Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications
Abstract
:1. The Blood–Brain Barrier
2. BBB Opening by Focused Ultrasound
2.1. Biological Effect Discovery
2.2. Histological Findings and Tissue Damage
2.3. Inflammatory Effect
2.4. Safety of Repeated Interventions
2.5. Vascular Observations
3. BBBO Optimization
3.1. Medical Image Detection
3.2. Microbubbles and Ultrasound Parameters
3.3. Detection and Control
4. Preclinical Validation of CNS Disease Treatment
4.1. BBBO for Brain Tumors (Smaller Drug Molecules)
4.2. BBBO for Brain Tumors (Large Molecular Drugs)
4.3. BBBO Anticancer Immune Modulation
4.4. BBBO for Alzheimer’s Disease Treatment
4.5. BBBO for Parkinson’s Disease Treatment
4.6. BBBO for Huntington’s Disease Treatment
5. Clinical Translation of BBBO
5.1. Medical Device Design
5.2. Clinical Brain Tumor Treatment
5.3. Clinical AD Treatment
5.4. Clinical Adoption for Other Diseases
6. Other CNS Applications
6.1. BBBO-Induced Neuromodulation and Sonogenetics
6.2. FUS-Mediated Thrombolysis
6.3. FUS-BBBO to Sensitize Liquid Biopsy
6.4. Opening the Brain–Retina and Brain–Spinal Cord Barriers
7. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Banks, W.A. From blood-brain barrier to blood-brain interface: New opportunities for CNS drug delivery. Nat. Rev. Drug Discov. 2016, 15, 275–292. [Google Scholar] [CrossRef] [PubMed]
- Profaci, C.P.; Munji, R.N.; Pulido, R.S.; Daneman, R. The blood-brain barrier in health and disease: Important unanswered questions. J. Exp. Med. 2020, 217. [Google Scholar] [CrossRef]
- Petersen, M.A.; Ryu, J.K.; Akassoglou, K. Fibrinogen in neurological diseases: Mechanisms, imaging and therapeutics. Nat. Rev. Neurosci. 2018, 19, 283–301. [Google Scholar] [CrossRef]
- Arvanitis, C.D.; Ferraro, G.B.; Jain, R.K. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat. Rev. Cancer 2020, 20, 26–41. [Google Scholar] [CrossRef] [PubMed]
- Venkataramani, V.; Tanev, D.I.; Strahle, C.; Studier-Fischer, A.; Fankhauser, L.; Kessler, T.; Korber, C.; Kardorff, M.; Ratliff, M.; Xie, R.; et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 2019, 573, 532–538. [Google Scholar] [CrossRef]
- Zeng, Q.; Michael, I.P.; Zhang, P.; Saghafinia, S.; Knott, G.; Jiao, W.; McCabe, B.D.; Galvan, J.A.; Robinson, H.P.C.; Zlobec, I.; et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 2019, 573, 526–531. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Wang, C.; Wang, L.; Chen, Y. A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment. Drug Deliv. 2019, 26, 551–565. [Google Scholar] [CrossRef]
- Sarkaria, J.N.; Hu, L.S.; Parney, I.F.; Pafundi, D.H.; Brinkmann, D.H.; Laack, N.N.; Giannini, C.; Burns, T.C.; Kizilbash, S.H.; Laramy, J.K.; et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018, 20, 184–191. [Google Scholar] [CrossRef] [PubMed]
- Hendricks, B.K.; Cohen-Gadol, A.A.; Miller, J.C. Novel delivery methods bypassing the blood-brain and blood-tumor barriers. Neurosurg. Focus 2015, 38, E10. [Google Scholar] [CrossRef] [PubMed]
- Da Ros, M.; De Gregorio, V.; Iorio, A.L.; Giunti, L.; Guidi, M.; de Martino, M.; Genitori, L.; Sardi, I. Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier. Int. J. Mol. Sci. 2018, 19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hambardzumyan, D.; Bergers, G. Glioblastoma: Defining Tumor Niches. Trends Cancer 2015, 1, 252–265. [Google Scholar] [CrossRef] [Green Version]
- Vykhodtseva, N.I.; Hynynen, K.; Damianou, C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med. Biol. 1995, 21, 969–979. [Google Scholar] [CrossRef]
- Hynynen, K.; McDannold, N.; Vykhodtseva, N.; Jolesz, F.A. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 2001, 220, 640–646. [Google Scholar] [CrossRef] [PubMed]
- Hynynen, K.; McDannold, N.; Sheikov, N.A.; Jolesz, F.A.; Vykhodtseva, N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 2005, 24, 12–20. [Google Scholar] [CrossRef]
- Hynynen, K.; McDannold, N.; Martin, H.; Jolesz, F.A.; Vykhodtseva, N. The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison (R)). Ultrasound Med. Biol. 2003, 29, 473–481. [Google Scholar] [CrossRef]
- McDannold, N.; Vykhodtseva, N.; Raymond, S.; Jolesz, F.A.; Hynynen, K. MRI-guided targeted blood-brain barrier disruption with focused ultrasound: Histological findings in rabbits. Ultrasound Med. Biol. 2005, 31, 1527–1537. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Wai, Y.Y.; Chen, W.S.; Chen, J.C.; Hsu, P.H.; Wu, X.Y.; Huang, W.C.; Yen, T.C.; Wang, J.J. Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging. Ultrasound Med. Biol. 2008, 34, 598–606. [Google Scholar] [CrossRef]
- Fan, C.H.; Liu, H.L.; Huang, C.Y.; Ma, Y.J.; Yen, T.C.; Yeh, C.K. Detection of intracerebral hemorrhage and transient blood-supply shortage in focused-ultrasound-induced blood-brain barrier disruption by ultrasound imaging. Ultrasound Med. Biol. 2012, 38, 1372–1382. [Google Scholar] [CrossRef] [PubMed]
