2. What are Nanoparticles?
• Nanoparticles (NPs) are defined as particles size ranging from
1 to 100 nm, but often used in the range of 300-500 nm not
strictly
• They are in many shapes such as sphere, rod, cylinder, and cube
and soft or hard, dispersed or aggregated.
• NPs show novel physiochemical , electronic, optical and
mechanical properties.
Nanoparticles Examples:
• Metals such as gold, silver, cobalt, iron, palladium, platinum,
rhodium, metal oxides, titanium dioxide, cobalt oxide, iron oxide,
zinc oxide, silica, quantum dots, Carbon nanotubes, fullerenes,
quantum dots(QDs), polystyrene nanoparticles. and solid or
flexible lipid based materials.
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3. Why NPs interaction with skin is considered?
• Increasing with the development of nanotechnology and new
applications of NPs in medicine
• For safety concerns we have to monitor the nanotoxicity due to
penetration into the skin and entire body.
• NPs penetrate through human skin which emphasis on their use in
drug delivery and NP properties may affect the penetration.
• Some properties such as particle size and shape, surface charges
and pH, formulation, including surface coating and application
methods are also play major role in NP skin penetration.
• NPs penetration in skin is may due to unintended exposure from
an environmental and occupational mode and it should be
controlled for health and safety point of view.
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5. Skin functions
• As one of the bigger organs of the human body, the skin fulfils many different
functions:
• It acts as the first barrier to xenobiotics
• It prevents dehydration and allows the metabolism of several compounds.
• Skin also plays an important role in the temperature regulation and in the
immunological response.
• This latter function is ensured by Langerhans cells, which are able to process
antigens and give rise to the inflammatory response to external insults.
• Skin does also play a role in the biosynthesis of constitutive substances, such as
keratin, collagen, melanin, lipids and carbohydrates;
• It allows neurosensory function by means of resident receptors for heat, touch
and pain.
• Skin holds glands like sebaceous, apocrine and eccrine sweat glands. The first
ones secrete sebum, which is a mixture of lipids that acts as antibacterial
agent, while the second ones produce a secretion that contains scent used in
the mark of the territory.
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8. Transport routes of substances across the
Stratum Corneum (SC)
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9. Skin absorption of chemicals
• Chemicals may be absorbed through skin by different
pathways. Which are:
1. the intercellular route, with partitioning into the lipid
matrix,
2. the intracellular route,
3. through sweat glands,
4. through hair follicles
• As regard the last one there is evidence that the hair follicle
(HF) can act as a shunt increasing the penetration and
absorption of topically applied substances and NPs.
• HF canal can be considered as a significant reservoir for
penetrated chemicals and NPs too, since substances stored
there can continuously diffuse to the surrounding spaces, cross
the capillary walls and even reach the blood system. 9
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10. Skin absorption of chemicals
• Skin exposure to irritant compounds may cause a disruption of
the stratum corneum either by means of protein denaturation
agents, such as detergents, or through lipids extraction from
stratum corneum increase both irritation effects and damage
to the skin.
• Skin diseases, such as irritant contact dermatitis, can increase
the risk of penetration, leading to a possible sensitization.
• Permeability increases in atopic eczema, a disease
characterized by an epidermal barrier dysfunction.
• Moreover, other factors such as gender, differences in skin
thickness, hair follicle density, blood flow, age, mechanical
flexions and systemic diseases, may all influence the skin
barrier function.
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11. Issues of nanoparticles skin absorption
• NPs skin absorption is an issue which the scientific
community has been addressing, since the hazard of a
transdermal flux of nanomaterials opens a debate on
toxicological, therapeutic and drug delivery questions
that have still to be defined.
• Nanoforms of the metal oxides such as titanium
dioxide and zinc oxide, commonly found in sunscreens
for UV protection and in cosmetic products may
penetrate the skin layers.
• It is possible that nanoparticles may deposit within the
hair follicles in the skin, however, this is this not
considered a genuine penetration of the skin. Typically,
these particles can be removed either by washing or by
sebum and hair growth.
