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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

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SLIDE 1

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 London, September 2-3, 2010 1st International Workshop on Nanomedicines

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SLIDE 2

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

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SLIDE 3

2010-09-06 IM2655 Intro to nanotech 3

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.

Definition

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SLIDE 4

Dendrimers Magnetic Nanoparticles Liposomes Polymer nanoparticles

Medical applicaltions

  • f nanoparticles
  • Magnetic resonance

imaging enhancement

  • Single cell study and bio‐

manipulation

  • Novel diagnostic tools for

early stage detection of diseases

  • Fast and more efficient

biosensors

  • Targeted drug delivery to

specific cells

  • Novel cancer theraphy

and hyperthermia treatments

Nature Nanotechnology, 2007, 2, 469-478 4

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SLIDE 5

Nanopar t i cl e Engi neer i ng Nanopar t i cl e Engi neer i ng

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SLIDE 6

Reactant gas molecules Chemical Reaction Chemical Reaction & Coagulation (coalescence) Precursors (Vapour, or fog) Condensati Nucleation & Condensation (surface reactions) Agglomeration & aggregation primary particles Clusters

Gas Phase Synthesis

Gas Phase Synthesis

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SLIDE 7

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

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SLIDE 8

Superparamagnetic and Thermally blocked nanoparticles with strong magnetic response

Design of tailored Magnetic Nanoparticles

  • Magnetite (Fe3

O4 )

  • Maghemite (γFe2

O3 )

  • Ferrites (CoFe2

O4, ZnFe2 O4, MnFe2 O4 , …)

  • Iron Platinum (FePt) & CoPt

Bio-compatibility and surface functionalisation

  • Inorganic: Gold, Silica, hydroxyappatite, ...
  • Organic: Dextran, PVA, PEG, mPEG, …
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SLIDE 9

A) B)

2 3 4 5 6 7 8 9 10 20 30 40 50 60 <D> = 5.7 nm

Frequency (%) Diameter (nm)

6 8 10 12 14 16 18 5 10 15 20 25 <D> = 12nm

Frequency (%) 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)

Magnetite

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SLIDE 10

Magnetic characterisation VSM measurement for SiO2 coated Fe3 O4 by co-precipitation

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SLIDE 11

Superparamagnetic iron oxide nanoparticles

  • Average particle size=12 nm
  • XAS shows nonstochiometric phase

Fe3 O4-δ , the curve shifts to Fe2+. After one year shelf storage

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SLIDE 12

Magnetic Nanoparticles

  • Oxide : magnetite, ferrite
  • Metal : Fe, Co, PtFe, CoPt

Coating

Surface Functionalization of Magnetic Nanoparticles

  • Gold
  • Silica
  • Hydroxyapatite
  • Dextran
  • Starch
  • Albumin
  • Sodium Oleate
  • Folic acid
  • L-aspartic acid
  • PVA
  • PEG
  • mPEG
  • PLLA (PDLLA)
  • PCL
  • PGA
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SLIDE 13

2 3 4 5 6 7 8 9 10 11

  • 0.05
  • 0.04
  • 0.03
  • 0.02
  • 0.01

0.00 0.01 0.02 0.03 0.04 0.05 0.06

ESA (mPa*M/V) pH Au@SPION SPION

ESA measurement of SPION and Au@SPION prepared by μE system

100 200 300 400 500 600

  • 0.5

0.0 0.5 1.0 1.5 2.0 2.5

(b) (a) Heat (mW/s) Temp (

  • C)

DSC analysis of bare and coated

  • nanoparticles. (a) Magnetite, and

(b) Au coated SPION.

Effect of surface modification Au Coating

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SLIDE 14

Silica Coated Magnetic Nanoparticles Control of thickness, porosity of coating layer

Silica layer Magnetic core

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SLIDE 15

Visualization SPION: MRI Contrast Agents

Fe3 O4 and/or γ-Fe2 O3 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

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SLIDE 16

Phase transfer through Surface Coating

Hydrophobic poly(propylene oxide) Hydrophilic poly(ethylene oxide)

ABA type triblock copolymer

Amphiphilic coating layer PF127/Oleic acid (POA)

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SLIDE 17

Hydrophobic-Hydrophilic Phase Transfer

Hydrophobic Hydrophilic

Organic coating molecules Amphiphilic macromolecules with PEG section Phase transfer Water Hexane Water Hexane SPION

SPION: Suiperparamagnetic iron oxide nanoparticles PEG: Poly(ethylene glycol)

  • J. Qin et al, Adv Mat (2007)
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SLIDE 18

