Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized BBB opening noninvasively and regionally. Intranasal (IN) administration has emerged as a promising approach for drug delivery to the brain. Traditionally, it has been successfully used as a convenient method for drug delivery to the systemic circulation, because IN administered drugs can be absorbed through a rich vascular network in the nasal cavity into the systemic circulation. Although most drugs absorbed into the blood circulation cannot enter the brain parenchyma because of the BBB, it has been demonstrated feasible in animal and clinical studies that drugs can be directly delivered from the nose to the brain, bypassing the BBB. Over the past few years, our team has shown that the BBB can be reproducibly opened using FUS and intravenously (IV)-administered microbubbles in a specific subcortical region associated with neurodegenerative disease. Molecules on the order of 0.5 kDa-4 MDa, including Dextran, neurotrophic factors and viral vectors, have been shown to be successfully delivered and localized within the intracellular space of neurons triggering signaling pathways within the neuronal cell. In this study, we hypothesize that the BBB opening can be applied entirely noninvasively (i.e., injection-free) while reducing the risk of systemic toxicity. FUS and intranasal delivery are therefore combined for the first time for enhancing the delivery efficiency of intranasally administered drugs to a targeted region while nanodroplets (ND) substitute microbubbles due to their smaller size that should facilitate intranasal delivery (FUS+IN+ND). We propose to develop an entirely noninvasive approach for trans-BBB deliver that offers the advantages of 1) an injection- free approach due to the intranasal (inhalation) administration , 2) higher selectivity due to the nanodroplet vehicle used and 3) lower toxicity due to both intranasal and nanodroplet approaches.
The specific aims are thus to: 1) demonstrate feasibility of BBB opening using nanodroplets administered intranasally; 2) demonstrate efficacy of facilitating protein and gene therapy in a Parkinsonian mouse model. Intranasal delivery of both the vehicle (nanodroplet) and the drug (protein or virus) in combination with FUS could provide an entirely noninvasive, more targeted and less toxic alternative to the currently used methodologies facilitating thus clinical translation and acceptance.

Public Health Relevance

Focused Ultrasound (FUS) in conjunction with microbubbles has been shown to be capable of inducing blood-brain barrier opening noninvasively, transiently and selectively. We propose to develop an entirely noninvasive approach for trans- BBB deliver that offers the advantages of 1) an injection-free approach, 2) reduced systemic toxicity and thus 3) reduced side-effects, 4) reduced administered drug dose and thus 5) lower cost as well as 6) higher percentage of volume administered reaching the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB021103-01A1
Application #
9053114
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Krosnick, Steven
Project Start
2016-01-15
Project End
2017-12-31
Budget Start
2016-01-15
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$251,630
Indirect Cost
$88,200
Name
Columbia University (N.Y.)
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Wu, Shih-Ying; Fix, Samantha M; Arena, Christopher B et al. (2018) Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery. Phys Med Biol 63:035002
Nyankima, A Gloria; Rojas, Juan D; Cianciolo, Rachel et al. (2018) In Vivo Assessment of the Potential for Renal Bio-Effects from the Vaporization of Perfluorocarbon Phase-Change Contrast Agents. Ultrasound Med Biol 44:368-376
Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan et al. (2016) Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor. Sci Rep 6:28599