with tunable optical resonances. In this article, an application of this technology to thermal ablative therapy for cancer is described. By tuning the nanoshells to strongly absorb light in the near infrared, where optical transmission through tissue is optimal, a distribution of nanoshells at depth in tissue can be used to deliver a therapeutic dose of heat by using moderately low exposures of extracorporeally applied near-infrared (NIR) light. Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35 W/cm2), as determined by using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of NIR illumination. Likewise, in vivo studies under magnetic resonance guidance revealed that exposure to low doses of NIR light (820 nm, 4 W/cm2) in solid tumors treated with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (DeltaT = 37.4 +/- 6.6 degrees C) within 4-6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (DeltaT < 10 degrees C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining, which are indicators of irreversible thermal damage. Control tissues appeared undamaged.

https://www.pnas.org/content/pnas/100/23/13549.full.pdf

Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance

PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material–enhanced MR images obtained minutes after sonications and repeated 1–48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power leve...

Noninvasive MR Imaging-Guided Focal Opening of the Blood-Brain Barrier in Rabbits

Background Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor. Methods From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. We assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Quest...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1300962

A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor

Continuous thermometry during a hyperthermic procedure may help to correct for local differences in heat conduction and energy absorption, and thus allow optimization of the thermal therapy. Noninvasive, three-dimensional mapping of temperature changes is feasible with magnetic resonance (MR) and may be based on the relaxation time T(1), the diffusion coefficient (D), or proton resonance frequency (PRF) of tissue water. The use of temperature-sensitive contrast agents and proton spectroscopic imaging can provide absolute temperature measurements. The principles and performance of these methods are reviewed in this paper. The excellent linearity and near-independence with respect to tissue type, together with good temperature sensitivity, make PRF-based temperature MRI the preferred choice for many applications at mid to high field strength (>/= 1 T). The PRF methods employ radiofrequency spoiled gradient-echo imaging methods. A standard deviation of less than 1 degrees C, for a temporal resolution below 1 second and a spatial resolution of about 2 mm, is feasible for a single slice for immobile tissues. Corrections should be made for temperature-induced susceptibility effects in the PRF method. If spin-echo methods are preferred, for example when field homogeneity is poor due to small ferromagnetic parts in the needle, the D- and T(1)-based methods may give better results. The sensitivity of the D method is higher that that of the T(1) methods provided that motion artifacts are avoided and the trace of D is evaluated. Fat suppression is necessary for most tissues when T(1), D, or PRF methods are employed. The latter three methods require excellent registration to correct for displacements between scans.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1522-2586%28200010%2912%3A4%3C525%3A%3AAID-JMRI3%3E3.0.CO%3B2-V

Magnetic resonance temperature imaging for guidance of thermotherapy

Local blood-brain barrier (BBB) opening is an advantageous approach for targeted drug delivery to the brain. Recently, it has been shown that focused ultrasound (US) exposures (sonications), when applied in the presence of preformed gas bubbles, caused magnetic-resonance (MR) proven reversible opening of the BBB in targeted locations. The cellular mechanisms of such transient barrier disruption are largely unknown. We investigated US-induced changes in endothelial cell fine morphology that resulted in the BBB opening in rabbits. To obtain evidence for the passage of blood-borne macromolecules through the opened transvascular routes, an immunocytochemical procedure for endogenous immunoglobulinG (IgG) was performed, in addition to the routine electron microscopy. An increased number of vesicles and vacuoles, fenestration and channel formation, as well as opening of some tight junctions, were seen in capillaries after low-power (0.55 W) sonication. Immunosignals presented in some of the vesicles and vacuoles, in the cytoplasmic channels and, so rarely, in intercellular clefts; immunosignals could also be seen in neuropil around the blood vessels. Damage to the cellular ultrastructure was not seen in these areas. However, cell destruction and leakage of IgG through defects of the endothelial lining took place at 3 W sonications. The data reveals that several mechanisms of transcapillary passage are possible after such sonications: 1. transcytosis; 2. endothelial cell cytoplasmic openings--fenestration and channel formation; 3. opening of a part of tight junctions; and 4. free passage through the injured endothelium (with the higher power sonications). These findings could be considered in further development of the strategy for drug delivery to brain parenchyma.

Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles.

A new temperature measurement procedure using phase mapping was developed that makes use of the temperature dependence of the water proton chemical shift. Highly accurate and fast measurements were obtained during phantom and in vivo experiments. In the pure water phantom experiments, an accuracy of more than +/- 0.5 degrees C was obtained within a few seconds/slice using a field echo pulse sequence (TR/TE = 115/13 ms, matrix = 128 x 128, number of slices = 5). The temperature dependence of the water proton chemical shift was found to be almost the same for different materials with a chemical composition similar to living tissues (water, glucide, protein). Using this method, the temperature change inside a cat's brain was obtained with an accuracy of more than +/- 1 degree C and an in-plane resolution of 0.6 x 0.6 mm. The temperature measurement error was affected by several factors in the living system (B0 shifts caused by position shifts of the sample, blood flow, etc.), the position shift effect being the most serious.

Calderon A

Papers

A precise and fast temperature mapping using water proton chemical shift.