Magnetic Drug Targeting, James Ritter, PhD


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Magnetic Drug Targeting, James Ritter, PhD

  1. 1. Magnetic Drug Targeting James A. Ritter, Armin D. Ebner and Jan Mangual Department of Chemical Engineering Swearingen Engineering Center University of South Carolina Columbia, SC 29208 Scientific Retreat on Bioengineering and Regenerative Medicine Charleston, SC March 24, 2010
  2. 2. Schematic of an MDT System <ul><li>Limitations of MDT systems </li></ul><ul><ul><li>The fluid drag forces in most instances overcome the magnetic forces. </li></ul></ul><ul><ul><li>Magnetic forces decrease dramatically at large distances from the magnet </li></ul></ul>
  3. 3. Proposed Implant-Assisted MDT System <ul><li>Use ferromagnetic implants to increase the magnetic force at the site by taking advantage of high gradient magnetic principles </li></ul><ul><li>Advantages </li></ul><ul><ul><li>Localized “stronger” forces </li></ul></ul><ul><ul><li>Distance effects minimized </li></ul></ul><ul><li>Disadvantages </li></ul><ul><ul><li>Mildly invasive technique </li></ul></ul>Ferromagnetic Implant
  4. 4. <ul><li>based on three commercially available technologies: </li></ul><ul><li>an external magnetic field source, such as an FeNdB permanent magnet or MRI facility </li></ul><ul><li>specially designed ferromagnetic and biocompatible implants, such as wires, needles, filaments, stents or even seeds </li></ul><ul><li>specially designed particles that are biocompatible, contain a drug or radiation, and contain a magnetic material </li></ul>Implant Assisted - MDT
  5. 5. Magnetic Fields from IA-MDT <ul><li>magnetic forces must overcome fluid drag forces experienced by magnetic drug carrier particles (MDCPs) </li></ul><ul><li>magnetic force ( F m ) exerted on object is proportional to both magnetic field ( H ) and magnetic field gradient ( ) </li></ul><ul><li>tiny ferromagnetic elements become magnetically energized in presence of external magnetic field </li></ul><ul><li>presence of these high curvature elements locally increases magnetic field gradient and hence force on MDCPs </li></ul>
  6. 6. Magnetic Drug Carrier Particles for IA-MDT Size : 50 - 2000 nm Superparamagnetic Particles - FeCo, ferrites, etc. - largest magnetization - 80 wt% max (40-50 vol%) Polymer - biocompatible - non-immunogenic - biodegradable - porous for drug transport Drug - free or fixed (radioactive)
  7. 7. MDCP Surrogates Bangs Laboratories, Inc. ~20 wt% Magnetite
  8. 8. Magnetic Implants for IA-MDT <ul><li>Stents & Catheters </li></ul><ul><li>Target: </li></ul><ul><ul><li>veins and arteries </li></ul></ul><ul><ul><li>urinary Tract </li></ul></ul><ul><ul><li>pancreatic and biliary ducts </li></ul></ul><ul><ul><li>digestive tract, etc </li></ul></ul><ul><li>Filaments & Needles </li></ul><ul><li>Target: </li></ul><ul><ul><li>vessels (listed above) </li></ul></ul><ul><ul><li>blood capillaries </li></ul></ul><ul><li>Nanosized Seeds (50-1000 nm) </li></ul><ul><li>Target: </li></ul><ul><ul><li>blood capillaries </li></ul></ul>They must be biocompatible! 0 - 80 cm/s 0 - 80 cm/s 0.01 - 1.0 cm/s Blood Vessel Velocity Range
  9. 9. Comsol Simulations Simulation for 0.96  m MDCPs with 60 wt% magnetite at an applied field of 0.65 T and a velocity of 2.1 cm/s. Magnetic Field Gradients MDCP Streamlines Last captured particle Trajectory
  10. 10. In Vitro Particle Capture Images Effect of Fluid Velocity on Particle Capture A1) A2) B1) B2) Images at velocities of A) 2.1, and B) 21.2 cm/s 1) before and 2) after 10 ml of solution have passed through the collection area at an applied magnetic field of 0.17 T.