- Arvanitis, C.D.; Vykhodtseva, N.; Jolesz, F.; Livingstone, M.; McDannold, N. Cavitation-enhanced nonthermal ablation in deep brain targets: Feasibility in a large animal model. J. Neurosurg. 2016, 124, 1450–1459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kovacs, Z.I.; Kim, S.; Jikaria, N.; Qureshi, F.; Milo, B.; Lewis, B.K.; Bresler, M.; Burks, S.R.; Frank, J.A. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc. Natl. Acad. Sci. USA 2017, 114, E75–E84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McMahon, D.; Bendayan, R.; Hynynen, K. Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome. Sci. Rep. 2017, 7. [Google Scholar] [CrossRef] [PubMed]
- McMahon, D.; Hynynen, K. Acute Inflammatory Response Following Increased Blood-Brain Barrier Permeability Induced by Focused Ultrasound is Dependent on Microbubble Dose. Theranostics 2017, 7, 3989–4000. [Google Scholar] [CrossRef]
- Sinharay, S.; Tu, T.W.; Kovacs, Z.I.; Schreiber-Stainthorp, W.; Sundby, M.; Zhang, X.; Papadakis, G.Z.; Reid, W.C.; Frank, J.A.; Hammoud, D.A. In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study. J. Neuroinflamm. 2019, 16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, R.R.; Jiang, J.; Li, H.W.; Chen, M.; Liu, R.F.; Sun, S.J.; Ma, D.; Liang, X.L.; Wang, S.M. Phosphatidylserine-microbubble targeting-activated microglia/macrophage in inflammation combined with ultrasound for breaking through the blood-brain barrier. J. Neuroinflamm. 2018, 15. [Google Scholar] [CrossRef] [PubMed]
- McDannold, N.; Arvanitis, C.D.; Vykhodtseva, N.; Livingstone, M.S. Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: Safety and efficacy evaluation in rhesus macaques. Cancer Res. 2012, 72, 3652–3663. [Google Scholar] [CrossRef] [Green Version]
- Downs, M.E.; Buch, A.; Sierra, C.; Karakatsani, M.E.; Teichert, T.; Chen, S.S.; Konofagou, E.E.; Ferrera, V.P. Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task. PLoS ONE 2015, 10, e0125911. [Google Scholar] [CrossRef]
- Horodyckid, C.; Canney, M.; Vignot, A.; Boisgard, R.; Drier, A.; Huberfeld, G.; Francois, C.; Prigent, A.; Santin, M.D.; Adam, C.; et al. Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: A multiparametric study in a primate model. J. Neurosurg. 2017, 126, 1351–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsai, H.C.; Tsai, C.H.; Chen, W.S.; Inserra, C.; Wei, K.C.; Liu, H.L. Safety evaluation of frequent application of microbubble-enhanced focused ultrasound blood-brain-barrier opening. Sci. Rep. 2018, 8, 17720. [Google Scholar] [CrossRef]
- Cho, E.E.; Drazic, J.; Ganguly, M.; Stefanovic, B.; Hynynen, K. Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood-brain barrier opening. J. Cereb. Blood Flow Metab. 2011, 31, 1852–1862. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nhan, T.; Burgess, A.; Cho, E.E.; Stefanovic, B.; Lilge, L.; Hynynen, K. Drug delivery to the brain by focused ultrasound induced blood-brain barrier disruption: Quantitative evaluation of enhanced permeability of cerebral vasculature using two-photon microscopy. J. Control. Release 2013, 172, 274–280. [Google Scholar] [CrossRef] [PubMed]
- Tsai, M.T.; Zhang, J.W.; Wei, K.C.; Yeh, C.K.; Liu, H.L. Assessment of temporary cerebral effects induced by focused ultrasound with optical coherence tomography angiography. Biomed. Opt. Express 2018, 9, 507–517. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Hsu, P.H.; Chu, P.C.; Wai, Y.Y.; Chen, J.C.; Shen, C.R.; Yen, T.C.; Wang, J.J. Magnetic resonance imaging enhanced by superparamagnetic iron oxide particles: Usefulness for distinguishing between focused ultrasound-induced blood-brain barrier disruption and brain hemorrhage. J. Magn. Reson. Imaging 2009, 29, 31–38. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Hua, M.Y.; Yang, H.W.; Huang, C.Y.; Chu, P.C.; Wu, J.S.; Tseng, I.C.; Wang, J.J.; Yen, T.C.; Chen, P.Y.; et al. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc. Natl. Acad. Sci. USA 2010, 107, 15205–15210. [Google Scholar] [CrossRef] [Green Version]
- Wang, P.H.; Liu, H.L.; Hsu, P.H.; Lin, C.Y.; Wang, C.R.; Chen, P.Y.; Wei, K.C.; Yen, T.C.; Li, M.L. Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model. J. Biomed. Opt. 2012, 17, 061222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vlachos, F.; Tung, Y.S.; Konofagou, E.E. Permeability assessment of the focused ultrasound-induced blood-brain barrier opening using dynamic contrast-enhanced MRI. Phys. Med. Biol. 2010, 55, 5451–5466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, J.; Zhang, Y.Z.; Vykhodtseva, N.; Jolesz, F.A.; McDannold, N.J. The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. J. Control. Release 2012, 162, 134–142. [Google Scholar] [CrossRef] [Green Version]
