Putting Drugs Where They Need To Go

Azeem Sarwar

Why Does it Matter ?

Main problems associated:

•Even bio-distribution of pharmaceuticals throughout the body.•Necessity of a large total dose of a drug to achieve high local concentration, with adverse side-effects.

Current practice of drug administration Systemic

(oral intake, intra vascular/muscular injections etc.)

Drug targeting or placing the drug where it needs to go (e.g. to tumor) can help:•Increase the concentration of the drug at its targeted site improving drug efficacy.•Lower the concentration at non-targeted site decreasing the toxic side effects.•Decrease the total drug intake.•Enable drug delivery across the blood barrier.

Can provide improved treatment and Help cure MORE people!

• Drugs will go only where ever the blood goes – inner ear, brain, and eye are behind a blood brain barrier and will not receive any drugs

Less than 0.1% of the administered drugs are taken up by tumor cells in chemotherapy

Administered drug

Tumor gets 1/30 of this

99.9% goes to the healthy tissues !!

Magnetic Drug Targeting(in general)

The Basics of Magnetic Drug Targeting

Magnetic drug delivery is the transport or focusing of therapeutic magnetic carriers to regions of disease by applied magnetic fields 100 –

250 nm

Magnetic carriers can be drug coated nanoparticles(e.g. sized to extravasateinto tumors)

ChemicellGermany

Or they can be other magnetic things …

Polymer capsule with magnetic cores

Micelle with mag cores

Cell with mag cores in or out

The first thing to ensure (obviously) is that the carriers are safe and bio-compatible.

The Basics of Magnetic Drug Targeting (continued)

The magnetic force on an object scales with its volume making the particle ×10 bigger increase the magnetic force by ×1,000

Magnetic fields and forces fall off quickly with the distance away from a magnet

or

++

magnet

STRONG magnet

a) b) c)

now ONOFFx

magnetic field strength |H| ~ 1/x3

magnetic force |F| ~ 1/x7

Magnetic fields are safe for people up to pretty strong fields (think MRI), but there is a limit (first due to inducing eddy currents). United States FDA has set 8 Tesla (adults), 4 Tesla (children) magnetic field, and 20 Tesla/second rate of change, as safe limits.

Current state of the art:Successful phase I human trials to focus magnetized chemotherapy to shallow inoperable tumors by a single permanent magnet

(Lubbe, Germany)0.8 Tesla

magnet

tumorinoperable

0.8 Tesla magnet

tumorinoperable

tumorinoperable 0.8 Tesla

magnet

tumorinoperable

0.8 Tesla magnet

tumorinoperable

tumorinoperable

Control goal: Do better

than a magneton a stick ...

Forces on Magnetic Nanoparticles

highH2

lowH2

Thus any single magnet will attract particles to itself …

NS

nanoparticleforce F

N S

force F

and polarity doesn’t matter (flipping H to –H leaves force, which goes as H2, the same)

In magnetic targeting, the force on a single particle can be written as

F = 1

2k ∇

H 2( ) where k is a constant and H is the magnetic field

This expression implies that a single particle will experience a force from a magnetic field region of low intensity to a magnetic field region of high intensity

Magnetic Drug Targeting to Ear

Why Ear?

•Ear disorder and disease affects millions of patients worldwide. The most common reason for visiting a US doctor is ear infection.

•Tinnitus, commonly described as a ringing or roaring sound in the ears is experienced by 1 in 10 people in the US.

• It can be very loud (90 dB) and can even cause suicidal tendencies.• Noise-induced hearing loss , and Ménière’s disease can cause Tinnitus.• No effective cure available – inner ear is behind blood-labyrinth barrier!

•Sudden Sensorineural Hearing Loss (SSHL) – now you hear tomorrow you won’t.

• Happens most often to people between the ages of 30 and 60• 4000 new cases reported in the US every year. • No effective cure available – inner ear is behind blood-labyrinth barrier!

•Middle Ear Infections (Otitis Media): Middle ear infections are most common in children under 5 years of age.

• Treatments (antibiotics) exists for acute infections, but the success rate varies and recurrences are common.

• Once acute infections develop into chronic, surgical procedure is required to treat the infection.

Single magnets pull. But there are cases where it is good to magnetically push (to inject). Specifically ...

