Engineering Nanoparticles for Biomedical Applications Mamoun Muhammed, Prof Chairman, Functional Materials Department Chairman, Functional Materials Department Royal Institute of Technology (KTH), Stockholm Royal Institute of Technology (KTH), Stockholm 1 st International Workshop on Nanomedicines London, September 2-3, 2010
Engineering Nanoparticles for Biomedical Applications 1.Magnetic Nanoparticles • SPION for MRI • Thermally blocked NP for biodiagnostics 2.Nanoparticles for Drug Delivery • Multifunctional NP • Thermosensetive NP 3.Ferrogel for drug delivery
Definition FDA calls it "nanotechnology" only if it involves all of the following: 1.Research and technology development, or products regulated by FDA, that are at the atomic, molecular or macromolecular levels, and where at least one dimension, that affects the functional behavior of the product, is in the length scale range of approximately 1-100 nanometers. ( Man-made materials) 2. Creating and using structures, devices and systems that have novel properties and functions because of their small and/or intermediate size. 3. Ability to control or manipulate at the atomic scale . 2010-09-06 IM2655 Intro to nanotech 3
Medical applicaltions of nanoparticles Liposomes Magnetic Nanoparticles Polymer nanoparticles Dendrimers • Magnetic resonance • Fast and more efficient imaging enhancement biosensors • Single cell study and bio ‐ • Targeted drug delivery to manipulation specific cells • Novel diagnostic tools for • Novel cancer theraphy early stage detection of and hyperthermia diseases treatments Nature Nanotechnology, 2007 , 2, 469-478 4
Nanopar t i cl e Engi neer i ng Nanopar t i cl e Engi neer i ng
Gas Phase Synthesis Gas Phase Synthesis Reactant gas molecules Chemical Reaction Chemical Reaction & Coagulation (coalescence) Clusters Precursors (Vapour, or fog) Nucleation & Condensati Condensation (surface reactions) primary particles Agglomeration & aggregation
Chemical Solution Methods for Nanoparticles synthesis • Precipitation Homogenous precipitation • Co-precipitation • Hydrolysis • Oxidative hydrolysis • Reductive precipitation • Electrochemical reduction • Condensation Sol-gel technique • Macro-molecular chemistry Evaporation • Spray-drying • Spray-pyrolysis • Freeze-drying • Aerosol technique • Templates Precipitation in microemulsion • Precipitation in presence of surfactants • Others Sono-chemical reactions
Design of tailored Magnetic Nanoparticles Superparamagnetic and Thermally blocked nanoparticles with strong magnetic response • Magnetite (Fe 3 O 4 ) Maghemite ( γ Fe 2 • O 3 ) • Ferrites (CoFe 2 O 4, ZnFe 2 O 4, MnFe 2 O 4 , …) • Iron Platinum (FePt) & CoPt Bio-compatibility and surface functionalisation • Inorganic: Gold, Silica, hydroxyappatite, ... • Organic: Dextran, PVA, PEG, mPEG, …
Magnetite A) <D> = 5.7 nm 60 50 Frequency (%) 40 30 20 10 0 2 3 4 5 6 7 8 9 Diameter (nm) <D> = 12nm B) 25 20 Frequency (%) 15 10 5 0 6 8 10 12 14 16 18 Diameter (nm) TEM images (left) and the corresponding particle size histograms (right) of magnetite nanoparticles prepared by controlled coprecipitation. (A) without heat treatment and (B) after heat treatment (80ºC for 1hrs)
Magnetic characterisation VSM measurement for SiO 2 coated Fe 3 O 4 by co-precipitation
Superparamagnetic iron oxide nanoparticles • Average particle size=12 nm • XAS shows nonstochiometric phase Fe 3 O 4- δ , the curve shifts to Fe 2+ . After one year shelf storage
Surface Functionalization of Magnetic Nanoparticles Magnetic Nanoparticles • Oxide : magnetite, ferrite • Metal : Fe, Co, PtFe, CoPt Coating • Gold • Silica • Hydroxyapatite • Dextran • Starch • Albumin • Sodium Oleate • Folic acid • L-aspartic acid • PVA • PEG • mPEG • PLLA (PDLLA) • PCL • PGA
Effect of surface modification Au Coating 2.5 0.06 0.05 2.0 0.04 0.03 1.5 ESA (mPa*M/V) 0.02 Heat (mW/s) (a) 0.01 1.0 0.00 0.5 -0.01 (b) -0.02 0.0 -0.03 Au@SPION SPION -0.04 -0.5 -0.05 2 3 4 5 6 7 8 9 10 11 100 200 300 400 500 600 o C) pH Temp ( ESA measurement of SPION DSC analysis of bare and coated and Au@SPION prepared by nanoparticles. (a) Magnetite, and μ E system (b) Au coated SPION.
