Magnetic Drug TargetingMagnetic Drug Targeting

James A. Ritter, Armin D. Ebner and Jan MangualJames A. Ritter, Armin D. Ebner and Jan MangualDepartment of Chemical EngineeringDepartment of Chemical Engineering

Swearingen Engineering CenterSwearingen Engineering CenterUniversity of South CarolinaUniversity of South Carolina

Columbia, SC 29208Columbia, SC 29208

Scientific Retreat onBioengineering and Regenerative Medicine

Charleston, SCMarch 24, 2010

Schematic of an MDT SystemSchematic of an MDT System

Limitations of MDT systemsLimitations of MDT systems

– The fluid drag forces in most The fluid drag forces in most instances overcome the instances overcome the magnetic forces.magnetic forces.

– Magnetic forces decrease Magnetic forces decrease dramatically at large distances dramatically at large distances from the magnetfrom the magnet

Proposed Implant-Assisted MDT SystemProposed Implant-Assisted MDT System• Use ferromagnetic implants to increase the magnetic force at

the site by taking advantage of high gradient magnetic principles

• Advantages

– Localized “stronger” forces

– Distance effects minimized

• Disadvantages

– Mildly invasive techniqueFerromagnetic

Implant

based on three commercially available technologies:based on three commercially available technologies:

an external magnetic field source, such as an FeNdB an external magnetic field source, such as an FeNdB permanent magnet or MRI facilitypermanent magnet or MRI facility

specially designed ferromagnetic and biocompatible specially designed ferromagnetic and biocompatible implants, such as wires, needles, filaments, stents or even implants, such as wires, needles, filaments, stents or even seedsseeds

specially designed particles that are biocompatible, specially designed particles that are biocompatible, contain a drug or radiation, and contain a magnetic contain a drug or radiation, and contain a magnetic materialmaterial

Implant Assisted - MDTImplant Assisted - MDT

Magnetic Fields from IA-MDTMagnetic Fields from IA-MDT magnetic forces must overcome fluid drag magnetic forces must overcome fluid drag

forces forces experiencedexperienced by magnetic drug by magnetic drug carrier particles (MDCPs)carrier particles (MDCPs)

magnetic force (magnetic force (FFmm) exerted on object is ) exerted on object is proportional to both magnetic field (proportional to both magnetic field (HH) ) and magnetic field gradient ( )and magnetic field gradient ( )

tiny ferromagnetic elements become tiny ferromagnetic elements become magnetically energized in presence of magnetically energized in presence of external magnetic fieldexternal magnetic field

presence of these high curvature elements presence of these high curvature elements locally increases magnetic field gradient locally increases magnetic field gradient and hence force on MDCPsand hence force on MDCPs

mF H H H

Magnetic Drug Carrier Particles Magnetic Drug Carrier Particles for IA-MDTfor IA-MDT

Size : 50 - 2000 nmSize : 50 - 2000 nm

Superparamagnetic ParticlesSuperparamagnetic Particles- - FeCo, ferrites, etc.FeCo, ferrites, etc.- - largest magnetizationlargest magnetization- - 80 wt% max (40-50 vol%)80 wt% max (40-50 vol%)

PolymerPolymer- - biocompatiblebiocompatible- - non-immunogenicnon-immunogenic- - biodegradablebiodegradable-- porous for drug transportporous for drug transport

DrugDrug- - free or fixed (radioactive)free or fixed (radioactive)

MDCP SurrogatesMDCP Surrogates

Bangs Laboratories, Inc.Bangs Laboratories, Inc.

~20 wt% Magnetite

Magnetic Implants for IA-MDTMagnetic Implants for IA-MDTStents & CathetersStents & Catheters

Target:Target: veins and arteriesveins and arteries urinary Tracturinary Tract pancreatic and biliary ductspancreatic and biliary ducts digestive tract, etcdigestive tract, etc

Filaments & NeedlesFilaments & NeedlesTarget: Target: vessels (listed above)vessels (listed above) blood capillariesblood capillaries

Nanosized SeedsNanosized Seeds (50-1000 nm)(50-1000 nm)Target:Target: blood capillariesblood capillaries

They must be biocompatible!

0 - 80 cm/s

0 - 80 cm/s

0.01 - 1.0 cm/s

Blood Vessel Velocity Range

Comsol SimulationsComsol Simulations

Simulation for 0.96 Simulation for 0.96 m MDCPs with 60 wt% magnetitem MDCPs with 60 wt% magnetiteat an applied field of 0.65 T and a velocity of 2.1 cm/s.at an applied field of 0.65 T and a velocity of 2.1 cm/s.