- Chai, W.Y.; Chu, P.C.; Tsai, M.Y.; Lin, Y.C.; Wang, J.J.; Wei, K.C.; Wai, Y.Y.; Liu, H.L. Magnetic-resonance imaging for kinetic analysis of permeability changes during focused ultrasound-induced blood-brain barrier opening and brain drug delivery. J. Control. Release 2014, 192, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Aryal, M.; Fischer, K.; Gentile, C.; Gitto, S.; Zhang, Y.Z.; McDannold, N. Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles. PLoS ONE 2017, 12, e0166061. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, K.J.; Liu, H.L.; Hsu, P.H.; Chung, Y.H.; Huang, W.C.; Chen, J.C.; Wey, S.P.; Yen, T.C.; Hsiao, I.T. Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood-brain barrier opening in the rat. Nucl. Med. Biol. 2009, 36, 853–861. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Hua, M.Y.; Chen, P.Y.; Chu, P.C.; Pan, C.H.; Yang, H.W.; Huang, C.Y.; Wang, J.J.; Yen, T.C.; Wei, K.C. Blood-Brain Barrier Disruption with Focused Ultrasound Enhances Delivery of Chemotherapeutic Drugs for Glioblastoma Treatment. Radiology 2010, 255, 415–425. [Google Scholar] [CrossRef]
- Liu, H.L.; Chen, P.Y.; Yang, H.W.; Wu, J.S.; Tseng, I.C.; Ma, Y.J.; Huang, C.Y.; Tsai, H.C.; Chen, S.M.; Lu, Y.J.; et al. In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low-frequency-ultrasound-induced blood-brain barrier opening in swine. J. Magn. Reson. Imaging 2011, 34, 1313–1324. [Google Scholar] [CrossRef]
- Chu, P.C.; Chai, W.Y.; Hsieh, H.Y.; Wang, J.J.; Wey, S.P.; Huang, C.Y.; Wei, K.C.; Liu, H.L. Pharmacodynamic analysis of magnetic resonance imaging-monitored focused ultrasound-induced blood-brain barrier opening for drug delivery to brain tumors. Biomed. Res. Int. 2013, 2013, 627496. [Google Scholar] [CrossRef] [Green Version]
- Hsu, P.H.; Wei, K.C.; Huang, C.Y.; Wen, C.J.; Yen, T.C.; Liu, C.L.; Lin, Y.T.; Chen, J.C.; Shen, C.R.; Liu, H.L. Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PLoS ONE 2013, 8, e57682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fan, C.H.; Lin, W.H.; Ting, C.Y.; Chai, W.Y.; Yen, T.C.; Liu, H.L.; Yeh, C.K. Contrast-enhanced ultrasound imaging for the detection of focused ultrasound-induced blood-brain barrier opening. Theranostics 2014, 4, 1014–1025. [Google Scholar] [CrossRef] [Green Version]
- Liu, H.L.; Hsu, P.H.; Lin, C.Y.; Huang, C.W.; Chai, W.Y.; Chu, P.C.; Huang, C.Y.; Chen, P.Y.; Yang, L.Y.; Kuo, J.S.; et al. Focused Ultrasound Enhances Central Nervous System Delivery of Bevacizumab for Malignant Glioma Treatment. Radiology 2016, 281, 99–108. [Google Scholar] [CrossRef]
- Samiotaki, G.; Vlachos, F.; Tung, Y.S.; Konofagou, E.E. A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood-brain barrier opening reversibility in vivo using MRI. Magn. Reson. Med. 2012, 67, 769–777. [Google Scholar] [CrossRef] [Green Version]
- Choi, J.J.; Feshitan, J.A.; Baseri, B.; Wang, S.G.; Tung, Y.S.; Borden, M.A.; Konofagou, E.E. Microbubble-Size Dependence of Focused Ultrasound-Induced Blood-Brain Barrier Opening in Mice In Vivo. IEEE Trans. Biomed. Eng. 2010, 57, 145–154. [Google Scholar] [CrossRef] [Green Version]
- Yang, F.Y.; Liu, S.H.; Ho, F.M.; Chang, C.H. Effect of ultrasound contrast agent dose on the duration of focused-ultrasound-induced blood-brain barrier disruption. J. Acoust. Soc. Am. 2009, 126, 3344–3349. [Google Scholar] [CrossRef]
- Mcdannold, N.; Vykhodtseva, N.; Hynynen, K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med. Biol. 2008, 34, 930–937. [Google Scholar] [CrossRef] [Green Version]
- Wu, S.K.; Chu, P.C.; Chai, W.Y.; Kang, S.T.; Tsai, C.H.; Fan, C.H.; Yeh, C.K.; Liu, H.L. Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening. Sci. Rep. 2017, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McMahon, D.; Lassus, A.; Gaud, E.; Jeannot, V.; Hynynen, K. Microbubble formulation influences inflammatory response to focused ultrasound exposure in the brain. Sci. Rep. 2020, 10. [Google Scholar] [CrossRef]
- McDannold, N.; Vykhodtseva, N.; Hynynen, K. Targeted disruption of the blood-brain barrier with focused ultrasound: Association with cavitation activity. Phys. Med. Biol. 2006, 51, 793–807. [Google Scholar] [CrossRef]
- Tung, Y.S.; Vlachos, F.; Choi, J.J.; Deffieux, T.; Selert, K.; Konofagou, E.E. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice. Phys. Med. Biol. 2010, 55, 6141–6155. [Google Scholar] [CrossRef] [Green Version]
- Arvanitis, C.D.; Livingstone, M.S.; Vykhodtseva, N.; McDannold, N. Controlled Ultrasound-Induced Blood-Brain Barrier Disruption Using Passive Acoustic Emissions Monitoring. PLoS ONE 2012, 7. [Google Scholar] [CrossRef]