Superparamagnetism Retained

Magnetization curve of (a) as-synthesized SPION and (b) POA@SPION

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SLIDE 19

Compare with Conventional Iron Oxide Nanoparticle Based Contrast Agents

Particles name Surface polymer r2 /r1 ratio (0.47 T, 310 K) Mean hydrodynamic diameter (nm) POA@SPION Pluronic F127 + Oleic acid

41.5

116

AMI-25 (Feridex; Advanced Magnetic s, Cambridge, Mass) Dextran 4.0 72 AMI-227 (Combidex; Advanced Mag netics, Cambridge, Mass) Dextran 2.2 19 MION-37 (R. Weissleder, Massachus etts General Hospital, Boston, Mass) Dextran T10 2.2 16-28 MION-37 (R. Weissleder, Massachus etts General Hospital, Boston, Mass) Dextran T10 2.2 18-24 NC100150 (Clariscan, Nycomed, A mersham, Oslo, Norway) Oxidized Starch 1.6 11.9 SH U 555 A (Schering AG, Berlin, Ge rmany) Carboxydextran 7.1 65 USPIO S (Schering AG, Berlin, Germa ny) Carboxydextran 2.3 21

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SLIDE 20

Dose response of Fe3 O4 nanoparticles in MRI

Kim, Do-Kyung, Thesis, KTH, 2001 , Qin, Adv. Mat 2007

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SLIDE 21

Néel Néel relaxation relaxation Brownian relaxation Brownian relaxation

External applied field External applied field

kT KV

e

N

τ τ =

τN = Nèel

  • rel. time

τ0 = characteristic

  • rel. time

k = Boltzmann constant T = temperature K = magnetic anisotropy V = single domain volume

kT V

H B

η τ 3 =

τB = Brownian rel. time VH = Hydrodynamic particle volume η = viscosity

Thermally Blocked Nanoparticles Magnetic Relaxation for Bio-Diagnostics

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SLIDE 22

Detect specific biomolecules by measuring changes in Brownian relaxation of thermally blocked magnetic nanoparticles.

Biosensor Based on Biosensor Based on Magnetic Relaxation Magnetic Relaxation

Kindly provided by IMEGO Institute (Göteborg - Sweden)

Fornara, A. et al, NanoLetters (2008) shift in the maximum of the imaginary magnetic susceptibility.

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SLIDE 23

Brownian relaxation process can be detected in the frequency domain

M = magnetisation H = alternating external magnetic field χ = complex magnetic susceptibility

H ) i ( H M

' ' '

χ χ χ − = =

Bio-diagnostics based on Magnetic Relaxation

IMEGO AB

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SLIDE 24

Synthesis of Thermally blocked Magnetic nanoparticles

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SLIDE 25

Quantitative detection of PSA by Brownian relaxation frequency measurements

1000 100

  • No pretreatment
  • Simple mixing of fluids
  • Fast
  • Multiple bio molecules detection
  • Practical for point of use

AC susceptometer Magnetic nanoparticles + LPS + serum sample Magnetic nanoparticles added to LPS Serum sample

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SLIDE 26

20 40 60 80 100 260 280 300 320 340 360 380 Serum Control

Median diameter [nm] Amount of positive serum %

0.00 0.05 0.10 0.15 0.20 280 300 320 340 360 380 400

mAb PSA66 Median diameter [nm] mAb [mg/mL] Fornara, A. et al, NanoLetters (2008)

Detection of Brucella Antibodies in Serum

Detection limit: 0.05 µg/ml

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SLIDE 27

Nanomaterials in Biology and Medicine

Targeted drug delivery – Targeted drug delivery using a multicomponent nanoparticle containing therapeutic as well as biological surface modifying agents

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SLIDE 28

Biocompatible Polymers

* O * O Poly ¥å

  • caprolactone

* O * O Poly lactide * O * O Poly glycolide * N H * O CH2 CH2 CH2 CH2 NH2 Poly L-lysine * CH2 * N O O Poly(ethyl-2-cyanoacrylate)

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SLIDE 29

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

poly ethylene glycol (PEG)

  • Biocompatible
  • Applicable as a hydrophilic segment in

amphiphilic copolymer

copolymerization

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SLIDE 30

Emulsion/evaporation (o/w) Hydrophilic drug i.e. proteins Modified-double-emulsion (w/o/w) Hydrophobic drug i.e. steroids

drug drug

biomolecules

drug

Strategies for Drug Delivery Systems

Surface modification s and activation

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SLIDE 31

Procedures for preparation of drug-loaded Nanospheres

Drug , Fe3O4 , & Quantum

dots loaded in the cavity

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SLIDE 32

Compositions of PLA-mPEG diblock copolymers

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SLIDE 33

TEM images of BSA-loaded nanospheres

BSA-loaded PLA-mPEG nanospheres BSA and Fe3 O4

  • loaded PLA-mPEG nanospheres

Drug Drug Fe3O4

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SLIDE 34

Thermo- sensetive Drug delivery system

  • Stable suspension at temperatures below body

temperature

  • Unstable at temperatures above body temp.

