magnetic nanoparticles applications and bioavailability for cancer therapy

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Magnetic Nanoparticles Applications and Bioavailability for Cancer

Therapy

Presented by: Chinchole Pravin SonuM Pharm

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Outline

• Types of Magnets

• How to produce nanomagnets and make them bioavailable

• Cancer therapies using these bioavailable nanomagnets

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Types of Magnets

• Ferromagnetic materials the magnetic moments of neighboring atoms align resulting in a net magnetic moment.

• Paramagnetic materials are randomly oriented due to Brownian motion, except in the presence of external magnetic field.

B

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Superparamagnetic

• Combination of paramagnetic and ferromagnetic properties Made of nano-sized (<20nm) ferrous magnetic particles, but affected by Brownian Motion.

• They will align in the presence of an external magnetic field.

• Magnetite naturally found in human body.

Hergt, Rudolf. Journal of Physics: Condensed Matter v18 2006 s2919-2934

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Dextran Coated Magnetite Nanoparticles

US Patent 5262176

• Synthesis of polysaccharide covered superparamagnetic oxide colloids (5,262,176)

For MRI imaging

• FDA max size for injectables = 220 nm.

• Smaller sizes (<100 nm) have longer plasma half-life. Blood clearance by Reticuloendothelial system (RES)Liver and Spleen

• Without coating, opsonin proteins deposit on Magnetite and mark for removal by RES

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Formation of Nanoparticles• Solution of Dextran and Ferric hexahydrate (acidic

solution) Less Dextran Larger Particles

• Drip in Ammonium hydroxide (basic) at ~2oC• Stirred at 75oC for 75 min. • Purified by washing and ultra-centrifugation • Resulting Size ~ 10-20 nm• Plasma half-life: 200 min

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Variation of Formation• Change Coating Material

Various other starches, Sulfated Dextran (for functionalization)

• Crosslinking coating material Increases plasma half-life Same Particle Size

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Magnetite Cationic Liposomes (MCL)• Why Cationic?

Interaction between + liposome and – cell membrane results in 10x uptake.

Shinkai, Masashige. Journal of Magnetism and Magnetic Materials 194 (1999) 176-184

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Formation of MCL• Colloidal magnetite dispersed in distilled water• N-(a-trimethyl-amminoacetyl)-didodecyl-D-

glutamate chloride (TMAG) Dilauroylphosphatidylcholine (DLPC) Dioleoylphosphatidyl-ethanolamine (DOPE) added to dispersion at ratio of 1:2:2

• Stirred and sonicated for 15 min• pH raised to 7.4 by NaCl and Na phosphate

buffered and then sonicated

Shinkai, Masashige. Journal of Magnetism and Magnetic Materials 194 (1999) 176-184

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Uses of Nano Magnets

• Hyperthermia An oscillating magnetic field on nanomagnets result in

local heating by (1) hysteresis, (2) frictional losses (3) Neel or Brown relaxation

• External Magnetic field for nanoparticle deliveryMagnetic nanoparticles loaded with

drug can be directed to diseased site for Drug Delivery or MRI imaging.

Hergt, Rudolf. J.Physics: Condensed Matter 18 (2006) S2919-S2934http://www.nist.gov/public_affairs/techbeat/tb2007_0201.htm#magnets

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History of Nano Magnet Hyperthermia• 1957 Gilchrist first proposed the use of

microparticle hyperthermia (0.01-0.1 kW/g).

• 1975 internationally recognized at the first international congress on hyperthermic oncology

• 1993 Jordan showed nanoparticles (~1 kW/g) release more heat than microparticles.

Ito. Cancer Immunological Immunotherapy (2006) v55 320-328Jordan. Journal of Magnetism and Magnetic Materials v201 (1999) 413-419Hergt, Rudolf. Journal of Physics: Condensed Matter v18 2006 s2919-2934

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Delivery Magnetic nanoparticles

Ito A., Honda H., Kobayashi T. Cancer Immunol Immunother Res 2006 55; 320-328

• Magnetite nanoparticles encapsulated in liposomes (1) Antibody conjugated (AML) (2) Positive Surface Charge

(MCL)• Sprague-Dawley rats injected

with two human tumors. Lipsomes injected into 1 tumor (black) and applied Alternating Magnetic Field

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Cancer Treatment

• Heating due to magnetic field results in two possibilities Death due to overheating Increase in heat shock proteins result in anti-cancer immunity.

Ito A., Honda H., Kobayashi T. Cancer Immunol Immunother Res 2006 55; 320-328

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Effect of Hyperthermia

TreatedTumor

UntreatedTumor

Rectum

After Treatment

Before Treatment

• Non-local heating in body is the result of eddy-currents The currents resulting from the

magnetic field produce heat

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Magnetic Drug Delivery System

• Using Magnetic Nanoparticles for Drug Delivery• Widder & others developed method in late 1970s• Drug loaded magnetic nanoparticles introduced through IV or IA

injection and directed with External Magnets • Requires smaller dosage because of targeting, resulting in fewer side

effects

Pankhurst, et. al. [2003] J Phys D 36:R167-R181.

Dobson [2006]. Drug Dev Res 67:55-60.Widder, et. al. [1978]. Proc Soc Exp Biol Med 58:141-146.

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Magnetic Nanoparticles/Carriers

• Magnetite Core• Starch Polymer Coating

• Bioavailable• Phosphate in coating for functionalization

• Chemo Drug attached to Coating • Mitoxantrone

• Drug Delivered to Rabbit with Carcinoma

Magnetite Core

Starch Polymer

M

M

M M

M

MM

R. Jurgons. Journal of Physics: Condensed Matter v 18. (2006) S2893-S2902

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Results of Drug Delivery

• External magnetic field (dark)

• deliver more nanoparticles to tumor

• No magnetic field (white)

• most nanoparticles in non tumor regions


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Results of Drug Delivery

• No treatment (white triangle)

• Growth of tumor size (ie metastases)

• With Treatment (dark circle)

• Complete remission• Only 20% of normal

dosage


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Conclusions• Nanomagnets can be made bioavailable by liposomal

encapsulation with targeting• Nanoparticles smaller than 20 nm can be useful for

local heat generation• Intracellular hyperthermia kills the cancer cell and

releases heat shock proteins. These are used to target and kill other cancer cells.

• Results in reduction in growth of tumor size

Dobson [2006] “Mangetic nanoparticles for drug delivery.” Drug Dev Res 67:55-60.Kubo, et. al. [2000] “Targeted delivery of anticancer drugs with intravenously administered magnetic liposomes in

osteosarcoma-bearing hamsters.” Int J Oncol 17:309-316.

magnetic nanoparticles applications and bioavailability for cancer therapy

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