Nanoparticle penetration of human skin - a double-edged sword

(Nanowerk Spotlight) Engineered nanoparticles are at the forefront of the rapidly developing field of nanomedicine. Their unique size-dependent properties, of which optical and magnetic effects are the most used for biological applications, makes them suitable for a wide range of biomedical applications such as cell labeling and targeting, tissue engineering, drug delivery and drug targeting, magnetic resonance imaging, probing of DNA structure, tumor destruction via heating (hyperthermia), and detection and analysis of biomolecules such as proteins or pathogens. Many of these applications can also be tailored to target skin to help in the early diagnosis of a skin disease, which then could also be treated via nanocarriers. In addition, a tissue engineering approach could be useful for skin wound healing therapies and the magnetic properties of these particles might help in directing and localizing these agents in a particular layer of the skin where their action is desired. Unfortunately, if nanoparticles are able to penetrate layers of skin for therapeutic purposes, they might equally be able to penetrate skin unintentionally. This raises the question if people, who are exposed to such nanomaterials, could accidentally be contaminated and thus exposed to a potential local and/or systemic health risk. Researchers in Italy now have begun to systematically evaluate both risks and applications of nanoparticle skin absorption.
The discussion about the safety of engineered nanoparticles has become quite polarized, with one side – activist groups – emphasizing the potential risks (e.g. "Nanomaterials, sunscreens and cosmetics: Small ingredients, big risks") and the other – the cosmetics industry – claiming that there is no reason for concern "Nanoparticles and the skin - a health risk for the consumer?" - pdf download 2.7 MB).
The existing literature on the ability of nanoparticulate material to penetrate skin is inconclusive at best. We reported on one recent research finding in a previous Nanowerk Spotlight that showed that fullerene-based peptides can penetrate intact skin and that mechanical stressors, such as those associated with a repetitive flexing motion, increase the rate at which these particles traverse into the dermis ("Fullerenes shown to penetrate healthy skin").
Researchers in Italy have investigated whether superficially modified iron-based nanoparticles, not designed for skin absorption but whose dimensions are compatible with those of skin penetration routes, are able to penetrate and perhaps permeate the skin. Their results, which showed profound skin penetration by these nanoparticles, opens up two main directions of investigation: a) nanomaterial toxicological risk assessment and awareness, b) potential exploitation of nanomaterials as carriers for drug delivery into and through the skin.
"So far, the skin, which is our first defense against the environment, has been considered an unlikely path of entry for engineered nanoparticles" Dr. Biancamaria Baroli explains to Nanowerk. "Yet these conclusions arise from investigations carried out with much bigger particulate vehicles than the ones we used (< 10 nm). Even bacteria and viruses are bigger; for instance, the dimension of adenovirus is around 150 nm. We think that the question, whether such small materials could penetrate and permeate the skin, is an important question to be asked."
Baroli, a researcher at the Department of Pharmacy at the University of Cagliari, is first author of a recent paper in Journal of Investigative Dermatology titled "Penetration of Metallic Nanoparticles in Human Full-Thickness Skin".
Nanoparticle characterization and recovery within human skin after few hours of contact
TMAOH ((tetramethylammonium hydroxide)-maghemite nanoparticle characterization and recovery within human skin after few hours of contact. Nanoparticles appeared to passively penetrate the skin through the transepidermal and transfollicular routes. A) Macroscopic appearance of a TMAOH-maghemite nanoparticle aqueous dispersion. B) TEM micrograph of TMAOH-maghemite nanoparticles. C) Hematoxylin-stained human skin exposed to TMAOH-maghemite nanoparticles. Using a light transmission microscope, nanoparticles are visible in the stratum corneum (yellow line) as brown areas. Unfortunately, digitalization does not allow to see smaller deposits in viable epidermis (pink line) or dermis (blue line). D) EDS-SEM micrograph showing nanoparticle deposits (white spots) within the stratum corneum, stratum corneum-viable epidermis junction, and a little below the junction. E) EDS spectrum of white spots within D, showing the presence of iron. (Images: Dr. Baroli)
In their recent work, Baroli and her collaborators applied two different stabilized nanoparticle dispersions to human skin samples. The results of this study showed that nanoparticles were able to passively penetrate the skin and reach the deepest layers of the stratum corneum (SC – the outermost layer of the skin) and hair follicle and, occasionally, reach the viable epidermis. Yet, nanoparticles were unable to permeate the skin. From a therapeutic point of view, these results represent a breakthrough in skin penetration because it is early evidence where rigid nanoparticles have been shown to passively reach the viable epidermis through the SC lipidic matrix.
"Our findings are in agreement with previously published results" says Baroli. "Although more experiments are needed to help us completely understand the penetration mechanism, this study represents a proof of principle and provides a major breakthrough in the study of skin absorption, which allows us to envisage potential toxicological risks and further nanoparticle biomedical applications.
"In fact, it is now possible to foresee synthesized particles that have been designed specifically to target the skin (as we are currently doing), both to understand the penetration mechanism and to study whether penetrated amounts could be of any use in biomedical applications. In addition, from a nanotoxicological point of view, one can question 'how much is enough' to trigger toxicological responses."
Unfortunately, researchers cannot answer this last question yet, as nanotoxicological risk assessment investigations have only recently been undertaken and the cutaneous route of exposure has not yet received great attention. Baroli points out that her team's commitment is instead to evaluate both risks and applications of nanoparticle skin absorption, hoping that their work will help to increase awareness and safety of a technology with great therapeutic potential.
"We are now investigating nanoparticles designed and synthesized for skin applications with the intent of better understanding penetration mechanisms and to finding simple but accurate methods for quantifying the amount of particles entered into the skin" says Baroli. "A better understanding of penetration mechanisms and our ability of finding methods to quantify particles in the skin may help to develop new nanoparticle-based formulations but also prevent accidental contamination and health risks."
Michael Berger By – Michael is author of three books by the Royal Society of Chemistry:
Nano-Society: Pushing the Boundaries of Technology,
Nanotechnology: The Future is Tiny, and
Nanoengineering: The Skills and Tools Making Technology Invisible
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