Abstract
Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness and relatively broad drug spatial distribution. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body with high spatial and temporal precision. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle meet these needs, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs, beyond a few niche applications. Here, we develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted delivery of hydrophobic drugs with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that are scalable and yield sterile, stable, and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, we exhibit a new potential application of these nanoemulsions for local control of vascular tone. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for efficacious, noninvasive, and localized ultrasonic drug uncaging for myriad targets in the brain and body.
Original language | English |
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Pages (from-to) | 73-86 |
Number of pages | 14 |
Journal | Biomaterials |
Volume | 206 |
DOIs | |
State | Published - Jun 2019 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2019 Elsevier Ltd
Funding
This work was funded with grant support from the National Institutes of Health (BRAIN Initiative RF1 MH114252 ), the National Cancer Institute/Stanford Center for Cancer Nanotechnology Excellence ( NIH U54 CA199075 ), the Dana Foundation, the Foundation of the American Society for Neuroradiology, and the Wallace H. Coulter Foundation. We would also like to thank William T. Newsome, PhD and the Stanford Neurosciences Institute for additional funding support. We would like to thank Yun-Sheng Chen, PhD for assistance in the design and preparation of the nanoemulsions, and Marko Jakovljevic, PhD and Jeremy Dahl, PhD for access to and training on the Siemens Acuson S2000 scanner. We would like to thank Kim Butts Pauly, PhD, Jennifer Dionne, PhD, and the whole Airan Lab for helpful discussions.
Funders | Funder number |
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National Cancer Institute/Stanford Center for Cancer Nanotechnology Excellence | NIH U54 CA199075 |
National Institutes of Health | BRAIN Initiative RF1 MH114252 |
National Cancer Institute | R01CA210553 |
Wallace H. Coulter Foundation | |
Dana Foundation | |
American Society of Neuroradiology |
Keywords
- Clinically translatable
- Drug delivery platform
- Focused ultrasound
- Noninvasive ultrasonic drug uncaging
- Spatiotemporally controlled release
- Targeted drug delivery