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Magnetic NanoparticlesApplications
Dan Laptoiu1, R.Marinescu1,D Popescu2, I.Antoniac21Colentina Clinical HospitalBucharest,2
University Politehnica ofBucharest, Romania
mailto:[email protected]:[email protected]:[email protected]:[email protected]8/12/2019 Magnetic Nanoparticles Applications
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What are the Joints?The body would be immobile if not for the movements
afforded by the joints.Joints can be large or small, and permit movements as varied
as walking, bending, reaching, and performing fine motorskills.
http://orthopedics.about.com/library/xrayimages/nllatknee.jpghttp://orthopedics.about.com/library/xrayimages/nllatknee.jpg8/12/2019 Magnetic Nanoparticles Applications
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Knee Joint
The knee is the largest joint inthe body, and one of the mosteasily injured.
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Cartilage
Within the joints, the ends of the bones are coveredwith hyalinecartilage.
- cushions the underlying bone against excessive pressureand allows the joint to move easily and without pain.
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Cartilage
damage or injury, it usually goes through a staged process of softening,
flaking, fragmenting, and finally complete loss, where the underlying
bone is exposed.
This process is commonly known as osteoarthritis or OA.
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Synovial Fluid Response to Movement
Fast Impact
ShockAbsorption
Viscosity
Flow
Slow Impact
Elasticity
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Intra-articular Injections
There are two main types of
intra-articular injections.
1. SteroidsInjected into the
joint to decrease inflammation.
2. ViscosupplementationInjected
into the joint to provide lubrication.
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Viscosupplementation
The active ingredient in theinjections is called hyaluronic acid.
There are many preparations ofhyaluronic Acid available; all have
similar properties and none has beenclinically proven more effective.
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What is hyaluronic acid? A long-chain biopolymer with
repeated sequences of N-acetyl-glucosamine and glucuronic acid
Avian / bacterial origin
Hylan:cross-link moleculesmodified from HAs (to increase
viscosity and clearance from thejoint)
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Biologic properties of HA
Lubrication, shock
absorption, viscoelastic
SF
Related to the molar massand concentration
Interaction with pain
receptors
Promotion of endogenousHA
Antiinflammatory properties
Nitrous oxide antagonist
Decr. Prostaglandin production
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How does it last long? 1 day intra-articular sustaining Variable onset of their efficacy
Hyalgan26 wks, Hylan G-F20 52 wks(labeled)
(Raman R The Knee(2008), doi:10.1016/j.knee.2008.02.012)
Inconclusive and controversial for thetherapeutic efficacy
(Adams MEDrug Safety2000;23(2):115-30
Wobig M Clin Ther1999;21:1549-62, Allard S Clin Ther2000;22:792-5)
Need a well designed prospective RCT to resolvethe uncertainty about magnitude of efficacy ofvarious products
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Arthroscopy
Arthroscopy is a day surgery thatis done using instruments and acamera that are placed into thejoint through small holes.
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Arthroscopy on target
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Other targeting methods ?
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Nanotechnology
1021=6000m2
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Outline
How to produce nanomagnets and make thembioavailable
Developing therapies using these bioavailablenanomagnets
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Types of Magnetic particles
Multi domain, single domain orsuperparamagnetic
Magnetite (Fe3O4)Ferrites (MeO . Fe2O3; Me = Ni, Co, Mg, Zn, Mn)
Maghemite (-Fe2O3)
Greigite (Fe3S4)
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Types of Magnets
Ferromagnetic materials=the magneticmoments of neighboring atoms alignresulting in a net magnetic moment.
Paramagnetic materials =randomly orienteddue to Brownian motion, exceptin thepresence of external magnetic field.
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Animal magnetism
Magnetosome chainsfrom the frontal tissuesof chinook salmon
S. Mann et al.:J. Exp. Biol.140(1988) 35-49.
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Magnetotactic bacteria
Various morphological typesexist
Gram-negative prokaryotes
Magnetic nanoparticlespresent in magnetosomes
Found in sediments indiverse aquaticenvironments
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Magnetic nanoparticles
Meteorite magneticnanoparticles resemblemagnetosomes from
Earth magnetotacticbacteria
Hypothesis:Was there atransfer of living
systems from Mars toEarth???
