focused ultrasound in drug delivery and...
TRANSCRIPT
![Page 1: Focused Ultrasound in Drug Delivery and Nanomedicineamos3.aapm.org/abstracts/pdf/90-25407-334462-107822.pdf · 2014. 7. 12. · Focused Ultrasound (HIFU or FUS) • Diagnostic ultrasound:](https://reader037.vdocuments.site/reader037/viewer/2022090811/611cc499bbaac44f9d176e9c/html5/thumbnails/1.jpg)
Focused Ultrasound in Drug
Delivery and NanomedicineBrian O’Neill, PhD AAPM Annual Meeting
July 2014
Thanks to:Nathan MacDannold, BWHKathy Ferrara, UCDNatalya Rapoport, U. Utah
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Motivation
• Delivering drugs exclusively to localized areas of
disease should increase effectiveness and reduce
side effects
• Nanoparticle drug carriers hold promise, but
relying on natural targeting and drug release has
failed to produce the expected results
• Focused ultrasound has advantages for “remote
control” in tissue: deep penetration, accuracy on
the mm scale, non-ionizing, feedback
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Course Outline
• Mechanisms of Ultrasound-Material
Interaction
• Ultrasound Alteration of Tissue Properties
• Enhanced Delivery via Hyperthermia
• BBB Disruption via Stable Cavitation
• Ultrasound Release from Drug Carriers
• Induced Release from micelles and liposomes
• Induced Release from microbubbles
• Release from phase-change nanodroplets
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Focused Ultrasound Focused Ultrasound Focused Ultrasound Focused Ultrasound
(HIFU or FUS)(HIFU or FUS)(HIFU or FUS)(HIFU or FUS)• Diagnostic ultrasound: 1-2 cycle pulses (time resolution), 1-15
MHz (spatial resolution)
• Therapeutic ultrasound: 103-104 cycle pulses, 0.2-3 MHz
• Focused ultrasound: beam is directed to diffraction limited
spot – ie. width ~ wavelength by geometry (single element), or
electronic shift of phase (multiple element array)
• With sound speed ~ 1.5 mm/us, 1MHz ultrasound has
wavelength 1.5 mm, so this is beam waist
• length depends on transducer diameter, for f=D, length~7
mm
• Intensity at focus is:
• For InSightec D = 15 cm, so focusing factor is 104
• Ixducer = 3 W/cm2, so If < 3x104 W/cm2
D
f
22/ dDIareaTAPI xducerf ×==
d
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Effects of Focused Ultrasound
Thermal effects
Hyperthermia (40-45 °C) -> altered blood flow, gene
upregulation, inflammation, apoptosis
Thermal Ablation (50+ °C ) -> cell death through necrosis
Thermal Dose:
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Thermal Conduction:
���� �, � �� �, � � !� " #$�$∆�$
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Effects of Focused Ultrasound
Mechanical effects
Cavitation (combination with bubbles)
&' ∝ )*/,-./
0- � 123
�45363 1 � 8…
-./
Sonoporation and sonolysis -> cell membrane damage
Sonochemistry -> ROS production
Radiation force/shear -> mechanotransduction, bioeffects
: � ; <�*�=>
Other??
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Therapeutic Effects
control pulsed-HIFU
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HIFU-Enhanced Transport
• Working with ultrasound only – very
attractive because clinical translation of
device is much easier
• Idea is that tissue transport properties
(diffusion, permeability) are altered by HIFU
• 5+ years of work on mouse and rabbit
models to understand mechanism
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Pulsed-HIFU treatment
therm
al d
ose (e
q. m
in)
(mm
)
(mm)
(b)
time (s)
pe
ak te
mpe
ratu
re (
°C)
(a)
O’Neill, et al., JMRI 2013
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Treatment Results
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Transport at 24 hours(conclusion: thermal effect)
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Ultrasound-mediated targeted drug
delivery in the brain†
Nathan McDannold
Dept. Radiology, Brigham & Women’s Hospital, Harvard Medical School,
Boston, MA
†used with permission
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William M. Pardridge. “Blood–brain barrier delivery” Drug Discovery Today Volume 12, Numbers 1/2 January 2007 p54-61
>98% of small
molecule drugs do not
cross the BBB
~100% of large
molecule drugs do not
cross the BBB
<1% of drug companies have
a BBB drug targeting program
<1% of academic neuroscience
programs emphasize BBB transport biology
Whole-body autoradiogram of a mouse sacrificed after IV injection of a small molecule (histamine, 111 Da)
Blood-brain barrier (BBB)
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Rabbit MRI Trypan blue in rat
• Low-power, pulsed exposures
• Combined with ultrasound contrast agent (Optison, Definity)
• Temporary (~hours), localized, non-invasive