Magnetic Field Magnetic Field GradientsGradients

MDCP MDCP StreamlinesStreamlines

Last captured Last captured particle particle

Trajectory Trajectory

In VitroIn Vitro Particle Capture Images Particle Capture ImagesEffect of Fluid Velocity on Particle CaptureEffect of Fluid Velocity on Particle Capture

A1)A1) A2)A2)

B1)B1) B2)B2)

Images at Images at velocities of A) velocities of A) 2.1, and B) 21.2 2.1, and B) 21.2 cm/s 1) before cm/s 1) before and 2) after 10 and 2) after 10 ml of solution ml of solution have passed have passed through the through the

collection area collection area at an applied at an applied

magnetic field magnetic field of 0.17 T.of 0.17 T.

Experimental and Model ResultsExperimental and Model Results Effect of Fluid VelocityEffect of Fluid Velocity

0

5

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0 10 20 30 40v (cm/s)

Capt

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Effic

ienc

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)

0.65 T0.17 T

DDp p = 0.87 = 0.87 mmxxfm fm = 25 wt%= 25 wt%DDw w = 125 = 125 mm Velocity negatively Velocity negatively

affects capture, affects capture, but even at high but even at high

velocities capture velocities capture is still attainable.is still attainable.

Capture seems to reach Capture seems to reach a steady value, where a steady value, where decrease in capture is decrease in capture is

greatly reduced.greatly reduced.

model

Particle Capture VideoParticle Capture Video

Dp = 0.87 m Dw = 125 m uB= 2.12 cm/s H = 0.15 T

Biodegradable Magnetic Stent Biodegradable Magnetic Stent FabricationFabrication

Poly(Poly(DLDL-lactic--lactic-coco-glycolic) acid (PLGA)-glycolic) acid (PLGA)– 50/50 copolymer ratio50/50 copolymer ratio

– Ball milled 30 minutes with magnetite Ball milled 30 minutes with magnetite nanopowdernanopowder

• 0, 10, 40% w/w magnetite0, 10, 40% w/w magnetite

– Melt extruded using fiber dyeMelt extruded using fiber dye

Extruder Parameters:Extruder Parameters: Melt temperature: 120ºCMelt temperature: 120ºC Extruder screw speed: 50 RPM Extruder screw speed: 50 RPM Extruder speed: ~1000mm/minExtruder speed: ~1000mm/min Torque: 30Torque: 30 Stent Stent

• 900 µm fiber diameter900 µm fiber diameter• 4 cm uncoiled4 cm uncoiled• 3 cm long coiled3 cm long coiled• 1.5 mm ID1.5 mm ID• 4 mm OD4 mm OD

Magnetite content (%w/w)Expected TGA

0

10

1.08±0.028

11.61±0.807

40 38.25±0.711

Thermogravimetric Analysis ResultsThermogravimetric Analysis Results

MDCP CaptureMDCP CaptureEffect of Fluid VelocityEffect of Fluid Velocity

• 100 nm Fe100 nm Fe33OO44 particles particles

• 0.3 T Magnetic Field0.3 T Magnetic Field

• 1.5 mg/mL1.5 mg/mL

• Flow rate:Flow rate: – 20 mL/min (5 cm/s)20 mL/min (5 cm/s)

– 40 mL/min (10 cm/s)40 mL/min (10 cm/s)

• Increasing fluid velocity has Increasing fluid velocity has negative effect on capture of negative effect on capture of particlesparticles

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0 10 40

Magnetite content (w/w%)

Cap

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Effi

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20mL/min

40mL/min

MDCP CaptureMDCP CaptureEffect of ConcentrationEffect of Concentration

• 100 nm Fe100 nm Fe33OO44 particles particles• 0.3 T Field0.3 T Field• 20 mL/min fluid velocity20 mL/min fluid velocity• Particle concentrationParticle concentration

– 1.5 mg/mL1.5 mg/mL– 0.75 mg/mL0.75 mg/mL

• Decreasing particle Decreasing particle concentration reduces their concentration reduces their capturecapture

– Particle agglomeration Particle agglomeration important for captureimportant for capture

0

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Magnetite content (w/w%)

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1.5mg/mL

0.75mg/mL

MDCP CaptureMDCP CaptureMagnetic Field EffectMagnetic Field Effect

• 100 nm Fe100 nm Fe33OO44 particles particles

• 1.5 mg/mL1.5 mg/mL

• 20 mL/min fluid velocity20 mL/min fluid velocity

• Increase in magnetic force Increase in magnetic force increases captureincreases capture

– Polymer/Iron oxide stent Polymer/Iron oxide stent and MDCP saturation and MDCP saturation reached at 0.3 Treached at 0.3 T

0

10

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60

0.1 0.2 0.3 0.5

Magnetic Field (T)

Cap

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Effi

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40wt%

10wt%

Implant Assisted-MDT ProjectsImplant Assisted-MDT Projects Development of Ferromagnetic Stents and Seed Development of Ferromagnetic Stents and Seed

Techniques for Minimally Invasive MDT (seeking Techniques for Minimally Invasive MDT (seeking NSF)NSF)