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Superparamagnetic in human
Combination of paramagnetic andferromagnetic properties
Made of nano-sized (~20nm) ferrous
magnetic particles, but affected by BrownianMotion.
They will align in the presence of an externalmagnetic field.
Magnetite naturally found in humanbody.
Hergt, Rudolf. Journal of Physics: Condensed Matter v18 2006 s2919-2934
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Coated Magnetite Nanoparticles
US Patent 5262176
Synthesis of polysaccharide coveredsuperparamagnetic oxide colloids (5,262,176)For MRI imaging
FDA max size for injectables = 220 nm.
Smaller sizes (
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Variation of Formation
Change Coating MaterialVarious other starches, Sulfated Dextran (forfunctionalization)
Crosslinking coating materialIncreases plasma half-life
Same Particle Size
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Application?
Three important bio- Biocompatible (in the broadest sense of this
word)
Biodegradable Biomimetic
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Targeted Use of Nano Magnets
External Magnetic field for nanoparticledelivery
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
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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 orIA injection and directed with External Magnets
Requires smaller dosage because of targeting, resulting in fewerside effects
Pankhurst, et. al. [2003] J PhysD 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
MagnetiteCore
Starch Polymer
M
M
MM
M
MM
R. Jurgons. Journal of Physics: Condensed Matter v 18. (2006) S2893-S2902
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Results of Drug Delivery
External magneticfield (dark)
deliver morenanoparticles to tumor
No magnetic field(white)
most nanoparticles innon tumor regions
R. Jurgons. Journal of Physics: CondensedMatter v 18. (2006) S2893-S2902
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NPS
Dynabeads
Homogeneous sizedistribution
Simple recovery with smallpermanent magnets
Magnetic nanoparticlespresent inside the beads
Available in plain, activated
and bioactive form
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Artromag Project - Synthesis
In a first stage we havesynthesized magnetic particles,which were covered by layer-bylayer method in consecutivelayers of protection (TMOHand IN / SEVEN / CS) and
hyaluronic acid; it is arelatively complex techniquebut very important for theactive biologic properties of thenanoparticles (bothbiocompatibility and quantity
of active substance increased).
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Biofunctionalization
Layer by layer
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NPS samples
No sample CompositionSample 1 (PM + TMOH) + HA
Sample 2 (PM + TMOH + APTEOS) + HA
Sample 3 PM/10 + HA
Sample 4 (PM + TMOH)/10 + HA
Sample 5 (PM + TMOH)/100 + HA
Sample 6 PM/100 + HA
Sample 7 (PM + TMOH + CS) + HASample 8 (PM + TMOH + IN) + HA
Sample 9 PM + HA
Sample 10 HA
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NPS Artromag
Final size of synthesized particles did notexceeded 100 nm (values measured by DLS),are stable and retain their character andmagnetic-polymer composites features
required magnetic nanoparticles to be usedfor its intended purpose.
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FTIR analysis demonstratedthe presence of magnetite andmaghemite in the synthesizedferrofluid, and a polymercoating characteristic groupsusing (3-amino-propyl
trietoxisilan,tetramethylammoniumhydroxide, inulin andhyaluronic acid), whichdemonstrated that thetechnique of embedding in
polymer layers by layer-by-layer method is viable.
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MP+TMOH+IN+HA
relative uniformdistribution around106 nm sizes allowspotentialintraarticular usewithout initialconcern for the
articular remanencestudies havedefined the pore sizefor the cartilagedense collagenmatrix around 60nm.
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Biocompatibility
cytotoxicity test using L929 mouse fibroblasts. The assay meetsthe requirements of international standards (ISO 10993-5,
"Tests for CytotoxicityIn Vitro Methods.
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Permanent magnets
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N38 N40
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Magnet Matrix
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Conclusions
The particles obtained have good sizedistribution, good magnetic qualities andhave no cytotoxicity.
The permanent magnets can manipulate these
particles and maintain them longer inside thejoint, therefore enhancing their qualities.
The results may be promising in TARGETED
therapy for KNEE osteoarthritis .
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QUESTON
How are the clinical results?
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Treatment?
struc ture mod i fy ing treatment
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Thank You!
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