Magnetic nanoparticles applications and bioavailability for cancer therapy
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Magnetic nanoparticles can be used for cancer therapy applications. They can be coated or encapsulated to be bioavailable. When exposed to an external alternating magnetic field, the nanoparticles generate heat through hysteresis, friction, and relaxation effects. This localized hyperthermia can directly kill cancer cells or induce heat shock proteins to stimulate anti-cancer immunity. The nanoparticles can also be used for magnetic drug delivery, where drugs are attached and targeted to tumor sites using an external magnetic field, requiring lower doses than conventional treatment and reducing side effects. Studies have shown magnetic nanoparticle hyperthermia and drug delivery can significantly reduce tumor growth in animal models.
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Magnetic nanoparticles applications and bioavailability for cancer therapy
- 1. 1 Magnetic Nanoparticles Applications and Bioavailability for Cancer Therapy Presented by: Chinchole Pravin Sonu M Pharm
- 2. 2 Outline • Types of Magnets • How to produce nanomagnets and make them bioavailable • Cancer therapies using these bioavailable nanomagnets
- 3. 3 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
- 4. 4 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
- 5. 5 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
- 6. 6 Formation of Nanoparticles • Solution of Dextran and Ferric hexahydrate (acidic solution) Less Dextran Larger Particles • Drip in Ammonium hydroxide (basic) at ~2o C • Stirred at 75o C for 75 min. • Purified by washing and ultra-centrifugation • Resulting Size ~ 10-20 nm • Plasma half-life: 200 min
- 7. 7 Variation of Formation • Change Coating Material Various other starches, Sulfated Dextran (for functionalization) • Crosslinking coating material Increases plasma half-life Same Particle Size
- 8. 8 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
- 9. 9 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
- 10. 10 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 delivery Magnetic 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-S2934 http://www.nist.gov/public_affairs/techbeat/tb2007_0201.htm#magnets
- 11. 11 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 320-328 Jordan. Journal of Magnetism and Magnetic Materials v201 (1999) 413-419 Hergt, Rudolf. Journal of Physics: Condensed Matter v18 2006 s2919-2934
- 12. 12 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
- 13. 13 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
- 14. 14 Effect of Hyperthermia Treated Tumor Untreated Tumor 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
- 15. 15 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.
- 16. 16 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 M M R. Jurgons. Journal of Physics: Condensed Matter v 18. (2006) S2893-S2902
- 17. 17 Results of Drug Delivery • External magnetic field (dark) • deliver more nanoparticles to tumor • No magnetic field (white) • most nanoparticles in non tumor regions R. Jurgons. Journal of Physics: Condensed Matter v 18. (2006) S2893-S2902
- 18. 18 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 R. Jurgons. Journal of Physics: Condensed Matter v 18. (2006) S2893-S2902
- 19. 19 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.
Editor's Notes
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Unless tumor specific, damage can be done to all cells. Intracellular hyperthermia is based on the principle that a magnetic particle can generate heat by hysteresis loss under an alternating magnetic field (AMF). In 1979, Gordon et al. [10] DDS techniques to develop antibody-conjugated liposomes (immunoliposomes) containing magnetite nanoparticles (antibody-conjugated magnetoliposomes, AMLs). The targeting ability of AMLs mainly depends on the specificity of the antibody and the quantity and quality (including homogenous antigen expression) of the antigen on the tumor cell surface. enhanced by conferring a positive surface charge to liposomes. We have developed ‘‘magnetite cationic liposomes’’ (MCLs) with improved adsorption and accumulation properties.
- Widder and others developed magnetic mciro- and nanoparticles to which cytotoxic drugs could be attached in late 1970s (1978). The drug/carrier complex is then injected into the subject either via intravenous or intra-arterial injection. High-gradient, external magnetic fields generated by rare earth permanent magnets (generally NdFeB, neodymium magnet, Neodymium, Iron & Boron) are used to guide and concentrate the drugs at target site (ie: tumor locations). Once the magnetic carrier is concentrated at the tumor or other target in vivo, the therapeutic agent is then released from the magnetic carrier, either via enzymatic activity or through changes in physiological conditions such as pH, osmolality, or temperature, leading to increased uptake of the drug by the tumor cells at the target sites.
- Core-shell structure: Core = magnetic iron oxide (usually magnetite – [Fe3O4] or maghemite [gamma-Fe2O3]) Shell = generally a polymer such as silica, dextran, or PVA, or metals such as gold to which functional groups can be attached vis cross-linkers Can be synthesized using both ionic and non-ionic surfactant techniques or encapsulated within a structure such as carbon cage or ferritin protein Functionalized by attaching carboxyl groups, amines, biotin, streptavidin, antibodies, and others. A number of groups have developed techniques for the synthesis of magnetoliposomes. Core = magnetic iron oxide Shell = artificial liposome Generally used for magnetic hyperthermia (JAMES), but may be useful in drug delivery More recently, gold/cobalt nanoparticles with core-shell structure and tailorable morphology have been synthesized in the size range of 5-25 nm Produced via the rapid decomposition of organometallic precursors in the presence of surfactants that control the size and shape of the particles. Major advantage = cobalt has a magnetic moment nearly twice that of magnetite or maghemite. Another strategy for synthesis involves the precipitation of magnetic iron oxide nanoparticles within a porous polymer micro- or nanoparticle scaffold. Advantage = possible to produce particles with a relatively tight size distribution and well-defined, spherical morphology.