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12. Issues of nanoparticles skin absorption
• The skin is a truly remarkable organ protecting the body
from a very wide range of external stressors from
diseases caused by microorganisms, to damaging UV
radiation, to noxious chemicals. These skin structures
and features also make it a highly effective barrier
against the penetration of manufactured nonmaterial .
• If active ingredients (such as drugs) are bound to the
nanoparticles, they will be released once inside the
follicles, and they can then be transported through the
skin into the bloodstream. This carrier and release
mechanism could facilitate future drug delivery and
vaccination systems avoiding the use of needles.
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13. Can nanoparticles interact with living organisms?
• The interaction with living systems is also affected by the dimensions
of the nanoparticles. Nanoparticles, can have the same dimensions
as biological molecules such as proteins and they enter
the tissues and fluids of the body.
• Nanoparticles not bigger than a few nanometres may reach well
inside biomolecules, which is not possible for larger nanoparticles.
• Nanoparticles may cross cell membranes. It has been reported
that inhaled nanoparticles can reach the blood and may reach other
target sites such as the liver, heart or blood cells.
• Some nanoparticles dissolve easily and their effects on living
organisms which depends on its solubility. Some nanoparticles does
not degrade or dissolve and they may accumulate in biological
systems and persist for a long time.
• The response of living organisms to the nanoparticles depends on
varying size, shape, chemical composition and surface characteristics
will categorize the toxicity of nanoparticles.
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14. • The NPs characteristics such as shape, size, surface charge, z potential and the
tendency to aggregate are crucial elements to define the interactions with
human skin surface.
• Size – Very small size nanoparticles able to cross cell membranes, reach the
blood and various organs because of their surface to volume ratio. This may be
one of the reasons why nanoparticles are generally more toxic than larger
particles of the same composition.
• Chemical composition and surface characteristics – The toxicity of
nanoparticles depends on their chemical composition, but also on the
composition of any chemicals adsorbed onto their surfaces. However, the
surfaces of nanoparticles can be modified to make them less harmful to health.
• Shape –the health effects of nanoparticles are likely to depend also on their
shape. A significant example is nanotubes, which may be of a few nanometres in
diameter but with a length that could be several micrometres.
• A recent study showed a high toxicity of carbon nanotubes which seemed to
produce harmful effects by an entirely new mechanism, different from the
normal model of toxic dusts.
Which characteristics of NPs are relevant for health effects?
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15. Mechanism of penetration and permeation of NPs to Skin
• NPs size, shape, charge, surface properties can affect skin
penetration. NPs permeation properties such as NPs dimension,
composition or surface chemistry, may change completely when
they interact with physiological media
• Background factors, vehicle, density, temperature, etc., may
determine NPs aggregation and agglomeration can change
surface charge. The surface charge can influence NPs permeation
and penetration,
• For some NPs, such as QD there is evidence that surface charge
as well as pH could influence NPs penetration
• The positive charge on particle surface enhance their
electrostatic interaction with the cell membrane and favours
their internalization, while the diffusion of negative charged NPs
seem to be slowed in the matrix by the electrostatic interactions
with positively charged liposomal component. 15
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16. Other factors of NPs to affect skin
Ions release (dissolution)
• Metal NPs can release a greater amount of ions compared to bulk material,
due to their high surface/mass ratio. Furthermore some NPs can reach the
hair follicles and from there work as a long lasting reservoir for ions release.
• A prolonged ions release could increase the risk of allergic contact dermatitis
for NPs containing sensitizing metals, such as nickel (Ni), palladium (Pd) and
cobalt (Co).
Impurities
• In the production process of NPs, impurities can be present (metals, toxic
chemicals) and may have specific effects. The presence of metals (Ni, Cr, Fe)
into carbon nanotubes, i.e., can influence their biological oxidative damage
with effects influenced by the metal release into the medium.
Skin conditions
• A damaged skin barrier allows a penetration and permeation of NPs or can
increase their absorption.
• This is a relevant matter in working scenarios, because there is a wide
percentage of workers with impaired skin function in many professions.