- O’Reilly, M.A.; Hynynen, K. Blood-Brain Barrier: Real-time Feedback-controlled Focused Ultrasound Disruption by Using an Acoustic Emissions-based Controller. Radiology 2012, 263, 96–106. [Google Scholar] [CrossRef] [Green Version]
- Huang, Y.X.; Alkins, R.; Schwartz, M.L.; Hynynen, K. Opening the Blood-Brain Barrier with MR Imaging-guided Focused Ultrasound: Preclinical Testing on a Trans-Human Skull Porcine Model. Radiology 2017, 282, 123–130. [Google Scholar] [CrossRef] [Green Version]
- Sun, T.; Zhang, Y.Z.; Power, C.; Alexander, P.M.; Sutton, J.T.; Aryal, M.; Vykhodtseva, N.; Miller, E.L.; McDannold, N.J. Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. Proc. Natl. Acad. Sci. USA 2017, 114, E10281–E10290. [Google Scholar] [CrossRef] [Green Version]
- Tsai, C.H.; Zhang, J.W.; Liao, Y.Y.; Liu, H.L. Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: Implementation of confocal dual-frequency piezoelectric transducers. Phys. Med. Biol. 2016, 61, 2926–2946. [Google Scholar] [CrossRef]
- McDannold, N.; Zhang, Y.Z.; Supko, J.G.; Power, C.; Sun, T.; Peng, C.G.; Vykhodtseva, N.; Golby, A.J.; Reardon, D.A. Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. Theranostics 2019, 9, 6284–6299. [Google Scholar] [CrossRef]
- Wei, K.C.; Chu, P.C.; Wang, H.Y.J.; Huang, C.Y.; Chen, P.Y.; Tsai, H.C.; Lu, Y.J.; Lee, P.Y.; Tseng, I.C.; Feng, L.Y.; et al. Focused Ultrasound-Induced Blood-Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study. PLoS ONE 2013, 8, e58995. [Google Scholar] [CrossRef] [Green Version]
- Liu, H.L.; Huang, C.Y.; Chen, J.Y.; Wang, H.Y.J.; Chen, P.Y.; Wei, K.C. Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment. PLoS ONE 2014, 9, e114311. [Google Scholar] [CrossRef] [PubMed]
- Treat, L.H.; McDannold, N.; Vykhodtseva, N.; Zhang, Y.Z.; Tam, K.; Hynynen, K. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int. J. Cancer 2007, 121, 901–907. [Google Scholar] [CrossRef]
- Beccaria, K.; Canney, M.; Goldwirt, L.; Fernandez, C.; Piquet, J.; Perier, M.C.; Lafon, C.; Chapelon, J.Y.; Carpentier, A. Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: An experimental study in rabbits. J. Neurosurg. 2016, 124, 1602–1610. [Google Scholar] [CrossRef] [Green Version]
- Zhang, D.Y.; Dmello, C.; Chen, L.; Arrieta, V.A.; Gonzalez-Buendia, E.; Kane, J.R.; Magnusson, L.P.; Baran, A.; James, C.D.; Horbinski, C.; et al. Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. Clin. Cancer Res. 2020, 26, 477–486. [Google Scholar] [CrossRef]
- Treat, L.H.; McDannold, N.; Zhang, Y.; Vykhodtseva, N.; Hynynen, K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med. Biol. 2012, 38, 1716–1725. [Google Scholar] [CrossRef] [Green Version]
- Aryal, M.; Vykhodtseva, N.; Zhang, Y.Z.; McDannold, N. Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: A safety study. J. Control. Release 2015, 204, 60–69. [Google Scholar] [CrossRef] [Green Version]
- Chen, P.Y.; Hsieh, H.Y.; Huang, C.Y.; Lin, C.Y.; Wei, K.C.; Liu, H.L. Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: A preclinical feasibility study. J. Transl. Med. 2015, 13, 93. [Google Scholar] [CrossRef] [Green Version]
- Kinoshita, M.; McDannold, N.; Jolesz, F.A.; Hynynen, K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc. Natl. Acad. Sci. USA 2006, 103, 11719–11723. [Google Scholar] [CrossRef] [Green Version]
- Kinoshita, M.; McDannold, N.; Jolesz, F.A.; Hynynen, K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem. Biophys. Res. Commun. 2006, 340, 1085–1090. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Wai, Y.Y.; Hsu, P.H.; Lyu, L.A.; Wu, J.S.; Shen, C.R.; Chen, J.C.; Yen, T.C.; Wang, J.J. In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: A magnetic resonance imaging study. J. Cereb. Blood Flow Metab. 2010, 30, 674. [Google Scholar] [CrossRef]
- Park, E.J.; Zhang, Y.Z.; Vykhodtseva, N.; McDannold, N. Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model. J. Control. Release 2012, 163, 277–284. [Google Scholar] [CrossRef] [Green Version]
- Liu, H.L.; Hsieh, H.Y.; Lu, L.A.; Kang, C.W.; Wu, M.F.; Lin, C.Y. Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response. J. Transl. Med. 2012, 10, 221. [Google Scholar] [CrossRef] [Green Version]
- Chen, P.Y.; Wei, K.C.; Liu, H.L. Neural immune modulation and immunotherapy assisted by focused ultrasound induced blood-brain barrier opening. Hum. Vaccines Immunother. 2015, 11, 2682–2687. [Google Scholar] [CrossRef] [Green Version]
- Chen, K.T.; Chai, W.Y.; Lin, Y.J.; Lin, C.J.; Chen, P.Y.; Tsai, H.C.; Huang, C.Y.; Kuo, J.S.; Liu, H.L.; Wei, K.C. Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. Sci. Adv. 2021, 7. [Google Scholar] [CrossRef]
