M A N D I H A L AWA N I

D E PA RT M E N T O F B I O LO G I C A L E N G I N E E R I N G

N S F P H YS I C S R E U S U M M E R P RO G R A M

Opening The Blood Brain Barrier (BBB)

W O R K I N G C L O S E LY W I T H T H E G R A D UAT E S T U D E N T M I C H A E L VA L D E Z

& K E Y S S T U D E N T S H E L B Y Y UA N

A L O N G S I D E T H E L A B S A N D R E S E A R C H E R S O F :

T E R RY M AT S U N A G A & M A R E K R O M A N O W S K I

The Laboratory of Dr. Theodore Trouard

The Blood Brain Barrier (BBB)

Neurovascular Unit Isolates brain tissue from blood Blood vessels contain tight cell-cell

junctions Very few substances can cross over

Endothelial Cells

Astrocytes Tight junction

Red Blood cells

Methods that are currently used in Drug Delivery across the BBB

98% of therapies do not cross into the brain tissue

Alzheimer's

Parkinson’s

Brain Tumors

Drilling into the skull and injecting the brain directly

Administering higher doses

Chemo therapy

More costly pharmaceuticals

Waste of resources

U S E O F FO C U S E D U LT R A S O U N D ( F U S )

N O N I N VA S I V E FO R D E L I V E R I N G T H E R A P Y AC RO S S T H E B LO O D B R A I N B A R R I E R ( B B B )

U S E O F M I C RO B U B B L E S

A New Method

Microbubbles

Lipid-coated, gas bubbles

1µm diameter

Travel throughout vascular system

microbubbles

Focused Ultrasound (FUS)

Applied trans cranially

Can be targeted

Microbubbles cavitate and sometimes burst

Focused Ultrasound (FUS)

Microbubbles cavitate and sometimes burst

Endothelial cells temporarily open between junctions

M Y G OA L WA S C R E AT I N G A L I P O S O M E -M I C R O B U B B L E C O M P L E X T O E N C A P S U L AT E T H E R A P E U T I C A G E N T S

T E S T E D I D E A T H R O U G H T H E U S E O F M A G N E T I C R E S O N A N C E I M A G I N G

Developing the Method

Therapeutic Administration

Liposome-Microbubble Complex Spheres of lipids

100 nm liposome

Enclose an aqueous compartment

Able to conjugate about a microbubble

Adapted From: www.sciencedirect.com

µbubble 1 µmLiposomes 0.1 µm

Liposome Production

Freeze/Thaw 10x to make lipid bilayer

Extrude 5mL through 200nm filter & 100nm filter 5x

M AG N E T I C R E S O NA N C E I M AG I N G ( M R I )

N E E D E D TO I M AG E S E V E R A L SA M P L E S AT O N C E

F LO R E S C E N T M I C RO S C O P Y

Carrying out Research

Carrying out Research

Designed cartridge in Solidworks to hold samples centered in the MRI

Printed the cartridge with 3D Printer

Results

Encapsulate known [gadolinium]

MRI images greater intensity than

liposomes with no encapsulated agent

Gd liposomesT1 = .3884 secBlank

liposomesT1 = 2.517 sec

Gd Controls

PBS control

7T MRI

Results

Florescence Imaging

Coated liposomes with florescent pink DiI

Shook to conjugate complex

Successful Liposome-Microbubble Complex

uB + liposomes Conjugated

uB + liposomes Not Conjugated

Results

Liposomes released their cargo in the presence of heat

Gd Liposomes before Heat is applied Gd Liposomes after 15 min in 69 Celsius bath

Gd LiposomesT1 = .3884 sec

Gd Control Gd ControlGd LiposomesT1= .0755 sec

Carrying out Research

Experiments for FUS are currently being performed

WHAT THE FUTURE WOULD HOLD ONCE THE METHOD IS PERFECTED

Future Prospects

Future Prospects

Test method on a mouse

Demonstrate application of FUS releasing therapy

Future Prospects

Expanded development of therapy

Neurological Pathologies

Parkinson’s

Alzheimer's

Targeted anywhere in the body

Vital Organs

TumorsCancers

Diabetes

M I K E VA L D E Z

E V E R Y O N E I N T H E L A B S O F D R . T H E O D O R E T R O U A R D , D R . M A R E K R O M A N O W S K I , D R . T E R R Y M AT S U N A G A

N AT I O N A L S C I E N C E F O U N D AT I O N

D R . M A N N E , D R . P I T U C C O

&

P H Y S I C S R E U M E N T O R S A N D P E E R S

Special Thanks

Questions