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17. NPs local effects on the skin
Mechanical action
• The mechanical flexion (lasting up to 60 or 90 min) can increase skin
penetration of small fullerene NPs (3.5 nm) which can be found in the
intercellular spaces of porcine skin stratum granulosum.
• On the contrary, the small quantum dots (QD) of 18 nm and QD565-COOH of 14
nm) flexed for a 60 min period, did not penetrate the skin at 8 and at 24 h after
application.
Irritation
• Mechanical friction on the skin exposed to some NPs can cause skin irritation.
Sensitization
• The NPs that can penetrate the epidermal layer may cause allergic reactions,
due to the release of substances with notorious sensitizing potential, such as
metals (e.g., nickel, cobalt, palladium), which can induce an allergic contact
dermatitis or respiratory symptoms and throat irritation, nasal congestion, facial
flushing and skin reaction.
• It is conceivable that metallic NPs containing cobalt, nickel or chromium could
trigger allergic responses, while NPs containing gold or silver, which are known
as non-allergenic substances, should not induce allergic phenomena.
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18. • Particulate matter present in air pollution, especially from
traffic emissions, is known to affect human health
• Inhaled particulate matter can be deposited throughout the
human respiratory tract, and an important fraction of
inhaled nanoparticles deposit in the lungs
• It move from the lungs to other organs such as the brain, the
liver, the spleen and possibly the foetus in pregnant women.
• Movement from organ to another can be considerable,
depending on exposure time.
• Even within the nanoscale, size is important and small
nanoparticles have been shown to be more able to reach
secondary organs than larger ones.
How can inhaled nanoparticles affect health?
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19. How can inhaled Nps affect health?
• Another potential route of inhaled nanoparticles within the body is
the olfactory nerve;
• Nanoparticles may cross the mucous membrane inside the nose and
then reach the brain through the olfactory nerve. Out of three human
studies, only one showed a passage of inhaled nanoparticles into the
bloodstream.
• The effects of inhaled nanoparticles in the body may include
lung inflammation and heart problems.
• Studies in humans show that breathing in diesel soot causes a
general inflammatory response and alters the system that regulates
the involuntary functions in the cardiovascular system, such as control
of heart rate.
• The pulmonary injury and inflammation resulting from
the inhalation of nanosize urban particulate matter appears to be due
to the oxidative stress that these particles cause in the cells.
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20. What are the health implications of nanoparticles used
as drug carriers?
• Nanoparticles can be used for drug delivery purposes, either as the drug
itself or as the drug carrier
• The product can be administered orally, applied onto the skin, or injected.
• The objective of drug delivery with nanoparticles is either to get more of the
drug to the target cells or to reduce the harmful effects of the free drug on
other organs, or both.
• Nanoparticles used in this way have to circulate long distances evading the
protection mechanisms of the body. To achieve this, nanoparticles are
conceived to stick to cell membranes, get inside specific cells in the body or
in tumours, and pass through cells.
• The surfaces of nanoparticles are sometimes also modified to avoid being
recognized and eliminated by the immune system.
• With dermal administration, it was found that particle size was less
important than the total charge in terms of permeation through the skin. For
instance, only negatively charged particles were found to overcome the skin
barrier and only when concentration of charge was high enough.
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21. What are the health implications of nanoparticles used as
drug carriers?
• Nanoparticles may be used effectively to deliver genes to cells, to
treat cancer, as well as in vaccination .
• The use of nanoparticles as drug carriers may reduce the toxicity of
the incorporated drug but it is sometimes difficult to distinguish the
toxicity of the drug from that of the nanoparticle.
• Toxicity of gold nanoparticles, for instance, has been shown at high
concentrations. In addition, nanoparticles trapped in the liver can
affect the function of this organ.
• Nanoparticles have the potential to cross the blood brain barrier,
which makes them extremely useful as a way to deliver drugs directly
to the brain.
• On the other hand, this is also a major drawback because
nanoparticles used to carry drugs may be toxic to the brain.
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