NANOMATERIALS AND ADVANCED MATERIALS

PROCESSING : HEALTH IMPACT

Shaharum Shamsuddin D. Phil. (Oxon.)

Biomedicine Programme

School of Health Sciences USM

For East Coast Environmental Health Seminar,

USM Health Campus, (18-19 July 2012)

NANOTECHNOLOGY

Nanotechnology involve research in the level of 100 nm and

below in at least one dimension

10-1 nm 100 nm 101 nm 103 nm 102 nm 10 4 nm > 10 5 nm

H2O Protein Ribosomes Nuclearpore

Mitochondrion

Cells Tissues

Comparisons of biological molecules found in nature with

representative sizes of `small’ object of man made Nanomaterials

NANOCARRIERS :

• Made from a material that is biocompatible,

• Well characterized, and easily functionalized;

• Exhibit high differential uptake efficiency in the target cells

• Soluble or colloidal under aqueous conditions for increased

effectiveness

• Have an extended circulating half-life,

• A low rate of aggregation

• A long shelf life.

NANOCARRIER ADVANTAGES

• Protect the drug from premature degradation;

• Prevent drugs from prematurely interacting with the biological

environment

• Enhance absorption of the drugs into a selected tissue (for example,

solid tumour);

• Control the pharmacokinetic and drug tissue distribution profile;

• Improve intracellular penetration.

NANOTOXICOLOGY IS IN ITS INFANCY

Do the unique material properties of nanomaterials equate to unique

biological properties as well?

Which of these properties are responsible for the biological effects?

Are the effects limited by the traditional defintion of nanomaterial (1-100 nm)?

Who should be studying the biocompatibility or toxicity of these new

materials?

What studies should be done?

APPLICATION OF NANOTECHNOLOGY IN MEDICINE

1 Khairunisak Abdul Razak

2 Azlan Abdul Aziz 3 Shaharum Shamsuddin 4 Laurent Levy

1 School of Material Science & Mineral Engineering (Engineering campus USM)

2 School of Physics (Main Campus,)

3School of Health Sciences (Health Campus)

4Nanobiotix SA, 60 rue De Wattignies, 75012 Paris, France

Nanobiotechnology Research & Innovation , Institute for Molecular Medicine (INFORMM)

(NanoBRI @ INFORMM)

UNIVERSITI SAINS MALAYSIA

TIMELINE OF NANOTECHNOLOGY VS LIFE SCIENCE & MEDICINE

The development of nanomaterial for human use must follow a very strict regulation

Seven challenges (Sanhai et al., 2008)

1. Determination of the distribution of NP in the body following

systemic administration

2. Development of imaging modalities for visualizing the distribution

over time

3. Understanding of mass transport across compartment boundaries

in the body (how NP negotiate with biological barriers)

4. The need to predict the risk of NP (will be discuss in next slide)

5. The need to predict the benefit of NP

6. Establishment of standard/reference material & consensus

protocol that can provide benchmark for the development of novel

classes of materials

7. Realization of an analytical tool kit for Nanopharmaceutical

manufacturing + specs sheet of toxicology, safety & biodistribution

properties obtained via standardized, validated methods

NANOTOXICITY…

- An emerging important sub-discipline in

Nanotechnology

- The study of the interaction of the

nanostructure with biological system

- How it can induce toxic biological response

KIND OF TOXICITY…

Type of Nanoparticles

Nanosilica

Nanomagnetic

NanoGold

Liposomes

Polymers

TiO2

Publication & Patent Boom

Nanotechnology publications and patents worldwide. Source :

Wagner et al., (2006). Nature Biotechnology Vol. 24, No. 10, pp 1211 - 1217

NANOTOXICOLOGY IS IN ITS INFANCY

236 January ‘08

Comparison of nanoparticle uptake as a function of size reported by (A) Chithrani et al. (2006) and (B) Lu et al.