The Inner Ear is Behind the Blood-Labyrinthine Barrier(which is similar to the blood-brain barrier)

Blood vessels that supply blood to most of the body have small pores. This allows drug molecules to diffuse out from blood into surrounding tissue. If a patient eats a pill or is injected with drugs, those drugs can get into most tissue.

Endothelial cells

BLOOD

drug molecules can exit

But blood vessels that supply blood to the inner ear have impermeable walls (to carefully protect the inner ear, and brain and eyes, from any potential contamination). This means that even though drugs are thought to exist for many inner ear pathologies, they cannot reach the inner ear.

There are a a number of inner ear diseases (tinnitus, sudden hearing loss, Meniere’s) that affect millions of patients, where drugs exist (e.g. steroids) but it is thought they do not reach the inner ear sufficiently to have therapeutic effect.

The developed magnetic push treatment to reach the inner ear ...

Step 1: Inject gel with magnetic particles into the middle ear through the ear drum.

The developed magnetic push treatment to reach the inner ear ...

NS

NS

magnetic injector

magnetic push force

Step 2: Use the magnetic injector to non-invasively push therapeutic nanoparticles through the round window membrane into the inner ear.

Then to pull from the opposite side of the head over 12-15 cm

It is much better to push over this short 3-5 cm distance

3-5 cm

It is possible/standard to locally deliver drugs to the middle ear

Magnetic push allows us to extend the delivery to reach the inner ear.

http://www.youtube.com/watch?v=FyZ0OLFEAm8

Pull Is Not Good Enough ...

Kopke et al pulled through the width of a rodents head

~ 2 cm

But even small humans have big heads

> 10 cm

Single magnets pull nanoparticles towards them ...

or

++

magnet

STRONG magnet

a) b) c)

now ONOFFx

magnetic field

||H|| ~ 1 / x3

applied magnetic force drops quickly with distance from magnet ||F|| ~ 1 / x7

To generate the same force as created by Kopke in guinea pigs, but over a 10 cm human head distance, would require a 11 Tesla magnet For comparison, clinical MRIs are in the range of 1-4 Tesla, magnetic field bio-effects can first be observed at 2 Tesla and higher (Allen 2001, Schenk 2005, Chakeres 2005).

11 T

How We Push: Create point of zero magnetic field at a distance (unstable node)

Create a point of zero magnetic field at a distance, a null or cancellation point.

Forces will emanate out from that null point.

NS

H1

H2

NS

Tilt, Flip, and Combine 2 Magnets Fields H just add, Maxwell’s equations are linear (H=H1+H2)

+

NS

A single magnet

Field lines (H) go from North to South

NS

H=0(magnetic

fields cancel)

NS F

H≠0(magnetic fields do

not cancel)

MIS

The Magnetic Injector System

=

How We Pushed: Simulation (of Maxwell’s equations) + 1st Experiments

+

NS

H

H

=

NS

NS

H=0(magnetic

fields cancel here, at point C)

NS F

H≠0(magnetic fields do

not cancel)

b) Magnetic Fields Add

A

B

NS

a) Single Magnetc) Magnetic Fields Cancel at the Node, Magnetic Forces Point Out

d) Magnetic Field e) Resulting Magnetic Forces

N

S

N

S

N

S

N

S

C

+

NS

NS

H

H

=

NS

NS

NS

NS

H=0(magnetic

fields cancel here, at point C)

NS

NS F

H≠0(magnetic fields do

not cancel)

b) Magnetic Fields Add

A

B

NS NS

a) Single Magnetc) Magnetic Fields Cancel at the Node, Magnetic Forces Point Out

d) Magnetic Field e) Resulting Magnetic Forces

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

N

S

C

push region

Pushed 300 nm diameter MNPs into inner ear (cochlea) in rats

NS S

N

And we have verified this treatment leaves rat hearing unharmed.

Eqn for ith element magnetic field:

How Can We Do This Better ? (here comes math)

Goal: Maximize push force at point (x0, y0) in space.

Mathematical Formulation: Use analytical expressions for simple bar magnet (Engel-Herbert et al)

),(),(),( 000000 yxByxAyxH iiiii

βα +=

),(),(),( 001

0000 yxByxAyxH ii

N

iii

βα += ∑

=

Push

Halbach Array

X

1 2

N

Y

(x0, y0)

Pull

θ

for appropriate , P, and Q.q

How: Consider a matrix of magnets (Halbach array). Need to figure out optimum magnetization direction (angle θ ) for each magnet.