- Burgess, A.; Dubey, S.; Yeung, S.; Hough, O.; Eterman, N.; Aubert, I.; Hynynen, K. Alzheimer Disease in a Mouse Model: MR Imaging-guided Focused Ultrasound Targeted to the Hippocampus Opens the Blood-Brain Barrier and Improves Pathologic Abnormalities and Behavior. Radiology 2014, 273, 736–745. [Google Scholar] [CrossRef] [Green Version]
- Leinenga, G.; Gotz, J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 2015, 7, 278ra33. [Google Scholar] [CrossRef] [Green Version]
- Raymond, S.B.; Treat, L.H.; Dewey, J.D.; McDannold, N.J.; Hynynen, K.; Bacskai, B.J. Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents in Alzheimer’s Disease Mouse Models. PLoS ONE 2008, 3, e2175. [Google Scholar] [CrossRef]
- Jordao, J.F.; Ayala-Grosso, C.A.; Markham, K.; Huang, Y.; Chopra, R.; McLaurin, J.; Hynynen, K.; Aubert, I. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease. PLoS ONE 2010, 5, e10549. [Google Scholar] [CrossRef] [Green Version]
- Nisbet, R.M.; Van der Jeugd, A.; Leinenga, G.; Evans, H.T.; Janowicz, P.W.; Gotz, J. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 2017, 140, 1220–1230. [Google Scholar] [CrossRef] [Green Version]
- Hsu, P.H.; Lin, Y.T.; Chung, Y.H.; Lin, K.J.; Yang, L.Y.; Yen, T.C.; Liu, H.L. Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction. Sci. Rep. 2018, 8. [Google Scholar] [CrossRef]
- Dubey, S.; Heinen, S.; Krantic, S.; McLaurin, J.; Branch, D.R.; Hynynen, K.; Aubert, I. Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2020, 117, 32691–32700. [Google Scholar] [CrossRef]
- Baseri, B.; Choi, J.J.; Deffieux, T.; Samiotaki, G.; Tung, Y.S.; Olumolade, O.; Small, S.A.; Morrison, B.; Konofagou, E.E. Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles. Phys. Med. Biol. 2012, 57, N65–N81. [Google Scholar] [CrossRef] [Green Version]
- Wang, F.; Shi, Y.; Lu, L.; Liu, L.; Cai, Y.L.; Zheng, H.R.; Liu, X.; Yan, F.; Zou, C.; Sun, C.Y.; et al. Targeted Delivery of GDNF through the Blood-Brain Barrier by MRI-Guided Focused Ultrasound. PLoS ONE 2012, 7, e52925. [Google Scholar] [CrossRef] [Green Version]
- Noroozian, Z.; Xhima, K.; Huang, Y.; Kaspar, B.K.; Kugler, S.; Hynynen, K.; Aubert, I. MRI-Guided Focused Ultrasound for Targeted Delivery of rAAV to the Brain. Methods Mol. Biol. 2019, 1950, 177–197. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.Y.; Hsieh, H.Y.; Pitt, W.G.; Huang, C.Y.; Tseng, I.C.; Yeh, C.K.; Wei, K.C.; Liu, H.L. Focused ultrasound-induced blood-brain barrier opening for non-viral, non-invasive, and targeted gene delivery. J. Control. Release 2015, 212, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.Y.; Hsieh, H.Y.; Chen, C.M.; Wu, S.R.; Tsai, C.H.; Huang, C.Y.; Hua, M.Y.; Wei, K.C.; Yeh, C.K.; Liu, H.L. Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson’s disease mouse model. J. Control. Release 2016, 235, 72–81. [Google Scholar] [CrossRef]
- Fan, C.H.; Ting, C.Y.; Lin, C.Y.; Chan, H.L.; Chang, Y.C.; Chen, Y.Y.; Liu, H.L.; Yeh, C.K. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease. Sci. Rep. 2016, 6, 19579. [Google Scholar] [CrossRef]
- Long, L.; Cai, X.D.; Guo, R.M.; Wang, P.; Wu, L.L.; Yin, T.H.; Liao, S.Y.; Lu, Z.Q. Treatment of Parkinson’s disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles. Biochem. Biophys. Res. Commun. 2017, 482, 75–80. [Google Scholar] [CrossRef]
- Lin, C.Y.; Lin, Y.C.; Huang, C.Y.; Wu, S.R.; Chen, C.M.; Liu, H.L. Ultrasound-responsive neurotrophic factor-loaded microbubble- liposome complex: Preclinical investigation for Parkinson’s disease treatment. J. Control. Release 2020, 321, 519–528. [Google Scholar] [CrossRef]
- Burgess, A.; Huang, Y.; Querbes, W.; Sah, D.W.; Hynynen, K. Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. J. Control. Release 2012, 163, 125–129. [Google Scholar] [CrossRef] [Green Version]
- Lin, C.Y.; Tsai, C.H.; Feng, L.Y.; Chai, W.Y.; Lin, C.J.; Huang, C.Y.; Wei, K.C.; Yeh, C.K.; Chen, C.M.; Liu, H.L. Focused ultrasound-induced blood brain-barrier opening enhanced vascular permeability for GDNF delivery in Huntington’s disease mouse model. Brain Stimul. 2019, 12, 1143–1150. [Google Scholar] [CrossRef]
- Elias, W.J.; Lipsman, N.; Ondo, W.G.; Ghanouni, P.; Kim, Y.G.; Lee, W.; Schwartz, M.; Hynynen, K.; Lozano, A.M.; Shah, B.B.; et al. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N. Engl. J. Med. 2016, 375, 730–739. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Hynynen, K. MR-guided focused ultrasound for brain ablation and blood-brain barrier disruption. Methods Mol. Biol. 2011, 711, 579–593. [Google Scholar] [CrossRef]
- Lipsman, N.; Meng, Y.; Bethune, A.J.; Huang, Y.X.; Lam, B.; Masellis, M.; Herrmann, N.; Heyn, C.; Aubert, I.; Boutet, A.; et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 2018, 9. [Google Scholar] [CrossRef] [Green Version]