In VitroIn Vitro Study of MDT in Isolated Swine Hearts Study of MDT in Isolated Swine Hearts with Ferromagnetic Stents (Sloan Foundation)with Ferromagnetic Stents (Sloan Foundation)

Mathematical Models for Design, Development, Mathematical Models for Design, Development, and Understanding of IA-MDT Systems (Sloan and Understanding of IA-MDT Systems (Sloan Foundation)Foundation)

In VivoIn Vivo Study of MDT in Isolated Rat Hearts with Study of MDT in Isolated Rat Hearts with Ferromagnetic Seeds (Sloan Foundation and USC Ferromagnetic Seeds (Sloan Foundation and USC SOM)SOM)

Part IV: Heart Tissue Perfusion Part IV: Heart Tissue Perfusion Model to Study Implant Assisted – Model to Study Implant Assisted – Magnetic Drug Targeting Using a Magnetic Drug Targeting Using a

Ferromagnetic StentFerromagnetic Stent1. M. O. Avilés, J.O. Mangual, A. D. Ebner, and J.A. Ritter, Heart Tissue Perfusion Heart Tissue Perfusion

Model to Study Implant Assisted – Magnetic Drug Targeting Using a Model to Study Implant Assisted – Magnetic Drug Targeting Using a Ferromagnetic StentFerromagnetic Stent, In preparation (2007).

Right Coronary Artery PerfusionRight Coronary Artery Perfusion• Swine heart (~225 g)

– Removed Left Atrium and Ventricle

– Cannulated Right coronary artery

– For each heart we performed two experiments, in the presence and absence of a magnet.

Right Coronary Artery was cannulated

Flow was kept at 40 mL/minStep Injection

1 ~500 mL of lidocaine/heparin/Saline Solution (400 mg/L Lidocaine, 5000 IU/L Heparin and 0.9w/w% NaCl)

2 Flush with 300 mL of saline solution (0.9wt% NaCl)

3 Inject 0.5 mL of 100 nm magnetite particle suspension (~ 2.8 mg/mL)

4 Flushed with 900 mL of saline solution (0.9w/w% NaCl)

5 Repeat steps 2 to 4 with the magnet

Artery Perfusion Experimental SetupArtery Perfusion Experimental Setup

Heart’s Right Ventricle

Saline Solution (0.9% NaCl) Reservoir

Peristaltic Pump~ 40 mL/min

Seed suspension 100 nm Fe3O4 2.8 mg/mL0.5 ml Injection

Collectionvessel

Magnet

Right Coronary Artery ResultsRight Coronary Artery Results

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No Magnet / NoStent

No Magnet / Stent Magnet / No Stent Magnet / Stent

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Effi

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Samples were analyzed using Atomic Absorption Spectroscopy for iron.

The stent is a SS430 500 m coil, 3 mm in diameter and 3 cm long,

Particle Capture at Stent AreaParticle Capture at Stent Area

From visual inspection the particles could be seen accumulated in the area where the stent is located. While there are particles in other areas of the artery, it appears to be less compared to the stent area.

SummarySummary• The perfusion model shows that a ferromagnetic implant is

capable of capturing and retaining the MDCP surrogates under clinically feasible conditions.

• The results demonstrate that the ferromagnetic implant plays a major role in improving the retention and localization of the particles.

• The proposed perfusion model could be used as an initial alternative to animal models.

Concluding RemarksConcluding Remarks This presentation has shown a few examples from a This presentation has shown a few examples from a

wide range of possibilities where ferromagnetic implants wide range of possibilities where ferromagnetic implants can be used to enhance the collection of magnetic drug can be used to enhance the collection of magnetic drug carrier particles at targeted sites in the body. carrier particles at targeted sites in the body.

The interesting notion is that the collection can take The interesting notion is that the collection can take place at almost any place in the body, with few place at almost any place in the body, with few exceptions.exceptions.

Magnetic implants can be inserted in any vessel (not Magnetic implants can be inserted in any vessel (not limited to blood vessels) where exceedingly high limited to blood vessels) where exceedingly high velocities exist to capillary networks where exceedingly velocities exist to capillary networks where exceedingly low velocities exist. low velocities exist.

Concluding RemarksConcluding Remarks Theoretical studiesTheoretical studies demonstrate that the idea of using an

IA-MDT is indeed feasible and give insight to better understand the mechanisms involve in IA-MDT.

Parametric studiesParametric studies have shown that the careful modification of particle properties and implant properties are fundamental to the success of this technology.

In vitroIn vitro experiments experiments have demonstrated the importance of the ferromagnetic implant in improving MDT, as well as provided the first of its kind fundamental data demonstrating the potential to develop a highly effective IA-MDT system.

• summarysummary• key pointskey points• Problems to resolveProblems to resolve• collaborations to develop collaborations to develop

Implant Assisted - MDTImplant Assisted - MDT