  11. 11. Experimental and Model Results Effect of Fluid Velocity D p = 0.87  m x fm = 25 wt% D w = 125  m Velocity negatively affects capture, but even at high velocities capture is still attainable. Capture seems to reach a steady value, where decrease in capture is greatly reduced. model
  12. 12. Particle Capture Video D p = 0.87  m D w = 125  m u B = 2.12 cm/s H = 0.15 T
  13. 13. Biodegradable Magnetic Stent Fabrication <ul><li>Poly( DL -lactic- co -glycolic) acid (PLGA) </li></ul><ul><ul><li>50/50 copolymer ratio </li></ul></ul><ul><ul><li>Ball milled 30 minutes with magnetite nanopowder </li></ul></ul><ul><ul><ul><li>0, 10, 40% w/w magnetite </li></ul></ul></ul><ul><ul><li>Melt extruded using fiber dye </li></ul></ul>Extruder Parameters: Melt temperature: 120ºC Extruder screw speed: 50 RPM Extruder speed: ~1000mm/min Torque: 30 <ul><li>Stent </li></ul><ul><ul><li>900 µm fiber diameter </li></ul></ul><ul><ul><li>4 cm uncoiled </li></ul></ul><ul><ul><li>3 cm long coiled </li></ul></ul><ul><ul><li>1.5 mm ID </li></ul></ul><ul><ul><li>4 mm OD </li></ul></ul>Thermogravimetric Analysis Results Magnetite content (%w/w) Expected TGA 0 10 1.08 ±0.028 11.61 ±0.807 40 38.25 ± 0.711
  14. 14. MDCP Capture Effect of Fluid Velocity <ul><li>100 nm Fe 3 O 4 particles </li></ul><ul><li>0.3 T Magnetic Field </li></ul><ul><li>1.5 mg/mL </li></ul><ul><li>Flow rate: </li></ul><ul><ul><li>20 mL/min (5 cm/s) </li></ul></ul><ul><ul><li>40 mL/min (10 cm/s) </li></ul></ul><ul><li>Increasing fluid velocity has negative effect on capture of particles </li></ul>
  15. 15. MDCP Capture Effect of Concentration <ul><li>100 nm Fe 3 O 4 particles </li></ul><ul><li>0.3 T Field </li></ul><ul><li>20 mL/min fluid velocity </li></ul><ul><li>Particle concentration </li></ul><ul><ul><li>1.5 mg/mL </li></ul></ul><ul><ul><li>0.75 mg/mL </li></ul></ul><ul><li>Decreasing particle concentration reduces their capture </li></ul><ul><ul><li>Particle agglomeration important for capture </li></ul></ul>
  16. 16. MDCP Capture Magnetic Field Effect <ul><li>100 nm Fe 3 O 4 particles </li></ul><ul><li>1.5 mg/mL </li></ul><ul><li>20 mL/min fluid velocity </li></ul><ul><li>Increase in magnetic force increases capture </li></ul><ul><ul><li>Polymer/Iron oxide stent and MDCP saturation reached at 0.3 T </li></ul></ul>
  17. 17. Implant Assisted-MDT Projects <ul><li>Development of Ferromagnetic Stents and Seed Techniques for Minimally Invasive MDT (seeking NSF) </li></ul><ul><li>In Vitro Study of MDT in Isolated Swine Hearts with Ferromagnetic Stents (Sloan Foundation) </li></ul><ul><li>Mathematical Models for Design, Development, and Understanding of IA-MDT Systems (Sloan Foundation) </li></ul><ul><li>In Vivo Study of MDT in Isolated Rat Hearts with Ferromagnetic Seeds (Sloan Foundation and USC SOM) </li></ul>
  18. 18. Part IV: Heart Tissue Perfusion Model to Study Implant Assisted – Magnetic Drug Targeting Using a Ferromagnetic Stent <ul><li>M. O. Avilés, J.O. Mangual, A. D. Ebner, and J.A. Ritter, Heart Tissue Perfusion Model to Study Implant Assisted – Magnetic Drug Targeting Using a Ferromagnetic Stent , In preparation (2007). </li></ul>
  19. 19. Right Coronary Artery Perfusion <ul><li>Swine heart (~225 g) </li></ul><ul><ul><li>Removed Left Atrium and Ventricle </li></ul></ul><ul><ul><li>Cannulated Right coronary artery </li></ul></ul><ul><ul><li>For each heart we performed two experiments, in the presence and absence of a magnet. </li></ul></ul>Right Coronary Artery was cannulated Flow was kept at 40 mL/min Step 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
  20. 20. Artery Perfusion Experimental Setup Heart’s Right Ventricle Saline Solution (0.9% NaCl) Reservoir Peristaltic Pump ~ 40 mL/min Seed suspension 100 nm Fe 3 O 4 2.8 mg/mL 0.5 ml Injection Collection vessel Magnet
  21. 21. Right Coronary Artery Results 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,
  22. 22. Particle 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.
  23. 23. Summary <ul><li>The perfusion model shows that a ferromagnetic implant is capable of capturing and retaining the MDCP surrogates under clinically feasible conditions. </li></ul><ul><li>The results demonstrate that the ferromagnetic implant plays a major role in improving the retention and localization of the particles. </li></ul><ul><li>The proposed perfusion model could be used as an initial alternative to animal models. </li></ul>
  24. 24. Concluding Remarks <ul><li>This presentation has shown a few examples from a wide range of possibilities where ferromagnetic implants can be used to enhance the collection of magnetic drug carrier particles at targeted sites in the body. </li></ul><ul><li>The interesting notion is that the collection can take place at almost any place in the body, with few exceptions. </li></ul><ul><li>Magnetic implants can be inserted in any vessel (not limited to blood vessels) where exceedingly high velocities exist to capillary networks where exceedingly low velocities exist. </li></ul>
  25. 25. Concluding Remarks <ul><li>Theoretical 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. </li></ul><ul><li>Parametric studies have shown that the careful modification of particle properties and implant properties are fundamental to the success of this technology. </li></ul><ul><li>In vitro 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. </li></ul>
  26. 26. <ul><li>summary </li></ul><ul><li>key points </li></ul><ul><li>Problems to resolve </li></ul><ul><li>collaborations to develop </li></ul>Implant Assisted - MDT