(2009). (C) The results of Chithrani et al. (2006) are re-plotted with the particle uptake expressed in pg/cell,

instead of number of particles per cell

Nanoparticles uptake by the cells

Chithrani et.al.,. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett

2006; 6: 6628.

Lu F, Wu SH, Hung Y, Mou CY. Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles.

Small 2009; 5: 1408-13.

The relationship between absorption, distribution, metabolism and

excretion (ADME) to detoxication and toxicity of a chemical.

Potential biodistribution of particles

Comparison on pharmacokinetics and distribution model between

small molecules and nanoparticles

How Nanomaterial can be toxic to human – The Seven

challenges (Sanhai et al., 2008)

1. Determination of the distribution of NP in the body following

systemic administration

2. Development of imaging modalities for visualizing the distribution

over time

3. Understanding of mass transport across compartment boundaries

in the body (how NP negotiate with biological barriers)

4. The need to predict the risk of NP (will be discuss in next slide)

5. The need to predict the benefit of NP

6. Establishment of standard/reference material & consensus

protocol that can provide benchmark for the development of novel

classes of materials

7. Realization of an analytical tool kit for Nanopharmaceutical

manufacturing + specs sheet of toxicology, safety & biodistribution

properties obtained via standardized, validated methods

Risk analysis is another important tool prior to scale up. The above figure

shows example of risk analysis of nanomaterial fabrication

Cellular Toxicity of Nanoparticle [ROS products such as superoxide (•O2-) and hydroxyl radical (•OH)]

(Event 1 - Cell membrane integrity leading to cell survivability will

be affected by ROS produced by a nanoparticle smaller than a

cell (red particle) as shown). Event 2 represents the situation

where a nanoparticle is internalized and then creates ROS

products. In Event 3, particle dissolution affect cellular function

after nanoparticle internalization while Event 4 represent any

mechanical damage to sub-cellular units such as the lysosome,

endoplasmic reticulum and nucleus itself. In Event 5, different

functional groups and surface electronic structures arising from

different nanostructured materials can determine the level of

interaction between the nanoparticles and their surroundings.

Overall size of the particle can play an important role as

represented by Event 6 since large particles can potentially

induce permanent damage to the cell membrane while small

particles can pass through the membrane and do harm inside

cell. Even 7 involved non-spherical particles which might have a

different biological response compared to the spherical

nanoparticles. Event 8 dissolutionn of NP into the cell may effect

the cell in various way

Important of Toxicity study (in vitro & in vivo)

Potential targets include:

- Liver and organs of the

reticuloendothelial system (RES)

- Kidney (e.g.: possibility of

urolithiasis, tubular lesions),

- Central nervous system (thru BBB)

- Reproductive organs

- Cardiovascular system (e.g.:

formation of aggregates),

- Development of inflammatory

reactions, which appear to constitute

a major risk for the respiratory tract,

related to the formation of

agglomerates

Nanotoxicity impact on human health (cont.)

Summary diagrams showing the possible areas of localization of nanoparticles to various tissues from the

blood circulation. Opsonization can result in uptake to the liver, but changes in size or surface

characteristics can result in accumulation in a wide range of other tissues.

Nanoparticles in vivo distribution : USM experience

Rifampicin + DID (fluorescence dye) encapsulate in Nanosilica particle

NanoDiD

NanoDiD + Rif DiD control mouse

Conclusion : Target organ for Nanosilica : Uterus-Ovary,

Liver, Muscle, Skin & Lung

Nanoparticles into the cells : Difficulties

1. Very few comprehensive quantitative studies of the kinetics of interaction

and uptake of nanomaterials into the cells – Time for saturation of

equilibrium, size/shape dependent ?

2. How to know exactly which species are taken up by the cell. Is it single

nanoparticles or aggregates formed prior to, or during interaction with the

membrane? Does functionalization of surface play important role ?

3. Passive uptake of nanomaterials always results in endosomal localization.

This is a stringent limitation for biological and biomedical applications and

therefore considerable efforts need to be done to escape/bypass the

endocytotic pathway

TERIMA KASIH