Theranostic USPIO‐Loaded Microbubbles for Mediating and Monitoring Blood‐Brain Barrier Permeation

Abstract

Efficient and safe drug delivery across the blood-brain barrier (BBB) remains to be one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, we show that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles within their shell, can be used to mediate and monitor BBB permeation. Upon exposure to transcranial ultrasound pulses, USPIO-MB are destroyed, resulting in acoustic forces inducing vessel permeability. At the same time, USPIO are released from the MB shell, they extravasate across the permeabilized BBB and they accumulate in extravascular brain tissue, thereby providing non-invasive R*-based magnetic resonance imaging information on the extent of BBB opening. Quantitative changes in R* relaxometry were in good agreement with 2D and 3D microscopy results on the extravascular deposition of the macromolecular model drug FITC-dextran into the brain. Such theranostic materials and methods are considered to be useful for mediating and monitoring drug delivery across the BBB, and for enabling safe and efficient treatment of CNS disorders.

Nanoparticle‐stabilized microbubbles for multimodal imaging and drug delivery

“…The novel NP-MBs also provide possibilities for image-guided delivery of NPs using both contrast enhanced ultrasound imaging and MRI [13,42], and the use of MRI to trace the NPs in various tissues. In addition, the NPs can be further targeted to specific biomarkers, allowing for active targeting and hence higher NP/drug accumulation at the disease site.…”

Nanotherapy for Early Dementia: Targeting Senile Dementia

“…Lastly, a completely separate and additional advantage of such LCM/ND lipid nanoemulsion(s), as a component of this combination therapeutic, stems from the characteristic lipid-coated microbubble subpopulation (D'Arrigo 2011) existing in this nanoemulsion type. Specifically, such preformed (lipidstabilized) microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment Alonso et al 2010;Alonso et al 2011;Aslund et al 2017;Bing et al 2014;D'Arrigo 2015;Delalande et al 2013;Goliaei et al 2015;Kotopoulis et al 2013;Kotopoulis et al 2014;Lammers et al 2015;Marquet et al 2011;Meairs 2015;Meng et al 2017;Miller and O'Callaghan 2017), or sonoporation (Aubry et al 2016;Bouakaz et al 2016;Burgess and Hynynen 2016;Castle and Feinstein 2016;Delalande et al 2015;Horodyckid et al 2016;O'Reilly et al 2017;Paefgen et al 2015;Qin et al 2016;Sennoga et al 2016), if additionally desired for the Alzheimer's patient.…”

Ultrasound contrast agents

“…Here, also sonoporation helps open the blood–brain barrier. [96] Anti-tumor drugs could be delivered using UCA, but studies on animals have not reached the point where clinical trials seem to be close.…”