- Meng, Y.; Shirzadi, Z.; MacIntosh, B.; Heyn, C.; Smith, G.S.; Aubert, I.; Hamani, C.; Black, S.; Hynynen, K.; Lipsman, N. Blood-Brain Barrier Opening in Alzheimer’s Disease Using MR-guided Focused Ultrasound. Neurosurgery 2019, 66, nyz310_208. [Google Scholar] [CrossRef] [Green Version]
- Carpentier, A.; Canney, M.; Vignot, A.; Reina, V.; Beccaria, K.; Horodyckid, C.; Karachi, C.; Leclercq, D.; Lafon, C.; Chapelon, J.Y.; et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci. Transl. Med. 2016, 8. [Google Scholar] [CrossRef]
- Sonabend, A.M.; Stupp, R. Overcoming the Blood-Brain Barrier with an Implantable Ultrasound Device. Clin. Cancer Res. 2019, 25, 3750–3752. [Google Scholar] [CrossRef] [Green Version]
- Wei, K.C.; Tsai, H.C.; Lu, Y.J.; Yang, H.W.; Hua, M.Y.; Wu, M.F.; Chen, P.Y.; Huang, C.Y.; Yen, T.C.; Liu, H.L. Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: A preliminary study in swine. Am. J. Neuroradiol. 2013, 34, 115–120. [Google Scholar] [CrossRef] [Green Version]
- Idbaih, A.; Canney, M.; Belin, L.; Desseaux, C.; Vignot, A.; Bouchoux, G.; Asquier, N.; Law-Ye, B.; Leclercq, D.; Bissery, A.; et al. Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin. Cancer Res. 2019, 25, 3793–3801. [Google Scholar] [CrossRef] [Green Version]
- Mainprize, T.; Lipsman, N.; Huang, Y.X.; Meng, Y.; Bethune, A.; Ironside, S.; Heyn, C.; Alkins, R.; Trudeau, M.; Sahgal, A.; et al. Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study. Sci. Rep. 2019, 9. [Google Scholar] [CrossRef] [Green Version]
- Park, S.H.; Kim, M.J.; Jung, H.H.; Chang, W.S.; Choi, H.S.; Rachmilevitch, I.; Zadicario, E.; Chang, J.W. One-Year Outcome of Multiple Blood-Brain Barrier Disruptions with Temozolomide for the Treatment of Glioblastoma. Front. Oncol. 2020, 10. [Google Scholar] [CrossRef]
- Park, S.H.; Kim, M.J.; Jung, H.H.; Chang, W.S.; Choi, H.S.; Rachmilevitch, I.; Zadicario, E.; Chang, J.W. Safety and feasibility of multiple blood-brain barrier disruptions for the treatment of glioblastoma in patients undergoing standard adjuvant chemotherapy. J. Neurosurg. 2021, 134, 466–474. [Google Scholar] [CrossRef]
- Chen, K.T.; Lin, Y.J.; Chai, W.Y.; Lin, C.J.; Chen, P.Y.; Huang, C.Y.; Kuo, J.S.; Liu, H.L.; Wei, K.C. Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: Clinical trial protocol. Ann. Transl. Med. 2020, 8, 673. [Google Scholar] [CrossRef]
- Meng, Y.; MacIntosh, B.J.; Shirzadi, Z.; Kiss, A.; Bethune, A.; Heyn, C.; Mithani, K.; Hamani, C.; Black, S.E.; Hynynen, K.; et al. Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. Neuroimage 2019, 200, 275–280. [Google Scholar] [CrossRef]
- Mehta, R.I.; Carpenter, J.S.; Mehta, R.I.; Haut, M.W.; Ranjan, M.; Najib, U.; Lockman, P.; Wang, P.; D’haese, P.F.; Rezai, A.R. Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease. Radiology 2021, 298, 654–662. [Google Scholar] [CrossRef]
- Todd, N.; Zhang, Y.Z.; Arcaro, M.; Becerr, L.; Borsook, D.; Livingstone, M.; McDannold, N. Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain. Neuroimage 2018, 178, 414–422. [Google Scholar] [CrossRef]
- McDannold, N.; Zhang, Y.Z.; Power, C.; Arvanitis, C.D.; Vykhodtseva, N.; Livingstone, M. Targeted, noninvasive blockade of cortical neuronal activity. Sci. Rep. 2015, 5. [Google Scholar] [CrossRef] [Green Version]
- Chu, P.C.; Liu, H.L.; Lai, H.Y.; Lin, C.Y.; Tsai, H.C.; Pei, Y.C. Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening. Sci. Rep. 2015, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abrahao, A.; Meng, Y.; Llinas, M.; Huang, Y.X.; Hamani, C.; Mainprize, T.; Aubert, I.; Heyn, C.; Black, S.E.; Hynynen, K.; et al. First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat. Commun. 2019, 10. [Google Scholar] [CrossRef] [Green Version]
- Gasca-Salas, C.; Fernandez-Rodriguez, B.; Pineda-Pardo, J.A.; Rodriguez-Rojas, R.; Hernandez, F.; Obeso, I.; Marin, D.M.; Guida, P.; del Alamo, M.; Bandera, C.O.; et al. Blood-Brain Barrier Opening with Focused Ultrasound in Parkinson’s Disease Dementia: A Safety and Feasibility Study. Neurology 2020, 94. [Google Scholar]
- Gasca-Salas, C.; Fernandez-Rodriguez, B.; Pineda-Pardo, J.A.; Rodriguez-Rojas, R.; Obeso, I.; Hernandez-Fernandez, F.; del Alamo, M.; Mata, D.; Guida, P.; Ordas-Bandera, C.; et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nat. Commun. 2021, 12. [Google Scholar] [CrossRef]
- Cui, Z.W.; Li, D.P.; Feng, Y.; Xu, T.Q.; Wu, S.; Li, Y.B.; Bouakaz, A.; Wan, M.X.; Zhang, S.Y. Enhanced neuronal activity in mouse motor cortex with microbubbles’ oscillations by transcranial focused ultrasound stimulation. Ultrason. Sonochem. 2019, 59. [Google Scholar] [CrossRef]
- Ibsen, S.; Tong, A.; Schutt, C.; Esener, S.; Chalasani, S.H. Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans. Nat. Commun. 2015, 6. [Google Scholar] [CrossRef] [Green Version]
