Open challenges in magnetic drug targeting.

The principle of magnetic drug targeting, wherein therapy is attached to magnetically responsive carriers and magnetic fields are used to direct that therapy to disease locations, has been around for nearly two decades. Yet our ability to safely and effectively direct therapy to where it needs to go, for instance to deep tissue targets, remains limited. To date, magnetic targeting methods have not yet passed regulatory approval or reached clinical use. Below we outline key challenges to magnetic targeting, which include designing and selecting magnetic carriers for specific clinical indications, safely and effectively reaching targets behind tissue and anatomical barriers, real-time carrier imaging, and magnet design and control for deep and precise targeting. Addressing these challenges will require interactions across disciplines. Nanofabricators and chemists should work with biologists, mathematicians, and engineers to better understand how carriers move through live tissues and how to optimize carrier and magnet designs to better direct therapy to disease targets. Clinicians should be involved early on and throughout the whole process to ensure the methods that are being developed meet a compelling clinical need and will be practical in a clinical setting. Our hope is that highlighting these challenges will help researchers translate magnetic drug targeting from a novel concept to a clinically available treatment that can put therapy where it needs to go in human patients.

Increasing the oscillation frequency of strong magnetic fields above 101 kHz significantly raises peripheral nerve excitation thresholds.

PURPOSE: A time-varying magnetic field can cause unpleasant peripheral nerve stimulation (PNS) when the maximum excursion of the magnetic field (ΔB) is above a frequency-dependent threshold level [P. Mansfield and P. R. Harvey, Magn. Reson. Med. 29, 746-758 (1993)]. Clinical and research magnetic resonance imaging (MRI) gradient systems have been designed to avoid such bioeffects by adhering to regulations and guidelines established on the basis of clinical trials. Those trials, generally employing sinusoidal waveforms, tested human responses to magnetic fields at frequencies between 0.5 and 10 kHz [W. Irnich and F. Schmitt, Magn. Reson. Med. 33, 619-623 (1995), T. F. Budinger et al., J. Comput. Assist. Tomogr. 15, 909-914 (1991), and D. J. Schaefer et al., J. Magn. Reson. Imaging 12, 20-29 (2000)]. PNS thresholds for frequencies higher than 10 kHz had been extrapolated, using physiological models [J. P. Reilly et al., IEEE Trans. Biomed. Eng. BME-32(12), 1001-1011 (1985)]. The present study provides experimental data on human PNS thresholds to oscillating magnetic field stimulation from 2 to 183 kHz. Sinusoidal waveforms were employed for several reasons: (1) to facilitate comparison with earlier reports that used sine waves, (2) because prior designers of fast gradient hardware for generalized waveforms (e.g., including trapezoidal pulses) have employed quarter-sine-wave resonant circuits to reduce the rise- and fall-times of pulse waveforms, and (3) because sinusoids are often used in fast pulse sequences (e.g., spiral scans) [S. Nowak, U.S. patent 5,245,287 (14 September 1993) and K. F. King and D. J. Schaefer, J. Magn. Reson. Imaging 12, 164-170 (2000)]. METHODS: An IRB-approved prospective clinical trial was performed, involving 26 adults, in which one wrist was exposed to decaying sinusoidal magnetic field pulses at frequencies from 2 to 183 kHz and amplitudes up to 0.4 T. Sham exposures (i.e., with no magnetic fields) were applied to all subjects. RESULTS: For 0.4 T pulses at 2, 25, 59, 101, and 183 kHz, stimulation was reported by 22 (84.6%), 24 (92.3%), 15 (57.7%), 2 (7.7%), and 1 (3.8%) subjects, respectively. CONCLUSIONS: The probability of PNS due to brief biphasic time-varying sinusoidal magnetic fields with magnetic excursions up to 0.4 T is shown to decrease significantly at and above 101 kHz. This phenomenon may have particular uses in dynamic scenarios (e.g., cardiac imaging) and in studying processes with short decay times (e.g., electron paramagnetic resonance imaging, bone and solids imaging). The study suggests the possibility of new designs for human and preclinical MRI systems that may be useful in clinical practice and scientific research.

Positron emission mammography: high-resolution biochemical breast imaging.

Positron emission mammography (PEM) provides images of biochemical activity in the breast with spatial resolution matching individual ducts (1.5 mm full-width at half-maximum). This spatial resolution, supported by count efficiency that results in high signal-to-noise ratio, allows confident visualization of intraductal as well as invasive breast cancers. Clinical trials with a full-breast PEM device have shown high clinical accuracy in characterizing lesions identified as suspicious on the basis of conventional imaging or physical examination (sensitivity 93%, specificity 83%, area under the ROC curve of 0.93), with high sensitivity preserved (91%) for intraductal cancers. Increased sensitivity did not come at a cost of reduced specificity. Considering that intraductal cancer represents more than 30% of reported cancers, and is the form of cancer with the highest probability of achieving surgical cure, it is likely that the use of PEM will complement anatomic imaging modalities in the areas of surgical planning, high-risk monitoring, and minimally invasive therapy. The quantitative nature of PET promises to assist researchers interested studying the response of putative cancer precursors (e.g., atypical ductal hyperplasia) to candidate prevention agents.

Positron emission mammography: initial clinical results.

BACKGROUND: Evaluation of high-risk mammograms represents an enormous clinical challenge. Functional breast imaging coupled with mammography (positron emission mammography [PEM]) could improve imaging of such lesions. A prospective study was performed using PEM in women scheduled for stereotactic breast biopsy. METHODS: Patients were recruited from the surgical clinic. Patients were injected with 10 mCi of 2-[18F] fluorodeoxyglucose. One hour later, patients were positioned on the stereotactic biopsy table, imaged with a PEM scanner, and a stereotactic biopsy was performed. Imaging was reviewed and compared with pathologic results. RESULTS: There were 18 lesions in 16 patients. PEM images were analyzed by drawing a region of interest at the biopsy site and comparing the count density in the region of interest with the background. A lesion-to-background ratio >2.5 appeared to be a robust indicator of malignancy and yielded a sensitivity of 86%, specificity of 91%, and overall diagnostic accuracy of 89%. No adverse events were associated with the PEM imaging. CONCLUSIONS: The data show that PEM is safe, feasible, and has an encouraging accuracy rate in this initial experience. Lesion-to-background ratios >2.5 were found to be a useful threshold value for identifying positive (malignant) results. This study supports the further development of PEM.