Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound
Authors: Beata Chertok
Robert Langer
Journal: Theranostics (2018)
Discipline: CLINICAL MEDICINE
Keywords: image-guided drug delivery; lung evading microparticles; magnetic microbubbles; remote-controlled drug delivery.; theranostics.
Affiliations: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States., Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA.

Abstract:  Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment. Methods: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting. Results: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (&gt;10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time. Conclusions: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues. 

Retracted: No

PubPeer comments:
 An image of an animal appears to be the same in Figure 5C1 and Figure 7B. Could the authors please check? They seem to be described differently. ***  , 
 #1 Dear Dr. Biskrensis, Thank you for your comment. Indeed, the subject displayed in Figure 7B (top panel, the u2018MF-,US-u2018 column) is the same as the one displayed in Figure 5C1. This subject was administered with MagMB-Cy5.5 without either magnetic or acoustic modulation. These treatment conditions are abbreviated as u2018MF-, US-u2018 in Figure 7B. The images provided in Figures 5C1 and 7B were acquired at different time points. In Figure 5C1, the data are provided for the kinetic sequence acquired between 2 min and 30 min post microbubble administration. In Figure 7B, the image was acquired at 120 min post administration. Hope this help. Best, Beata Chertok , 
 #2 Thank you for your response. My concern was that they not only appear to be the same subject, they seem to have been taken at the same time as the position of the animal appears identical to my eye. This would not be expected for images taken nearly 2 hours apart. Here is a false color image to help illustrate my point. ***  , 
 #1 15, 25 and 30 minutes in C1 all look the same to me. , 
 Thank you for your comments. During longitudinal kinetic scans, the subjects remain deeply anesthetized through continuous inhalation of gas anesthetics. If subjects are not repositioned within the IVIS acquisition chamber between consecutive scans, they often preserve largely the same position. Although the images appear to be similar, they are nevertheless distinct as they were separately acquired at different time points. This becomes apparent if one conducts close examination of image features. Here are a few examples of image features that convey image differences: 1.tPlease note the features of the subjectu2019s mouth on the 15-min and the 2-hr images. On the 2-hr image, the mouse is open slightly wider. There is a discernable dip between the lower and upper jaws on the 2-hr image, which is not present on the 15-min image. 2.t Please note the contour of the backward forepaw in both images. In the 2-hr image, this forepaw stretches a little further out from the body compared to the 15-min image. Positioning differences in both (1) and (2) are small, which is consistent with small movements of the animal due to breathing. 3.tThe signal patterns within the liver are discernably different. Again, although these differences are discernable, they are relatively small. This is perhaps unsurprising provided that the profile of dye accumulation in the liver reaches saturation at about 15 min post administration of the labelled microbubbles, as can be inferred from the quantitative analysis in Figure 5C2. Hope this helps. Best, Beata Chertok ,