),( yxA

),( yxB

magnetic field eqn for

magnetic field eqn for

Then for the entire Halbach array:

minα i ,βi

∇

H 2 (x0, y0 )( )x

122 ≤+ ii βα

Objective:

Subject to

minq

qT P

q

qTQi

q ≤ 1,1 ≤ i ≤ N:

Can be written in matrix from

P and Q are symmetric, but not semi- definite. Non-Convex problem!

for all ,f (q) ≤ F(

q)

q

How Can We Do This Better ? (more math)

Step 1: Semi-definite Relaxation (SDR)

Lower bound

Upper bound

Sub-optimal feasible solution extracted from SDR optimizer

Number of iterations 1

Step 2: Majorization Method

For symmetric matrices P, and Q

,qT P

q = Tr(P

qqT )

qTQi

q = Tr(Qi

qqT )

Define, . G := qqT

minG

Tr(PG) Tr(QiG) ≤ 1,1 ≤ i ≤ N:

And Q ≥ 0, rank ( Q ) = 1

Now the new problem is:

Convex

Non-convex

The relaxed problem is convex with global optimum guaranteed. Q* is the optimizer.

SDR optimizer

The eigen vector corresponding to the largest eigen value of Q* is a feasible solution.

q#

)()()()()(:)( #####

qqqqqfqqqfqF T

q

T −−+∇−+= λ

The majorizer for , at , is : f (q) :=

qT Pq

q#

f (q## ) ≤ F(

q## ) ≤ F(

q# ) = f (

q# )

If minimizes , then we haveq##

F(q)

and at , F(q# ) = f (

q# )

q#

2 3 4

How Can We Do This Better (design examples)

Push Force Design: Generates ×26 more push force than the bench mark magnet (of same volume)

Pull Force Design: Generates ×5 more pull force than the bench mark magnet (of same volume)

Magnetic Pushing at Human Head Working Distance

- 5

0

5 - 50

5

- 5

0

5

y [ c m ]x [ c m ]

z[cm

]A simple two magnet optimal design

2.5 3 3.5 4 4.5 5 5.5 6

8

6

4

2

0

-2

-4

-6

Distance from the yz face of the magnet [cm]

(∇ H

2 ) x [A

2 /m3 ]

Push

Pull

× 10108

6

4

2

0

-2

-4

-6

(∇ H

2 ) x [A

2 /m3 ]

Push

Pull

× 1010

8

6

4

2

0

-2

-4

-6

(∇ H

2 ) x [A

2 /m3 ]

Push

Pull

× 1010

Magnet

Force profile of the designed magnet

Target region

3cm 5cm

scrape for push of red fluorescent nanoparticles

magnetic injector held for 1 hour at a 3 cm adult-human magnet-to-inner-ear distance

Magnets can be nasty!

Animal Experiments

Treating Noise Trauma Hearing Loss

We are carrying out rat experiments for noise trauma hearing loss.

We have a very nice rat model to measure hearing loss ...

If you startle a rat, it jumps

What happened?!?

Stop doing that!

and if you first warn the rat, it jumps less high

time

ampl

itud

e

BEEP

(e.g. at 10 kHz)

But how would you get a rat to tell if its hearing is good or bad?

Huh? Whathappened?!?

If rat has hearingloss, it can’t hearthe beep warning, jumps higher

ampl

itud

e

timerat’s hearing loss

Noise Trauma Hearing Loss: Preliminary Rat Experiment Results

A rat with no magnetic treatment exhibited low pre-pulse inhibition of the startle reflex for a tone warning in a 12-20 kHz range. They could not hear the tones in this range.

A rat with magnetic treatment exhibited normal pre-pulse inhibition of the startle reflex. They could hear the tone warning.

Induced hearing loss in rats by 1 hour of 1/3rd octave, 118 dB band of noise centered on 16kHz.

Then we injected Chemicell 300 nm diameter particles coated with the steroid prednisolone (an anti inflammatory) into their inner ears and measured jump heights after a tone-warning-then-startle sequence ...

We are also testing our magnetic treatment for noise-induced tinnitus ... Tinnitus is the perception of sound (ringing or roaring) when no sound is present. It is common: 1 in 10 people have noticeable level of tinnitus. It can be debilitating (up to 90 dB), in some cases leading to suicidal tendencies.

