Adnan Nasir, MD
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Nanotechnology is a relatively new branch of engineering and medicine that is making rapid inroads in dermatology. Nanotechnology applies the unique properties of matter on the nanoscale (1000 nm and smaller) for the purposeful design of new materials. Dermatology is already one of the leading beneficiaries of nanotechnology. In Part I of this series, we discussed the benefits of nanotechnology in dermatology. In Part II, we discuss some of the risks. Matter on the nanoscale has the potential for significant chemical volatility, which carries with it an increased risk of cellular and tissue damage. This article summarizes some of the theoretical safety concerns regarding nanotechnology and offers suggestions for addressing them.
nanotechnology, dermatology, drug delivery, sunscreens, safety
Nanotechnology traces its beginnings to the middle of the last century, when physicists at the California Institute of Technology (Caltech) theorized that machines making reduced scale replicas of themselves could, over a series of iterations, create assembly lines and factories on a molecular scale. Scientists at the Massachusetts Institute of Technology (MIT) made computer models of molecular machines that could self-assemble based on the charge, polarity, and steric fit (spatial arrangement of atoms) of individual components.1-4 As physicists and chemists studied matter on the molecular or nanoscale, they began discovering properties that departed from the bulk starting material. Glass, which shatters, is flexible (like spaghetti) on the nanoscale, and can conduct electricity. Nanoparticles that are smaller than the wavelength of light display interesting optical properties; for example, they can be tuned to resonate with light of characteristic quantized frequencies. In the past two decades, these properties have been used individually and in combination to create a broad range of consumer goods (e.g., light weight, yet strong, tennis racquets) to cutaneous and systemic drug delivery systems.5-11 The potential benefits are clear to scientists in academia and industry, as well as to clinicians. Furthermore, patents in nanotechnology are being issued at a geometric rate.
Any discussion of nanotechnology should include mention of the theoretic risks and concerns.12-14 Risk factors associated with toxicity are summarized in Table 1. One basis of toxicity is size, because as a particle shrinks, the proportion of atoms exposed on its surface increases (Figure 1 and Figure 2). This increase in surface-to-volume expression is exponential. If the surface moiety has any chemical, electric, or polar reactivity, the aggregate reactivity of individual particles increases with decreasing size.
Metals such as titanium dioxide are potently oxidizing on the nanoscale. They are capable of generating superoxide and hydroxyl radicals in a surrounding aqueous medium. These radicals are highly reactive and can trigger catalytic reactions in organic media, which can result in damage to DNA, RNA, and proteins, as well as promote cell membrane lipid peroxidation.15-19 In vitro studies have shown the generation of oxygen radicals in cells exposed to nanoparticulate titanium. In vivo studies in mice have demonstrated induction of DNA instability and DNA damage,20 and the progression of benign fibrosarcoma to an aggressive form.21 The mechanism in these studies is the generation of reactive oxygen species.
|Basis of Toxicity||Route of Toxicity|
|Particle factors: size, shape, concentration, impurities, surface characteristics, presence of penetration enhancers, biocompatibility, pharmacokinetics, presence or absence|
of mitigating substances (i.e., aggregators, anti-oxidants,
|Epidermal: follicular, interfollicular, flexural skin, periorificial skin|
|Host factors: age, barrier function, metabolic elimination pathways, immunocompetence, pregnancy, comorbidities||Noncutaneous: eyes, nasociliary tract, respiratory tract, gastrointestinal tract, genitourinary tract, parenteral, ingestion|
|Table 1. Principal nanomaterial risk factors|
|Figure 1. Risk factors associated with nanomaterials.|
Upper left: Surface properties of the nanoparticle. If nanoparticles have a surface that is highly reactive, toxicity increases.
Upper right: Surface-to-volume ratio of the nanoparticle. As particles shrink in size, their surface-to-volume ratio increases geometrically and so does their reactivity. Furthermore, smaller particles penetrate the skin more readily and disperse in tissues more widely.
Lower left: Impurities associated with nanoparticle manufacture can carry toxicity.
Middle right: Particles that are biodegradable (broken dots), excreted (arrow leaving body) are less toxic than particles that persist (solid dot inside body).
Shaded area to left of body: Host health. If the skin barrier is damaged or disrupted, nanomaterial toxicity is enhanced. If the host is less able to eliminate or degrade or neutralize nanomaterials, then toxicity is enhanced.
