Worldwide, neurodegenerative diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease while the average age of Americans is steadily increasing. Today, over 35 million Americans are over the age of 65. Within the next 30 years this number is likely to double, putting more and more people at increased risk of neurodegenerative disease. The underlying hypothesis of this study is that the microbubble parameters play a major role in dictating the blood-brain barrier (BBB) properties using Focused Ultrasound (FUS). Over the past funding period in mice in vivo, our group has demonstrated that the lipid-shelled monodisperse microbubbles of separate diameter ranges could be engineered and used for BBB opening. In this renewal study, the primary objective is thus to utilize the previously acquired knowledge on the importance of the microbubble parameters on the BBB opening in mice and investigate how it affects trans-BBB drug delivery in both mice and monkeys. Ideally, the microbubble can be tailored to the molecule to be delivered through the FUS-induced BBB opening, i.e., achieving the highest permeability and volume of diffusion for that molecule while excluding larger ones. The multi-disciplinary team assembled encompasses all critical specialty areas required, such as ultrasound and microbubble engineering as well as MRI, PET and fluorescence brain imaging, drug delivery, behavioral assessment and mouse model development as they pertain to neuroscience and neurology.
The specific aims are thus to: 1) assess the role of the microbubble in trans-BBB drug delivery;2) assess the role of the microbubble in the safety of BBB opening and 3) assess the role of the microbubble in drug delivery and safety in large animals. The role of the microbubble in drug delivery and safety will be defined in this study. This could allow for better control over the efficacy and safety of the technique through bubble optimization and customization to the drug to be delivered. Parkinson's disease will be targeted but the findings should pertain to all other CNS diseases.
Focused Ultrasound (FUS) in conjunction with microbubbles has been shown to be capable of inducing blood-brain barrier opening noninvasively, transiently and selectively. The primary objective of this study is to determine whether through control of the microbubble shell and size the BBB opening properties can be predicted and/or adjusted. A secondary objective entails assessment of its potential for translation to larger animals and thus establish pre-clinical feasibility.
|Wang, S; Olumolade, O O; Sun, T et al. (2015) Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther 22:104-10|
|Chen, Hong; Chen, Cherry C; Acosta, Camilo et al. (2014) A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery. PLoS One 9:e108880|
|Chen, Hong; Konofagou, Elisa E (2014) The size of blood-brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. J Cereb Blood Flow Metab 34:1197-204|
|Marquet, Fabrice; Teichert, Tobias; Wu, Shih-Ying et al. (2014) Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates. PLoS One 9:e84310|
|Wang, Shutao; Samiotaki, Gesthimani; Olumolade, Oluyemi et al. (2014) Microbubble type and distribution dependence of focused ultrasound-induced blood-brain barrier opening. Ultrasound Med Biol 40:130-7|
|Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice et al. (2014) Transcranial cavitation detection in primates during blood-brain barrier opening--a performance assessment study. IEEE Trans Ultrason Ferroelectr Freq Control 61:966-78|
|Samiotaki, Gesthimani; Konofagou, Elisa E (2013) Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. IEEE Trans Ultrason Ferroelectr Freq Control 60:2257-65|
|Chen, Cherry C; Wu, Shih-Ying; Finan, John D et al. (2013) An experimental study on the stiffness of size-isolated microbubbles using atomic force microscopy. IEEE Trans Ultrason Ferroelectr Freq Control 60:524-34|
|Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying et al. (2013) Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets. J Control Release 172:795-804|
|Feshitan, Jameel A; Vlachos, Fotis; Sirsi, Shashank R et al. (2012) Theranostic Gd(III)-lipid microbubbles for MRI-guided focused ultrasound surgery. Biomaterials 33:247-55|
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