Stanford University

Noninvasive and Targeted Brain Drug Delivery using Transcranial Focused Ultrasound

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Muna Aryal, PhDDepartment of Radiology

Mentors: Drs. Raag Airan & Jeremy Dahl

SCIT SeminarJuly 31, 2019

Stanford University

Outline

v Existing Approaches for Brain Drug Delivery1. Vascular Opening

(Focused Ultrasound + Microbubbles)

2. Without Vascular Opening(Focused Ultrasound + Nanodroplets)

v New Approach for Brain Drug Delivery

vConclusions

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Brain’s Fluid Compartments and Barriers

1. Cerebrospinal fluid: 10%2. Blood vasculature: 10%3. Interstitial fluid: 12-20% 4. Intracellular fluid: 60-68%

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Brain’s Fluid Compartments and Barriers

1. Cerebrospinal fluid: 10%2. Blood vasculature: 10%3. Interstitial fluid: 12-20% 4. Intracellular fluid: 60-68%

Blood-Brain Barrier (BBB)

Blood-CSF Barrier (BCSFB)

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However, those vascular barriers, the BBB, and the BCSFB limit drug delivery for neurological disorders.

Stanford UniversityAryal et al. Advanced Drug Delivery Review; 2014

v Direct Injectionv Implantable devices v Intrathecal/Intraventicular Injectionv BBBD via arterial injection of osmotic solution

• Invasive

• Trans-Nasal Delivery

• Biopharmaceutical

• New: Focused Ultrasound

Approaches for Brain Drug Delivery

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Vascular Opening

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Vascular Opening

ü FDA approved for phase 0/1 trial in brain cancer and alzheimer

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Without Vascular Opening

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Without Vascular Opening

Aryal* & Wang* et al., Neuron. 2018, * equally contributedZhong et al., Biomaterials. 2019

ü Preclinical models for neuroscience and cancer applications

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Left Right

35 min

Left Right

70 minC

ontr

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Left Right FUS Left

RightFUS

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0 35 70 105

Gad

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Time After Gadolinium Injection (Min)

Control Cohort: Right Side Control Cohort: Left SideFUS Cohort: Left Side (Non-Treated)FUS Cohort: Right Side (Treated)

ns*

**

***

*****

105 min

Left Right

LeftRightFUS

Normalized Contrast-Enhanced T1-weighted Magnetic Resonance Images of rat brain

Note: black colored stars & ns: two tailed paired t-test between left (non-treated) and right(treated) hemisphere of the brain in FUS cohortsblue colored stars & ns: two tailed unpaired ttest between Control and FUS Cohort of right hemispheres

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Acknowledgement

Airan’s Lab

Ø Laura J. PisaniØ Frezghi G. HabteØ Aurea Pascal-TenorioØ Niloufar Hosseini Nassab

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Thank you