Beatriz Macarena Cobaleda Siles, PhDNANOSAFE 2016

Grenoble, 7-10 November

Safer-by-Design strategies in GUIDEnano

Safety by Design

Human learning: Trial-and-error approach + bad decision

Synthesis of product

Toxic metals and environmentally

unfriendly

Change the regulatory

rules

Design safer product

Safety by Design

Design safer product

Synthesis of product with toxic

metals andenvironmentally

unfriendly

1. Safety is addressed at the design stage of a process or product rather thantested after their development

2. Not develop toxic technologies3. Design or re-design protocols to avoid make mistakes

Angew. Chem. Int. Ed. 2014, 53,2-18

http://www.safenano.org

State of the art

Int. J. Nanomedicine. 2015,10,3989-4008

Safer by Design strategiesDeveloped to modulate the main factors determining safety of NMs: • Intrinsic toxicity • Release/bioavailability potential• Persistence

To reduce toxicity of NMs:- Shape and size modifications- Increase in hydrophilicity to decrease thepotential to cross biological membranes- Changing oxidation state to mitigatereactivity

To reduce release of NMs from theirmatrices:- Induction of strong Van der Waalsand covalent bonding between theNMs and their matrices- Development of barriers bymultilayer approaches (multilayerfilms) or multicoating approaches- Self-healing pairs of NM/matrix byionic approach to avoid release ofNMs

To reduce persistence of NMs:- Induction of self-assembly of NMs to increase the coalescent character of the NMsin aqueous media or at high temperatures to promote the sintering intomicroaggregates- Development of new high biodegradable NMs under certain temperature oroxidative conditions

Environ. Sci.: Processes Impacts, 2013, 15, 23

Physico-chemical Characteristics of NMs

• Green Chemistry• Design to avoid changes in the activity orproperties• Proper and extense physico-chemicalcharacterization

Reducing toxicity of NMs

nanomicro

Size ≥ 10 µm

Control of Nanoparticle aggregation

Ionic strengthpH of the dispersionSurface charge

Size modifications

Frustrated phagocytosis

J. Environ. Sci. Health Part A, 2009, 44, 1485–1495Particle and Fibre Toxicology, 2010, 7:5

Reactivity

T iO 2 _ In d iv id u a l_ 1 5 n m

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0

1

2

3

T iO 2 _ S m a ll_ 5 0 n m

W a v e le n g h t(n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0

1

2

3

T iO 2 _ L a r g e _ 1 1 6 n m

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0

1

2

3

A U C T iO 2 3 0 0 -8 0 0 n m

T im e (h )

AU

C

0 5 1 0 1 5 2 0 2 5 3 0 3 5

0

1 0 0

2 0 0

3 0 0

T iO 2_ In d iv id u a l_ 1 5 n m

T iO 2_ S m a ll_ 5 0 n m

T iO 2_ L a rg e _ 1 1 6 n m

Sedimentation of TiO2

A g N P _ 1 5 n m

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

1 .2

1 .4

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 9 0 3 9 5 4 0 0 4 0 5 4 1 0 4 1 5

1 .0 01 .0 2

1 .0 4

1 .0 6

1 .0 8

1 .1 0

1 .1 2

1 .1 4

1 .1 6

1 .1 8

1 .2 0

1 .2 2

1 .2 4

1 .2 6

1 .2 8

1 .3 0

A g N P _ 5 0 n m

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

1 .2

W a v e le n g th (n m )

Ab

so

rb

an

ce

4 2 0 4 3 0 4 4 0 4 5 0 4 6 0

1 .0 5

1 .1 0

1 .1 5

A g N P _ 1 5 0 n m

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

A U C A g N P 3 0 0 -8 0 0 n m _ 4 8 h

t im e (h )

AU

C

0 5 1 0 1 5 2 0 2 5 3 0 3 5

5 0

1 0 0

1 5 0

2 0 0

2 5 0

A g N P 1 5 n m

A g N P 5 0 n m

A g N P 1 5 0 n m

Sedimentation of Ag

Reducing release of NMsRisk assessment: The release of NMs from their matrices. Objective: avoid the release of the NM or release as ions. Procedure: Protect the NP using polymer coatings (PVP)

Nano Lett., 2015, 15 (1), 365–371

AgNW-cloth overall emissivity is much less than that of normal cloth and provides greatinsulation against radiative heat loss (higher IR reflectance and thermal insulation capability)

Reducing release of NMs

“Several studies have shown that AgNP suspensions are toxic. However, there have been no systematic studies, which analyze to which degree varying amounts of silver ions

present in AgNP suspensions contribute to their toxicity”

Risk assessment: The ion release is more toxic than the NP. Objective: avoid the degradation of the NM. Procedure: Protect the NP using coating ligands

Environ Sci Nano., 2014, 1(2), 144–153.

Safer-by-design nanostructured materials

• ZnO NPs absorb UV wavelengths ranging from 280 to 400 nm (ideal component in cosmetic creams and sunscreens)

• Generation of reactive oxygen species (ROS) which led to DNAdamage, cell viability reduction, and apoptosis (released ions anddirect particle interactions with cells)

• SiO2 shell exhibits less DNA damage in comparison to the uncoatedones

• Minimizing the ZnO nanoparticle dissolution and direct contact withthe cells inhibiting toxicity

Reducing persistance of NMs

• The addition of protective agents to avoid the spontaneous transformation of NMs, forinstance using albuminization strategy.

• Studying the transformation of NMs and their corresponding toxicity by changing the NMcomposition, such as Ag+ and Ag2S in the presence of S2- ions.

Controlling and monitoring the evolution of NMs

AgNP

Ag2S

+ coating ligand

albumin

Nature Nanotechnology, 2009, 4, 546 – 547J. Nanobiotechnol, 2015, 13, 84

A g N P _ 1 5 0 n m _ H 2 O 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .1

0 .2

0 .3

0 .4

t0

t60

t1 20

t1 80

t2 40

t3 00

t3 60

t2 1h

t2 4h

t2 8ht4 8h

Corrosion of Ag

N 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

D M E M

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

H 2 O 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .2

0 .4

0 .6

N 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .1

0 .2

0 .3

0 .4

D M E M

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .1

0 .2

0 .3

0 .4

H 2 O 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .1

0 .2

0 .3

0 .4

N 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .5

1 .0

1 .5

2 .0

D M E M

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0

0 .1

0 .2

0 .3

H 2 O 2

W a v e le n g th (n m )

Ab

so

rb

an

ce

3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0

0 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8

0 .1 0

Development of biodegradable NMs under certain temperature or oxidative conditionsAgNP_15 nm AgNP_50 nm AgNP_150 nm

Safer not Safe or safety by design

Proper and extense characterization of NMs to obtain an optimal design

Controlling and monitoring our NMs “from cradle to grave”

Controlling the size, shape, possible oxidation states during lifecycle….

Controlling the release of the NM from the solid/of the ions from the NM

Controlling the persistance of NMs: transformation, corrosion,…

Solid is a friend, aqueous solution is an ally but airborne is the enemy

Safety aspects should inform about the design of a product or process at theinception point, along with other key concepts such as function, quality and cost

Conclusions

The outcomes reflected in this work were performed under the ongoing GUIDEnano project funded by European Commission´s Framework Programme

(FP7/2007-2013) under grant agreement №604387

Design and Pharmacodynamic of Nanoparticles Group

Acknowledgment