- Huang, Y.S.; Fan, C.H.; Hsu, N.; Chiu, N.H.; Wu, C.Y.; Chang, C.Y.; Wu, B.H.; Hong, S.R.; Chan, Y.C.; Wu, A.Y.T.; et al. Sonogenetic Modulation of Cellular Activities Using an Engineered Auditory-Sensing Protein. Nano Lett. 2020, 20, 1089–1100. [Google Scholar] [CrossRef]
- Tachibana, K.; Tachibana, S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995, 92, 1148–1150. [Google Scholar] [CrossRef]
- Mizushige, K.; Kondo, I.; Ohmori, K.; Hirao, K.; Matsuo, H. Enhancement of ultrasound-accelerated thrombolysis by echo contrast agents: Dependence on microbubble structure. Ultrasound Med. Biol. 1999, 25, 1431–1437. [Google Scholar] [CrossRef]
- Lee, T.H.; Yeh, J.C.; Tsai, C.H.; Yang, J.T.; Lou, S.L.; Seak, C.J.; Wang, C.Y.; Wei, K.C.; Liu, H.L. Improved thrombolytic effect with focused ultrasound and neuroprotective agent against acute carotid artery thrombosis in rat. Sci. Rep. 2017, 7, 1638. [Google Scholar] [CrossRef] [Green Version]
- Wang, B.; Wang, L.; Zhou, X.B.; Liu, Y.M.; Wang, M.; Qin, H.; Wang, C.B.; Liu, J.; Yu, X.J.; Zang, W.J. Thrombolysis effect of a novel targeted microbubble with low-frequency ultrasound in vivo. Thromb. Haemost. 2008, 100, 356–361. [Google Scholar] [CrossRef] [PubMed]
- Ren, S.T.; Zhang, H.; Wang, Y.W.; Jing, B.B.; Li, Y.X.; Liao, Y.R.; Kang, X.N.; Zang, W.J.; Wang, B. The preparation of a new self-made microbubble-loading urokinase and its thrombolysis combined with low-frequency ultrasound in vitro. Ultrasound Med. Biol. 2011, 37, 1828–1837. [Google Scholar] [CrossRef] [PubMed]
- Zhu, L.; Cheng, G.; Ye, D.; Nazeri, A.; Yue, Y.; Liu, W.; Wang, X.; Dunn, G.P.; Petti, A.A.; Leuthardt, E.C.; et al. Focused Ultrasound-enabled Brain Tumor Liquid Biopsy. Sci. Rep. 2018, 8, 6553. [Google Scholar] [CrossRef]
- Pacia, C.P.; Zhu, L.; Yang, Y.; Yue, Y.; Nazeri, A.; Michael Gach, H.; Talcott, M.R.; Leuthardt, E.C.; Chen, H. Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model. Sci. Rep. 2020, 10, 7449. [Google Scholar] [CrossRef]
- Meng, Y.; Pople, C.B.; Suppiah, S.; Llinas, M.; Huang, Y.; Sahgal, A.; Perry, J.; Keith, J.; Davidson, B.; Hamani, C.; et al. MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors. Neuro Oncol. 2021. [Google Scholar] [CrossRef]
- Park, J.; Zhang, Y.; Vykhodtseva, N.; Akula, J.D.; McDannold, N.J. Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles. PLoS ONE 2012, 7, e42754. [Google Scholar] [CrossRef] [PubMed]
- Weber-Adrian, D.; Thevenot, E.; O’Reilly, M.A.; Oakden, W.; Akens, M.K.; Ellens, N.; Markham-Coultes, K.; Burgess, A.; Finkelstein, J.; Yee, A.J.M.; et al. Gene delivery to the spinal cord using MRI-guided focused ultrasound. Gene Ther. 2015, 22, 568–577. [Google Scholar] [CrossRef] [Green Version]
- Payne, A.H.; Hawryluk, G.W.; Anzai, Y.; Odeen, H.; Ostlie, M.A.; Reichert, E.C.; Stump, A.J.; Minoshima, S.; Cross, D.J. Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability. Neural Regen. Res. 2017, 12, 2045–2049. [Google Scholar] [CrossRef]
- Saunders, N.R.; Dreifuss, J.J.; Dziegielewska, K.M.; Johansson, P.A.; Habgood, M.D.; Mollgard, K.; Bauer, H.C. The rights and wrongs of blood-brain barrier permeability studies: A walk through 100 years of history. Front. Neurosci. 2014, 8, 404. [Google Scholar] [CrossRef]
- Chen, K.T.; Wei, K.C.; Liu, H.L. Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment. Front. Pharmacol. 2019, 10, 86. [Google Scholar] [CrossRef] [Green Version]
Disease Model | Pathogenesis and Unmet Need of Disease | Therapeutic Effect Induced by FUS-BBBO | Agents of Delivery or Reaction Related to FUS Treatment | Main Results | |
---|---|---|---|---|---|
Category | Therapeutic Agents | ||||
Primary brain tumor—glioblastoma | Infiltrative growth of glioma cells limiting surgical total removal nearly impossible | Enhance drug delivery | Smaller molecules | Temozolomide [60,61], carmustine [40], carboplatin [59], irinotecan [63], doxorubicin [62], paclitaxel [64], liposomal-doxorubicin [57,65,66] | Increase drug concentration in all studies, and potential survival benefit [45,59] |
Larger molecules (>1 kDa) | IL-12 [67], dopamine D4 receptor-targeting antibody [68], humanized antihuman EGFR2 monoclonal antibody [69], bevacizumab [45] | ||||
Enhance anticancer immunity | Macrophage [70], TILs [67,73,74] | ||||
Metastatic brain tumor | Small and multiple metastasis, refractory to systemic therapy | Enhance drug delivery | Tratuzumab [71] | Cause tumor regression and survival benefit [71] | |
Alzheimer’s disease | 1. Progressive formation and accumulation of amyloid plaques and tau proteins 2. Degeneration of hippocampal neurons | Clear amyloid plaques | Antiabeta antibody (BAM) [78], RN2N tau specific antibody [79], GSK-3 inhibitor, IVIG [81] | Decrease amyloid plaques, boost neurogenesis, improve behavior performance | |
Enhance immunity | Microglia [75,76] | ||||