As a particle shrinks, its ability to penetrate the skin and disseminate in tissues increases (Figure 1 and Figure 2). Some studies have shown that nanoparticles of titanium dioxide can penetrate the skin, albeit to a small extent.22 Other studies indicate titanium dioxide nanoparticles form aggregates that result in undetectable or nonsignificant dermal penetration through the epidermis.23,24 Skin that is diseased or flexed, as well as the skin of neonates and the elderly has greater susceptibility to transepidermal water loss and may be more permeable. In fact, studies show that tape-stripped skin and flexed areas allow enhanced penetration of nanoparticles.25
Additionally, particles that are formulated with penetration enhancers and solvents are more likely to infiltrate the skin.26 At least one study has shown that nanoparticles can cause damage across tissues without direct physical contact between the nanomaterial and the target tissue.27 This study has implications for transplacental toxicity. Nonepidermal routes of penetration include the eyes, nose, mouth, and genitourinary orifices.11,14,28,29 Therefore, the prospects are undeniable for topically applied nanomaterials to bypass the skin and enter the body via these routes.
Another basis of toxicity is impurity (Figure 1). Some nanoparticles are pure, but their yield is low, and making such particles is costly for manufacturers. Impurities can take two forms: the nanoparticles themselves and the byproducts of synthesis. The size of nanoparticles can vary from a tight distribution of only a few nanometers to a broad range from tens of nanometers to microns. Byproducts of synthesis can include other nanoparticles, as well as solvents and reagents used during the manufacturing process.
Accumulation and Elimination
A third basis of toxicity is accumulation (Figure 1). Some nanoparticles, such as carbohydrate-based polymers, are biodegradable. Others, such as carbon nanotubes,30,31 have no natural elimination pathway. If these accumulate in tissues, there is a potential that even small doses over many years can lead to disease, either through crowding of vital organs (as in scleromyxedema), reaching a critical threshold of toxicity, triggering protein misfolding (as in prion diseases or Alzheimer’s disease), or eliciting an inflammatory response (as in sarcoidosis). Accumulation without elimination can also have long-term implications; for example, by establishing a depot of toxicity in females decades before a pregnancy, which can eventually affect a developing fetus. Accumulation can also occur through biomagnification in the food web.
A fourth basis of toxicity is host health (Figure 1). Hosts with increased skin permeability, impaired defenses, or impaired bioelimination pathways may be more vulnerable to any adverse effects posed by nanoparticles. In fact, nephrogenic systemic fibrosis may be an example of the first modern nanodermatoses triggered by nanoparticulate gadolinium in patients incapable of renal elimination.32
|Figure 2. |
As particles shrink in size, the percentage of atoms and molecules exposed on the outside surface increases exponentially. This contributes to nanoparticle reactivity.
Safety standards for nanomaterials should include an understanding of the basic biologic activity of a given compound. Ideally, nanomaterials that are developed for human use should be minimally reactive, biodegradable, and biocompatible. Nanosubstances should be easily eliminated from tissues and should not accumulate in the body. They should be manufactured to the highest purity grade possible and without the use of reagents that are toxic and potentially carcinogenic. If particles demonstrate toxicity, they should either not be used or formulated to minimize toxicity. For example, sunscreen manufacturers claim that nanoparticulate sunscreen is coated to minimize reactivity and aggregate to inhibit penetration, as observed in corroborative data published.24 Nevertheless, toxicity data should be made publicly available for scrutiny.
Occupational challenges for nanomaterial production remain. Hazards to workers manufacturing, handling, or transporting nanomaterials are real33-35 and are expected to grow as the technological advances unfold and their utility becomes more widespread. The advent of these changes will require implementation of workplace and environmental safety standards and increasing expertise from dermatologists.36
Nanotechnology exploits unexpected properties of matter on the nanoscale. Nanomaterials differ from their raw starting material in their stability, reactivity, and ability to interact with neighboring molecules. Because of their large surface- to-volume ratio, nanoparticle reactivity increases with decreasing particle size, this occurs on a logarithmic scale. Much of the reactivity that is of biologic concern relates to the potential for generating reactive oxygen species. Smaller particles may be able to penetrate the skin and other tissues and cause harm. Nanoparticles that are indestructible (e.g., carbon nanotubes) or do not follow a natural elimination pathway may accumulate in vital organs and cause ailments reminiscent of genetic storage diseases. They may also linger in the environment and become magnified in the food web. Manufacturers of nanomaterials need to be concerned about workplace hazards. For nanotechnology to be successful, the real and theoretical concerns of toxicity from nanomaterials delivered to the skin and released into the environment should be addressed. Ideally, as nanomaterials are manufactured, their potential for immediate and delayed toxicity should be explored and mitigated.
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