Use body increase of temp to trigger release Use external heating source -hyperthermia

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SLIDE 35

‘Smart’ polymeric Nanoparticles Systems

Poly(N-isoprorylacrylamide)

T<LCST T>LCST Drug Drug LCST : Lower critical solution temperature

Under the condition that temperature exceeds the LCST, amphiphlic micelles are collapsed so as to start to release the entrapped drug.

Thermosensitive polymer

Jo, Y. S., et al., Macromolecular Rapid Communications 2003, 24, 957.

Qin et al (2006)

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SLIDE 36

Schematic View of Modified-Double-Emulsion-Method (MDEM)

BSA: Bovine serum albumin PEG: Poly(ethylene glycol) PDLA: Poly(D, D-lactide) PLLA: Poly(L, L-lactide) PNIPAAm: Poly(N-isopropylacrylamide) PVA: Poly (vinyl alcohol) SPION: Superparamagnetic iron oxide nanoparticles

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SLIDE 37

(a) transparency change of the PNIPAAm-PDLA solution (b) differentiated curve of (a) (c) w/o/w’ emulsion

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SLIDE 38

Thermogram of Polymeric Structures

25 30 35 40 45 50 55
  • 1.5
  • 1.0
  • 0.5
0.0 0.5 1.0 Endo LCST : 36.4
  • C
(b) (a) Heat flow [mW] Temperature [
  • C]

Tg of PLLA segment PEG segment

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SLIDE 39

Schematic View of the “Shell-in-Shell” Structure

PNIPAAm: hydrophilic, stable PNIPAAm: hydrophobic, unstable

LCST: Lower critical solubility temperature

Below LCST Drug release Above LCST

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SLIDE 40

Temperature-dependent Bovine Serum Albumin (BSA) Release

Conditions: PBS (a) 37 °C (b) 22 °C Membrane Mw cut-off: 100 kDa

Suk, J et al (adv. Funct mat 2005)

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SLIDE 41

Toxicity Assay Au@PLLA-PEG@PNIPAAm-PDLA and PLLA-PEG@PNIPAAm-PDLA

(a) (c) (b)

1000 μg/mL uncoated 1000 μg/mL Au control

(a) (c) (b)

1000 μg/mL uncoated 1000 μg/mL Au control

TCCV assay

MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium TCCV: Two-color cell fluorenscence viability

Green spots = living cells Red spots = dead cells

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SLIDE 42

Mathematical modeling

  • f controlled release rate
  • Diffusion model
  • Dissolution model

⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ∂ ∂ + ∂ ∂ = ∂ ∂ r c r r c D t c 2

2 2

⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ∂ ∂ + ∂ ∂ = ∂ ∂ r c r r c D t c 2

2 2

( )

∑

∞ − − ∞

+ + + − =

1 2 2 1 1

2 2

) 3 9 ( 1 6 1

n Dt R q n

n

e q c c α α α α

) (

1

c K c k dt dc r

p d

− = − =

⎥ ⎦ ⎤ ⎢ ⎣ ⎡ + − − + = ) 1 exp( 1 ) 1 (

1

kt K c c

p

α α α

Diffusion Diffusion Dissolution

Time

  • Jo. Y. S,et al, Nanotechnology 2004, 15 (9),1186-1194.
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SLIDE 43

Self-assembly of gold nanoparticles

  • n the surface of PLA-mPEG nanospheres

Silanization Gold nanoparticle self-assembly

  • Y. S. Jo, M. Muhammed, et al., J. Materials Science: Materials in

Medicine 2005

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SLIDE 44

TEM images of ‘shell-in-shell’ structure nanoparticles

a) PLLA-PEG micelle b) ‘shell-in-shell’ structures covered with Au nanoparticles in part c) - d) ‘shell-in-shell’ structures fully covered with Au nanoparticles

  • Y. S. Jo, J Mat Sci.; Mat in Medicine

(2004)

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SLIDE 45

Drug Release Profile

Dissolution regime

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 5 10 15 20 Time [hrs] c1∞Vr/c0 Diffusion model Dissolution model DL1