Neurogenesis | Hippocampal neurogenesis [75] | ||||
Parkinson’s disease | Progressive degeneration of dopaminergic motor neurons in substantia nigra | Neurogenesis | Gene-encoded viral vector | Recombinant AAV-2 [43,84] | Enhance gene expression and enhance neurotrophic factors delivery at targeted region, even behavioral improvement [87,89] |
Gene-encoded nonviral vector | Liposomal plasmid [85], gene-liposome–microbubble complex [86,89], cationic plasmid microbubble [87], Nrf2 gene plasmid–microbubble [88] | ||||
Neurotrophic factors | BDNF, GDNF, neuturin [82,83] | ||||
Huntingtin disease | Genetically inherited mutant Htt overproduction to damage neurons | Increase the expression of the mutant Htt | RNAi [90] | Reduce Htt expression |
Trial No. | Study Title | Indication | Microbubble/Drug | Device/ Treatment Cycle/ Parameters | Location | Status | Main Results |
---|---|---|---|---|---|---|---|
Brain Tumors | |||||||
NCT02253212 | Safety of BBBO with SonoCloud | rGBM (n = 27) | SonoVue (0.1 mL/kg)/carboplatin | SonoCloud/multiple/0.5–1.1 MPa | France | Completed [96] | Repeated BBBO in combination with carboplatin was safe. |
NCT03626896 | Safety of BBB disruption using NaviFUS system in rGBM multiforme patients | rGBM (n = 9) | SonoVue (0.1 mL/kg) | NaviFUS/single/escalated exposure average 10–16 W | Taiwan | Completed [74] | Targeted and reversible BBBO was safely induced. |
NCT03712293 | ExAblate BBB disruption for glioblastoma in patients | Glioblastoma (n = 10) | Definity (4 μL/kg)/standard chemotherapy | ExAblate Neuro/multiple/PCD-based power regulation | Korea | Completed [101] | Multiple BBBO in combination with temozolomide was safe. |
NCT03714243 | BBB disruption using MRgFUS in the treatment of HER2+ breast cancer brain metastases | Breast cancer with brain metastases (n = 10) | Definity (4 μL/kg)/trastuzumab | ExAblate Neuro/multiple/PCD-based power regulation | Canada | Recruiting | Not available |
NCT04446416 | Efficacy and safety of NaviFUS system with add-on bevacizumab in rGBM patients | rGBM (n = 10) | SonoVue (0.1 mL/kg)/bevacizumab | NaviFUS/multiple/PCD-based power regulation | Taiwan | Recruiting | Not available |
NCT03616860 | Assessment of safety and feasibility of ExAblate BBB disruption for treatment of glioma | Glioblastoma (n = 20) | Definity (4 μL/kg)/TMZ | Insightec/multiple/PCD-based power regulation | Canada | Recruiting | Not available |
AD | |||||||
NCT02986932 | BBBO using FUS with intravenous contrast agents in patients with early AD | AD (n = 6) | Definity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation (average 4.6 W) | Canada | Completed [94] | Targeted BBBO was safe and precise without inducing group-wise amyloid change. |
NCT03119961 | BBBO in AD | AD (n = 10) | SonoVue (0.1 mL/kg) | SonoCloud/multiple/0.5–1.1 MPa | France | Completed | Not available |
NCT03671889 | ExAblate BBB disruption for the treatment of AD | AD (n = 20) | Definity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation | USA | Recruiting [95,104] | FUS-BBBO transiently affect frontoparietal network function. |
NCT03739905 | ExAblate BBBO for treatment of AD | AD (n = 30) | Definity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation | Canada | Recruiting | Not available |
NCT04118764 | Noninvasive BBBO in AD patients using FUS | AD (n = 6) | Definity (10 μL/kg) | Single-element exploratory device/multiple | USA | Recruiting | Not available |
PD and Others | |||||||
NCT03608553 | Evaluate temporary BBB disruption in patients with PDD | PDD (n = 10) | Definity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation | Spain | Not yet recruiting | Not available |
NCT04250376 | Use of transcranial FUS for the treatment of neurodegenerative dementias | PDD (n = 10) | Luminity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation | USA | Recruiting [110,111] | Repeated BBBO is safe and may induce mild cognitive improvement. |
NCT03321487 | BBBO using MR-guided FUS in patients with ALS | ALS (n = 8) | Definity (4 μL/kg) | ExAblate Neuro/multiple/PCD-based power regulation | Canada | Recruiting [109] | FUS-BBBO in motor cortex was safe. |
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Chen, K.-T.; Wei, K.-C.; Liu, H.-L. Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications. Pharmaceutics 2021, 13, 1084. https://doi.org/10.3390/pharmaceutics13071084
Chen K-T, Wei K-C, Liu H-L. Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications. Pharmaceutics. 2021; 13(7):1084. https://doi.org/10.3390/pharmaceutics13071084
Chicago/Turabian StyleChen, Ko-Ting, Kuo-Chen Wei, and Hao-Li Liu. 2021. "Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications" Pharmaceutics 13, no. 7: 1084. https://doi.org/10.3390/pharmaceutics13071084