BBB disruption with focused ultrasound
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• Occurs due to mechanically-induced changes and/or stimulation to vasculature
• Caused by microbubble/US interaction
• Not due to heating
• Exact mechanism(s) not known
BBB disruption with Focused Ultrasound
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Results: # TJ proteins reduced after BBBD; restored at 4h
Sheikov et al. Ultras. Med Biol (2008)
ZO-1 Claudin 5
Occludin Claudin-1
gold
part
icle
s p
er
µm
Time after sonication (h)
gold
part
icle
s p
er
µm
Time after sonication (h)
gold
part
icle
s p
er
µm
Time after sonication (h)
gold
part
icle
s p
er
µm
Time after sonication (h)
Electron microscopy study: tight junctions
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Hynynen et al., Neuroimage 2004
Mechanical interaction between US, microbubbles, and vessel walls results in:
• Transient disassembly of tight junction proteins
• Stimulation of active transport
At higher exposure levels, inertial cavitation occurs, leading to vessel damage
BBB disruption with focused ultrasound
Leakage through tight junctions
Vesicular transport
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Electron microscopy study: active transport
Capillary
Venule
Arteriole
5 m
in a
fter F
US
1h
afte
r FU
S
N. Sheikov et al. Ultrasound Med. Biol. 2008
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Raymond et al., PLoS One 2008
Alzheimer’s model mouse
Endogenous IgG (green)
+Trypan blue bound to Amyloid plaque (red)
Small animal studies:• Reliably induce BBB
disruption without tissue damage
• Deliver a range of molecules to the brain, including therapeutics
• Improve outcomes in animal disease models
Glioma, Alzheimer’s
Trypan
Blue
Anti-Aβ
antibodies
BBB disruption with focused ultrasound
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J. Park et al. J Control Release. 2012
Characterizing BBBD with dynamic contrast enhanced MRI
t½: ~2h
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Summary of therapeutic agents delivered via FUS-BBBD
• Chemotherapy
BCNU, methotrexate, doxorubicin, liposomal doxorubicin
• Antibodies
Herceptin, BAM10 (Alzheimer’s)
• Nanoparticles
Magnetic nanoparticles
Gold nanoparticles
• Neuroprotective agent
BDNF, GDNF (Parkinson’s, stroke, traumatic brain injury)
• Viruses
siRNA for Htt (Huntington’s disease)
• Cells
Neural precursor cells (stem cells)
Natural killer cells
• Nothing!
BBBD alone might help Alzheimer’s disease, induce neurogenesis
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FUS Induced Release from
NanoparticlesTwo general approaches: Thermal and
Mechanical
Thermal:Thermal:Thermal:Thermal: Competes with many other
modalities: RF, laser, AMF
Relies of heat sensitive liposomes, heat
sensitive polymers – maybe reversible
Mechanical:Mechanical:Mechanical:Mechanical: based on cavitation
Microbubbles, nanodroplets – not reversible
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Thermally sensitive liposomes
Liposomes are spherical lipid bilayers that can
be used for carrying hydrophilic drugs
Problem: either too leaky or too stable
Sol’n: Lipid bilayers undergo gel to liquid
phase transition with temperature
dependent on composition. Leaky during
transition due to phase mismatch
LTSL: developed at Duke, now used many
placesMills & Needham, BBA Biomembranes, 2005; 1716(2):77–96
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Thermal sensitive polymeric NPs
Many kinds of nanoparticles built of polymers
as drug carriers – generally slow diffusion
Some polymers undergo conformational phase
change that alters solubility in water
(expansion, collapse, micelle formation,
disassociation…)
Huge potential, barely
scratching surface
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Ablation + long circulating LTSL†
16 element annular array (IMASONIC)
3 MHz center frequency
14 MPa PPP, -7.7 MPa PNP
7 s CW, single spot >65 °C
Ferrara lab
†used with permission
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64Cu-LCL – no US
260% ID/cc
25 % ID/cc
1cm
6 hours6 hours6 hours6 hours 20 hours20 hours20 hours20 hours 48 hours48 hours48 hours48 hours
Ferrara lab
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MRgFUS + 64Cu-LCL
270% ID/cc
25 % ID/cc
1cm
6 hours6 hours6 hours6 hours 20 hours20 hours20 hours20 hours 48 hours48 hours48 hours48 hours
Ferrara lab
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Complexation of Cu(II) and Dox within liposomes
Ammonium sulfate method
Copper gluconate/TEA method
6
3
7
54
pH
Problem: Even liposomal doxorubicin has substantial cardiac toxicity and dose cannot exceed 500 mg/m2 in lifetime.