Currently, no effective treatments for tinnitus (Action On Hearing Loss market report, Goldman and Holme 2010)

We also have a very nice rat model to measure tinnitus ...

We already know that if you startle a rat, it jumps

What happened?!?

Stop doing that!

If you first warn the rat, it jumps less high

time

ampl

itud

e

BEEP

I knew thatwas coming

Can also warn the rat with a silent gap

SILENT GAP

ampl

itud

e

constant tone (e.g. at 12 kHz)time

Huh? Whathappened?!?

We are also testing our magnetic treatment for noise-induced tinnitus ... Tinnitus is the perception of sound (ringing or roaring) when no sound is present. It is common: 1 in 7 people have noticeable level of tinnitus. It can be debilitating (up to 90 dB), in some cases leading to suicidal tendencies.

Currently, no effective treatments for tinnitus (Action On Hearing Loss market report, Goldman and Holme 2010)

We also have a very nice rat model to measure tinnitus ...

We already know that if you startle a rat, it jumps

What happened?!?

Stop doing that!

If you first warn the rat, it jumps less high

time

ampl

itud

e

BEEP

ampl

itud

e

constant tone (e.g. at 12 kHz)time

rat’s tinnitus

If rat has tinnitusIt can’t hear thegap warning, jumps higher

Induced tinnitus in rats by 1 hour of 114 dB noise, 1/3rd of an octave (114 dB is loud enough to create tinnitus but not hearing loss, measured by ABR).

Then we injected Chemicell 300 nm diameter particles coated with the steroid prednisolone (an anti inflammatory) into their inner ears and measured jump heights after a silent-warning-then-startle sequence ...

Rats with no magnetic treatment exhibited less pre-pulse inhibition of acoustic startle for a silent-gap in a 12-16 kHz background tone. They could not hear the tones under their tinnitus.

Rats with magnetic treatment exhibited normal pre-pulse inhibition of acoustic startle. They could hear the background tone and the silent gap warning.

Middle Ear Infections (Otitis Media)

• Single biggest reason to visit a doctor in the US – over 15 million cases in the US

reported last year

• Mostly occur in children under 5 years of age

• Current state of the art :

Step 1: Systemic ingestion of antibiotics

One millionth of the total blood flow reaches the middle ear and, hence, may require strong drug dosage that only reduces the symptoms!

Bacteria in the middle ear may even develop immunity to the antibiotics because of the low dosage that reaches the middle ear which is BAD!

Step 2: Puncture the ear drum and put a tube through it to deliver medication

Tympanostomy tube to access the middle ear(Dohar 2011)

Doesn’t make kids happy

Middle Ear: Treating Otitis Media without Ear Drum Puncture

(Preliminary results) Investigating if magnetic injection can deliver drugs to the middle ear, without a need for ear drum puncture

magnetic injector

NS

N S

magnetic transport

magnetic particles placed in outer ear

200 µm

with magnetic force observed fluorescent particles on cochlea bone (red speckles)

200 µm

vs

no magnetic force, no observed particles at the back of the middle ear

First Test: Rat Middle Ear Tissue Scrapes

Tympanostomy tube to access the middle ear(Dohar 2011)

vs

Clinical Practice

Nano Science

The Big Picture!

Controls

Magnetic Drug Targeting

Tumor

The Big Picture!

Magnetic field shaping

Inhaled therapeutic

particles

Clinical Practice

Nano Science

Controls

Magnetic Drug Targeting

Drug Targeting in Lungs Directing Therapy to Strokes

Medication for stroke can cause blood leakage - Need to steer the drug at the clot location!

AcknowledgementsCollaborators

Benjamin Shapiro – UMDDidier Depireux – UMDRoger Lee – UMDDiego Preciado – Children’s National Medical Center, DCArkadi Nemirovski – Georgia Tech

Undergraduates

Reza Basiri – UMDMohammad Ahmed– UMD

Funding support

Children’s National Institute for Pediatric Surgical Innovation; State of Maryland TEDCO (Technology Development Corporation) and MIPS (Maryland Industrial Partnerships); Action on Hearing Loss and NIGMS-NIH (National Institutes of Health).

Thank you for your attention!