Silica Coated Magnetic Nanoparticles Silica layer Magnetic core Control of thickness, porosity of coating layer
Visualization SPION: MRI Contrast Agents O 4 and/or γ -Fe 2 Fe 3 O 3 Widely used current commercial T2 contrast agent (Aq. Soln. Synthesis) Controlled Synthesis in organic liquids (at 300 C) Qin, J. et al., Adv. Mat. 2007
Phase transfer through Surface Coating ABA type triblock copolymer Hydrophilic poly(ethylene oxide) Hydrophobic poly(propylene oxide) Amphiphilic coating layer PF127/Oleic acid (POA)
Hydrophobic-Hydrophilic Phase Transfer Hydrophobic Hydrophilic SPION Phase transfer Hexane Hexane Water Water Organic coating molecules Amphiphilic macromolecules with PEG section J. Qin et al, Adv Mat (2007) SPION: Suiperparamagnetic iron oxide nanoparticles PEG: Poly(ethylene glycol)
Superparamagnetism Retained Magnetization curve of (a) as-synthesized SPION and (b) POA@SPION
Compare with Conventional Iron Oxide Nanoparticle Based Contrast Agents Particles name Surface polymer r 2 / r 1 ratio Mean hydrodynamic (0.47 T, 310 K) diameter (nm) POA@SPION Pluronic F127 + Oleic 41.5 116 acid Dextran 4.0 72 AMI-25 (Feridex; Advanced Magnetic s, Cambridge, Mass) AMI-227 (Combidex; Advanced Mag Dextran 2.2 19 netics, Cambridge, Mass) MION-37 (R. Weissleder, Massachus Dextran T10 2.2 16-28 etts General Hospital, Boston, Mass) MION-37 (R. Weissleder, Massachus Dextran T10 2.2 18-24 etts General Hospital, Boston, Mass) NC100150 (Clariscan, Nycomed, A Oxidized Starch 1.6 11.9 mersham, Oslo, Norway) Carboxydextran 7.1 65 SH U 555 A (Schering AG, Berlin, Ge rmany) USPIO S (Schering AG, Berlin, Germa Carboxydextran 2.3 21 ny)
Dose response of Fe 3 O 4 nanoparticles in MRI Kim, Do-Kyung, Thesis, KTH, 2001 , Qin, Adv. Mat 2007
Thermally Blocked Nanoparticles Magnetic Relaxation for Bio-Diagnostics Néel Néel relaxation relaxation τ N = Nèel rel. time KV τ 0 = characteristic rel. time External τ = τ k = Boltzmann constant kT e applied T = temperature 0 N field K = magnetic anisotropy V = single domain volume Brownian relaxation Brownian relaxation η 3 τ B = Brownian rel. time V τ = External V H = Hydrodynamic particle H applied volume B kT η field = viscosity
Biosensor Based on Biosensor Based on Magnetic Relaxation Magnetic Relaxation Detect specific biomolecules by measuring changes in Brownian relaxation of thermally blocked magnetic nanoparticles . shift in the maximum of the imaginary magnetic susceptibility. Kindly provided by IMEGO Institute (Göteborg - Sweden) Fornara, A. et al, NanoLetters (2008)
Bio-diagnostics based on Magnetic Relaxation Brownian relaxation process can be detected in the frequency domain = χ = χ − χ ' ' ' M H ( i ) H M = magnetisation H = alternating external magnetic field χ = complex magnetic susceptibility IMEGO AB
Synthesis of Thermally blocked Magnetic nanoparticles
Quantitative detection of PSA by Brownian relaxation frequency measurements Serum sample Magnetic nanoparticles Magnetic nanoparticles AC added to LPS + LPS + serum sample susceptometer • No pretreatment • Simple mixing of fluids • Fast • Multiple bio molecules detection • Practical for point of use 100 1000
Detection of Brucella Antibodies in Serum 400 Median diameter [nm] 380 380 Median diameter [nm] 360 360 340 340 320 320 mAb 300 300 PSA66 Serum 280 280 Control 0.00 0.05 0.10 0.15 0.20 260 mAb [mg/mL] 0 20 40 60 80 100 Amount of positive serum % Detection limit: 0.05 µg/ml Fornara, A. et al, NanoLetters (2008)
Nanomaterials in Biology and Medicine Targeted drug delivery – Targeted drug delivery using a multicomponent nanoparticle containing therapeutic as well as biological surface modifying agents
Biocompatible Polymers O O O * * * * * * O N O H CH 2 Poly glycolide Poly lactide CH 2 CH 2 CH 2 NH 2 Poly L-lysine O O O * CH 2 * * O * N Poly(ethyl-2-cyanoacrylate) Poly ¥å -caprolactone
Amphiphilic copolymer for biodegradable nanosphere fabrication Lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) • Biocompatible • Degradable under physiological condition • Applicable as a hydrophobic segment in amphiphilic copolymer copolymerization poly ethylene glycol (PEG) • Biocompatible • Applicable as a hydrophilic segment in amphiphilic copolymer
Strategies for Drug Delivery Systems Hydrophobic drug i.e. steroids Surface Hydrophilic drug modification i.e. proteins Emulsion/evaporation s and (o/w) activation Modified-double-emulsion (w/o/w ) biomolecules drug drug drug
Procedures for preparation of drug-loaded Nanospheres Drug , Fe 3 O 4 , & Quantum dots loaded in the cavity
Compositions of PLA-mPEG diblock copolymers
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