Solution: Create a doxorubicin salt that is very stable in circulation
Kheirolomoom et al Molecular Pharmaceutics
0
50
100
3 5 7 8
Do
x re
lati
ve F
l (%
)D
ox
rela
tive
Fl (
%)
Do
x re
lati
ve F
l (%
)D
ox
rela
tive
Fl (
%)
pH pH pH pH
***
**
**
Ferrara lab
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CuDox-lipo Cu-lipo
100 nmDoxil
100 nm
Complex of Cu(II) & Dox with liposomes
Lasic, D.D. et al., Biochimica
Biophysica Acta (1995) vol.
1239, 145-156
Kheirolomoom et al Molecular Pharmaceutics2010
Ferrara lab
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* p<0.05 compared to control*** P<0.001 compared to control
Tumor growth
0
20
40
60
80
100
120
0 50 100 150 200 250
Su
rviv
al, %
Su
rviv
al, %
Su
rviv
al, %
Su
rviv
al, %
Day post treatmentDay post treatmentDay post treatmentDay post treatment
Control
CuDox-LTSLs
CuDox-LTSLs+US
-500
500
1500
2500
3500
4500
5500
0 10 20 30 40 50
Tum
or
gro
wth
, %Tu
mo
r g
row
th, %
Tum
or
gro
wth
, %Tu
mo
r g
row
th, %
Day post treatmentDay post treatmentDay post treatmentDay post treatment
Control
Control+US
CuDox-LTSLs
CuDox-LTSLs+US
200 250
*******
~ ~
US
Treat 2x/week, 4 weeks, 6 mg/kg
Kheirolomoom et al, JCR 2013
Ferrara lab
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-10
-5
0
5
10
15
20
25
30
0 5 10 15 20 25 30We
igh
t c
ha
ng
e, %
Day post treatment
ControlCuDox-LTSLsCuDox-LTSLs+US
*
0
5
10
15
20
25
WBC, K/µL RBC,M/µL
Blo
od
ce
ll c
ou
nt
Blo
od
ce
ll c
ou
nt
Blo
od
ce
ll c
ou
nt
Blo
od
ce
ll c
ou
nt
CuDox-LTSLs
Control
***
0
2
4
6
8
10
Albumin Total protein
Pro
tein
, g
/dL
CuDox-LTSLs
Control
0
400
800
1200
1600
Org
an
we
igh
t, m
g
CuDox-LTSLs
Control
Toxicity is low
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0.01
0.1
1
10
100
0.3 0.7 1.0 2.0 4.0
%ID
Time insonation (hrs)
0.5 cm
1 cm
2 cm
4 cm
Assumes 5% blood volume in tumor10 sec tumor blood refresh5 L blood volume
Diameter
%ID delivered depends on volume insonified, time of insonation
Why do we favor thermally-sensitivenanoparticles?
Ferrara lab
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Non-Thermal Release
Release driven via pressure changes,
cavitation – rapid release, no change in T
Types include drug loaded microbubbles, gas
containing liposomes, liposomes attached to
microbubbles, phase shifting ‘nanodroplets’
The latter are PFC with bulk liquid-gas
transitions around body temperature that are held together by Laplace pressure:Δ@ � !A
2
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Liposomes or oil carriers on bubbles
Microbubble
Nanoparticle
A
A
AA
A
A
B
B
B
PEG
UMB 2006,JCR, 2006 and 2007
Fluid Concentration (Bubble-bead aggregates/mL)
105 106 107
Ferrara lab
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NanodropletsNanodropletsNanodropletsNanodroplets†††† (Courtesy of N. (Courtesy of N. (Courtesy of N. (Courtesy of N. RapoportRapoportRapoportRapoport, U. of Utah) , U. of Utah) , U. of Utah) , U. of Utah)
Versatile structures with properties that depend on
the core and shell compositions
Core:PFP, Tb = 29 °CPFCE, Tb= 140 ° C
PFC droplet
Hydrophobic part of the shellwith drug
Hydrophilic corona
Shell: PEG-PDLAPEG-PLLAPEG-PCLPluronic
†used with permission
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Ultrasound effect on the Ultrasound effect on the Ultrasound effect on the Ultrasound effect on the nanodropletnanodropletnanodropletnanodroplet
Scheme of the ultrasound-induced drug release
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Ovarian Carcinoma ModelOvarian Carcinoma ModelOvarian Carcinoma ModelOvarian Carcinoma Model
Rapoport, N. et al., J Control Release 2009; 138(3): 268-276
• Chemotherapy by PTX/PFP/PEG-PLLA nanodroplets and ultrasound
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Rapoport, N. et al., J Control Release 2011; 153(1): 4-15
MRgFUS MRgFUS MRgFUS MRgFUS Tumor TreatmentsTumor TreatmentsTumor TreatmentsTumor Treatments• Small Animal LabFUS System (Image Guided Therapy, Inc.)