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SLIDE 46

Drug Release Profile Dissolution- Diffusion Regimes

0.1 0.2 0.3 0.4 0.5 0.6 5 10 15 20 Time [hrs] c1∞Vr/c0 Diffusion model Dissolution model LL2

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SLIDE 47

in vivo test: estrogen release by PLA-PEO DDS

Group D PLA-PEO DDS (loading 17¥â

  • estradiol) injected

Dosage; (39.6 ¥ì g / 39.6 ¥ì g / 550 ¥ì L = 17¥â

  • estradiol / PLA-PEO DDS /

PBS buffer solution) D-II D-I Group N 550 ¥ì L of PBS buffer solution injected N-II N-I Group P P-I; 550 ¥ì L of positive control solution (17¥â

  • estradiol

dissolved in olive oil) injected P-II; 17¥â

  • estradiol tablet implanted

P-II P-I

Aromatase P450 (P450arom) Knocked-Out (ArKO) mice used in this work

Androgen precursor ster Estrogens Aromatase P450

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SLIDE 48

Injectable Drug Delivery Systems

Hydrogels - Ferrogels

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SLIDE 49

Injectable Drug Delivery Systems

  • Biocompatible
  • Liquid at Room temperature
  • Solid at Body temperature
  • Can be loaded with drugs
  • Controlled drug release

HO O O O O O OH

99 65 98

Pluronic F127

Pluronic F127 copolymer undergoes reversible sol‐ gel transition at different T as a function of concentration

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SLIDE 50
  • 2

2 4 6 8 10 12 14 16 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

(a)

35%

(b)

  • 2

2 4 6 8 10 12 14 16 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

34%

(c)

  • 2

2 4 6 8 10 12 14 16 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

33%

(e)

  • 5

5 10 15 20 25 30 35 40 45 1 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

17.5%

(f)

10 20 30 40

  • 6
  • 4
  • 2

2 4 G', G'' (Pa) Temperature (

  • C)

G' G''

8.75%

Effect

  • f Concentration
  • n

Gelation Temperature

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SLIDE 51

Injectable Drug Delivery Systems Magnetic-Sensitive Ferrogel

HO O O O O O OH

99 65 98

Pluronic F127

  • 5

5 10 15 20 25 30 35 40 1 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

Transition point

5 10 15 20 25 30 35 16 18 20 22 24 26 28 30 32 34 36

Concetration (%) T em perature (deg. celcius)

Working Range

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SLIDE 52

Reversible sol‐gel transition

  • 5

5 10 15 20 25 30 35 40 1 10 100 1000 10000 lgG', G'' (Pa) Temperature (

  • C)

G' G''

Transition point

17.5%

  • Qin. J., et al Adv. Func . Mat. 2008
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SLIDE 53

SPION in organic solvent and (b) embedded in the ferrogel

Magnetic-Sensitive Ferrogel

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SLIDE 54
  • 1000
  • 500

500 1000

  • 60
  • 40
  • 20

20 40 60

  • 100
  • 50

50 100

  • 30
  • 15

15 30

Magnetization (Am

2kg

  • 1)

Applied field (mT)

Sensitive to the External Magnetic Field

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SLIDE 55

Magnetic Sensetive Release rate

10 20 30 40 50 60 70 20 40 60 80 100

1 2 3 4 10 20 30 Total released (%) Time (h)

  • ff
  • n
  • ff
  • n
  • n

Total released (%) Time (h)

  • ff
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SLIDE 56

2000 4000 6000 20 40 60 80 100

No magnetic field In magnetic field

Cumulative release (%) Time (minute)

t1/2= 3195 min t1/2= 1500 min

Drug release profiles

Magnetic Enhanced Drug delivery

  • Qin. J., et al Adv. Func . Mat. 2008
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SLIDE 57

Hearing Research Hearing Research

Nan NanO O ear ear

B Bjelke

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SLIDE 58

Summary

Nanomaterials and Multifunctional Nanoparticles have tremendous

potentials for developing smart and novel medical treatments MFNP can carry different Payloads; pharmca, genes, DNA, etc can be designed to be environmentally resposnive

  • Magnetic ,
  • Temperature ,
  • Concentration of biomolecules (sugar, pH,..)
  • Targeting devices can be attached for delivery at specific sites
  • Injectable hydrogels offers new ways for intoducing DDS without

surgical operation

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SLIDE 59

Funding: Swedish Agencies. (FASS, FORMAS, VR, SSF, VINOVVA EU ( Framework Programs: FP 5, FP 6, FP 7)