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Future Treatment of Oxidative-Stress Related Disorders with Nanotechnology. Dr. Beverly A Rzigalinski Virginia College of Osteopathic Medicine Virginia Polytechnic & State University Blacksburg, VA. Cerium Oxide. Cerium - Rare earth element Cerium atom surrounded by oxide lattice

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future treatment of oxidative stress related disorders with nanotechnology

Future Treatment of Oxidative-Stress Related Disorders with Nanotechnology

Dr. Beverly A Rzigalinski

Virginia College of Osteopathic Medicine

Virginia Polytechnic & State University

Blacksburg, VA

cerium oxide
Cerium Oxide
  • Cerium - Rare earth element
  • Cerium atom surrounded by oxide lattice
    • Cerium has multiple valence states
    • Oxide lattice can have numerous “defects”
    • Micro sized particles used in coatings, particularly catalytic converters
    • Redox Reactions
    • NOX
slide3

What is Nano - Cerium Oxide?

  • Nanoscale materials behave differently from their micro-sized counterparts
  • Valence states of Cerium may change more quickly
  • Oxygen vacancies or “defects” increase dramatically at the nano scale
  • Better redox?
slide4

A Single Dose of Engineered Cerium Oxide

Nanoparticles Increases Brain Cell Longevity

Control

Nano-Treated

Days

Average Life Span

slide5

27 DIV Organotypic brain cell

culture

27 DIV Organotypic brain cell

Culture treated with 10 nM Ceria

Nanoparticles at 10 DIV

123 DIV Organotypic brain cell

Culture treated with 10 nM Ceria

Nanoparticles at 10 DIV

slide6

Nanoparticle-Treated Cultures Maintain Normal Neuronal

Signaling Throughout Their Extended Lifespan

400

28 DIV Nano-Treated

28 DIV Control

300

[Ca2+]i

(nM)

200

68 DIV Nano-Treated

-

100

Time (Seconds)

100 mM Glutamate

slide8

Ce+3

O2

Free

Radical

O2

  • Regeneration:
    • Lattice Rearrangements?
  • Reaction with H2O?
  • Adsorption of OH or H+?
  • Other cellular reactants?

Ce+4

O2--x?

slide9

Cerium Oxide Nanoparticles Scavenge Hydroxyl Radicals

Generated by the Fenton Reaction

Fenton Reaction

+10 nm Ceria

+7 nm Ceria

+Fe-doped Ceria

slide10

Cerium Oxide Nanoparticles Scavenge

Superoxide Radicals

Irradiated

riboflavin

+7 nm Ceria

+10 nm Ceria

+Fe-doped Ceria

slide11

CeO2-Nanoparticles Have Activity SOD, GSH,

And Catalase-Like Activity

10 nm

7 nm

Activity

(Units)

SOD

Glutathione

Peroxidase

Catalase

slide13

Cerium Oxide Nanoparticles Protect Cells Against Oxidative

Stress Induced by H2O2 - Size Dependency

Control

Control

160

160

Control

Control

50nm particles

50nm particles

50 nm Particles

50 nm Particles

20nm particles

20nm particles

10 nm Particles

10 nm Particles

140

140

7nm particles

7nm particles

7 nm Particles

7 nm Particles

120

120

4

100

100

80

80

Injured Cells x 10

60

60

40

40

4

20

20

Injured Cells x 10

0

0

m

m

m

m

Control 1nM 10nM 100nM 1

Control 1nM 10nM 100nM 1

M 10

M 10

M

M

Concentration

Concentration

slide15

Cerium Oxide Nanoparticles Protect Organotypic

Brain Cell Cultures From In Vitro Trauma

(10 nM, 10 DIV)

Injured

Cells/mg protein

(x 106)

n=16, in triplicate

7.5 mm

Injury

(Severe)

6.5 mm

Injury

(Moderate)

Uninjured

slide16

Cerium Oxide Nanoparticles Protect Organotypic

Brain Cell Cultures From In Vitro Trauma

4

_

Nano-Treated

1 hr Post Injury

_

Control

3

Injured

Cells/mg protein

(x 106)

_

2

_

1

7.5 mm

Injury

Uninjured

6.5 mm

Injury

slide17

No Response

No Response

No Response

D [Ca2+]i 100-265 nM

D [Ca2+]i 100-265 nM

D [Ca2+]i 100-265 nM

D [Ca2+]i >265 nM

D [Ca2+]i >265 nM

D [Ca2+]i >265 nM

Nanoparticles Preserve Normal Glutamate Signaling in Injured Neurons

120

Uninjured

100

24 Hr post

Moderate Injury

80

24 Hr post

Moderate Injury

Nano-Treated

Percentage

Of Neurons

Examined

60

40

20

0

slide19

Ab Peptide

+ 10 nm Ceria

Ceria Alone

Ceria + Albumin

Cerium Oxide Nanoparticles Block

Amyloid-beta –Induced Free Radical Production

slide20

Cerium Oxide Nanoparticles Protect Neurons from

Aβ(1-42) -Induced Toxicity

100

80

)

4

60

Total injured cells(x10

40

20

0

Control 10CeONP 100CeONP Aβ Aβ+10 CeONP Aβ+100CeONP

Treatment Groups

slide21

Control

Ab

Aβ+10nm Cerium Oxide NP (10 nM)

Aβ+100nm Cerium Oxide NP ( 100 nM)

slide23

Cerium Oxide Nanoparticles Increase the Life Span

Of Female Drosophila and Maintain

Normal Geotaxis with Aging

100

80

60

Percent Survival

40

Control

20

10nM CeO2

0

0

20

40

60

80

Days

Geotactic Response

slide24

120

Control

m

100

1

M CeO2 NP

80

60

Percent Survival

40

20

0

1

3

5

7

24

48

72

Post-paraquat Time (in hours)

Cerium Oxide Nanoparticles Decrease Paraquat Toxicity

In Middle-Aged Female Drosophila

5 flies lived out

Normal lifespan

what about mammalian models
What About Mammalian Models?
  • Mice – 90 nmols total, tail vein injection
    • Accumulation in brain, heart, lung
    • No metabolism?
  • Rats – Up to 150 mg injected.
    • No toxicity noted
    • No adverse tissue pathology
a new generation of nanopharmaceuticals
A New Generation of Nanopharmaceuticals
  • Cerium Oxide - A promising agent to treat diseases associated with oxidative stress.
  • More ground to cover…..
    • How much free radical scavenging is too much?
    • Controlled free radical scavenging?
    • Toxicity profile
nanoneurolab at vcom
Undergraduate Students

Eric Amateis

Matt Kurnick

Julie Karafakis

Clinical

Dr. Jill Cramer

Post Doctoral

Dr. Shaadi Elswaifi

Dr. Igor Danelison

Research Associates

Neeraj Singh

Courie Cohen

Kevin Hockey

Chine Logan

Collaborators

Dr. Kathleen Meehan

Dr. Rick Davis

Dr. David Cox

Nanophase Inc.

Advanced Powder Tech.

NanoNeuroLab at VCOM