• 16-element annular transducer, f = 3 MHz, rc = 3.5 cm
transducer
agar
holdertumor
water-filled tubes
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Treatment monitoring: Treatment monitoring: Treatment monitoring: Treatment monitoring:
MR ThermometryMR ThermometryMR ThermometryMR Thermometry
Ultrasound Parameters•3-MHz•P = 3.4 MPa•1 x 3 mm focal spot•Grid trajectory, 4 x 5 mm•5 minute sonication time
Coronal slice orientation
agar holder
tumor
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MR thermometry responseMR thermometry responseMR thermometry responseMR thermometry response
3
1
2
Maximum temperature projection in time
MR Parameters
•SegEPI sequence, EPI=3
•2x2x3 mm (ZFI to 1x1x3mm)
•1.3 seconds
•TR/TE = 60/10 ms
•Flip angle = 15°
•752 Hz/pixel
•Referenceless reconstruction
1
3
tumor @ 33°C
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Tumor ResolutionTumor ResolutionTumor ResolutionTumor Resolution
Tumor cells were transfected with RFP; only viable cells generated fluorescence
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Growth Curves Growth Curves Growth Curves Growth Curves
Pancreatic CancerPancreatic CancerPancreatic CancerPancreatic Cancer
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Lifespan resultsLifespan resultsLifespan resultsLifespan results
Treatment GroupTreatment GroupTreatment GroupTreatment Group Average Life SpanAverage Life SpanAverage Life SpanAverage Life Span, , , ,
weeks (mean weeks (mean weeks (mean weeks (mean ±±±± std)std)std)std)
Control (N=7) 3.5 ± 0.5
No injection, MRgFUS (N=6)** 4.8 ± 2.3
Empty droplets, MRgFUS (N=6)** 3.5 ± 2.1
PTX droplets, no MRgFUS (N=7) 7.0 ± 0.8
PTX droplets, MRgFUS (CW, injection-
MRgFUS time=8 hrs, N=8)***
10.3 ± 1.6
**Mice that died within several days after treatment (P>4.2 MPa) were excluded***Survivors (N=2 for the grid trajectory) were excluded
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Results Courtesy of N. Rapoport, U. of Utah
• PTX-loaded nanodroplets + MRgFUS dramatically decrease pancreatic tumor growth
• MR guidance improves treatment outcome
• Detailed anatomic visualization
• Tumor targeting and treatment planning
• Real-time MR temperature imaging
• Treatment success is a function of ultrasound parameters
• In the absence of drug, hyperthermic conditions could increase perfusion and inflammation thus accelerating tumor growth.
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Study Participants
Natalya Rapoport
Allison Payne
Christopher Dillon
Jill Shea
Roohi Gupta
University of Utah, Salt Lake City, Utah, USA
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Understanding Ultrasound/Drug Synergy
• Going beyond the anecdotal evidence
• Look at thermal, mechanical interactions
independently
• Understand biological mechanism
• Clues to what drugs might work best
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HIFU Treatment with Drugs
(Sonodynamic Therapy?)
0
20
40
60
80
100
120
control 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Via
bilit
y o
n d
ay
3 (
%)
Via
bilit
y o
n d
ay
3 (
%)
Via
bilit
y o
n d
ay
3 (
%)
Via
bilit
y o
n d
ay
3 (
%)
[Doxorubicin], ug/mL, N=8[Doxorubicin], ug/mL, N=8[Doxorubicin], ug/mL, N=8[Doxorubicin], ug/mL, N=8
HIFU duty cycle = 0%
HIFU duty cycle = 30%
HIFU duty cycle = 50%
control
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Control HIFU RB3 HIFU+RB3
‘Sonodynamic Therapy’
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Conclusions
Use of ultrasound to alter tissue properties or
drive release from nanocarriers is a very
promising approach to targeted drug delivery
Challenges: need to visualize the target before
you can hit it (metastatic disease problem)
- regular ultrasound limitations: no
penetration in air, little through bone
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Potential Areas for Application
Cancer – large or infiltrative tumor
Cardiac – plaques or thrombii
Neuro – target drugs to specific sites of the
brain, spine
Orthopedic – joints, near surface bone lesions
Ophthalmology – drugs to the retina, through
cornea
Others?