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.

Key Words:
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.

Risks

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.

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.

Particle Size

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.

Impurities

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.

Host Health

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.

Cautionary Observations

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 real^33-35 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

Conclusion

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.

References

1. Drexler KE. Machine-phase nanotechnology. Sci Am 285(3):74-5 (2001 Sep).
2. Drexler KE. Nanosystems: molecular machinery, manufacturing, and computation. New York: John Wiley & Sons, Inc. (1992).
3. Hall JS. Nanofuture: what’s next for nanotechnology. Amherst: Prometheus Books (2005).
4. Nasir A. Nanodermatology: a bright glimpse just beyond the horizon – part I. Skin Therapy Lett 15(8):1-4 (2010 Sep).
5. Bhushan B, editor. Springer handbook of nanotechnology, 2nd ed. Heidelberg: Springer-Verlag (2007).
6. Jenning V, Gohla SH. Encapsulation of retinoids in solid lipid nanoparticles (SLN). J Microencapsul 18(2):149-58 (2001 Mar-Apr).
7. Katz LM. Nanotechnology and applications in cosmetics: general overview. ACS Symp Ser 961:193-200 (2007).
8. Nasir A. The future of nanotechnology in dermatology. US Dermatology 3(1)9-13 (2008).
9. Nasir A. Nanotechnology in vaccine development: a step forward. J Invest Dermatol 129(5):1055-9 (2009 May).
10. Nasir A. Nanotechnology and dermatology: part I–potential of nanotechnology. Clin Dermatol 28(4):458-66 (Jul-Aug 2010).
11. Nasir A. Nanovehicles: topical transportation of the future. Skin and Aging 18(5):36-40 (2010 May 6).
12. Nasir A. Dermatologic toxicity of nanoengineered materials. Arch Dermatol 144(2):253-4 (2008 Feb).
13. Nasir A. Nanotechnology and dermatology: part II–risks of nanotechnology. Clin Dermatol 28(5):581-8 (2010 Sep-Oct).
14. Nel A, Xia T, Madler L, et al. Toxic potential of materials at the nanolevel. Science 311(5761):622-7 (2006 Feb 3).
15. Cunningham MJ, Magnuson SR, Falduto MT, Gene expression profiling of nanoscale materials using a systems biology approach. Toxicol Sci 84(S-1):9 (2005).
16. Ding L, Stilwell J, Zhang T, et al. Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast. Nano Lett 5(12):2448-64 (2005 Dec).
17. Sayes CM, Wahi R, Kurian PA, et al. Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 92(1):174-85 (2006 Jul).
18. Schilling K, Bradford B, Castelli D, et al. Human safety review of “nano” titanium dioxide and zinc oxide. Photochem Photobiol Sci 9(4):495-509 (2010 Apr).
19. Zhang LW, Yu WW, Colvin VL, et al. Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes. Toxicol Appl Pharmacol 228(2):200-11 (2008 Apr 15).
20. Trouiller B, Reliene R, Westbrook A, et al. Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res 69(22):8784-9 (2009 Nov 15).
21. Onuma K, Sato Y, Ogawara S, et al. Nano-scaled particles of titanium dioxide convert benign mouse fibrosarcoma cells into aggressive tumor cells. Am J Pathol 175(5):2171-83 (2009 Nov).
22. Bennat C, Muller-Goymann CC. Skin penetration and stabilization of formulations containing microfine titanium dioxide as physical UV filter. Int J Cosmet Sci 22(4):271-83 (2000 Aug).
23. Lademann J, Weigmann H, Rickmeyer C, et al. Penetration of titanium dioxide microparticles in a sunscreen formulation into the horny layer and the follicular orifice. Skin Pharmacol Appl Skin Physiol 12(5):247-56 (1999 Sep-Oct).
24. Sadrieh N, Wokovich AM, Gopee NV, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci 115(1):156-66 (2010 May).
25. Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. J Invest Dermatol 127(1):143-53 (2007 Jan).
26. Alvarez-Roman R, Naik A, Kalia YN, et al. Skin penetration and distribution of polymeric nanoparticles. J Control Release 99(1):53-62 (2004 Sep 14).
27. Bhabra G, Sood A, Fisher B, et al. Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol 4(12):876-83 (2009 Dec).
28. Elder A, Gelein R, Silva V, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 114(8):1172-8 (2006 Aug).
29. Oberdorster G, Sharp Z, Atudorei V, et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16(6-7):437-45 (2004 Jun).
30. Cui D, Tian F, Ozkan CS, et al. Effect of single wall carbon nanotubes on human HEK293 cells. Toxicol Lett 155(1):73-85 (2005 Jan 15).
31. Monteiro-Riviere NA, Nemanich RJ, Inman AO, et al. Multi-walled carbon nanotube interactions with human epidermal keratinocytes. Toxicol Lett 155(3):377-84 (2005 Mar 15).
32. High WA, Ayers RA, Chandler J, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 56(1):21-6 (2007 Jan).
33. Brouwer DH, Kroese R, Van Hemmen JJ. Transfer of contaminants from surface to hands: experimental assessment of linearity of the exposure process, adherence to the skin, and area exposed during fixed pressure and repeated contact with surfaces contaminated with a powder. Appl Occup Environ Hyg 14(4):231-9 (1999 Apr).
34. Que Hee SS, Peace B, Clark CS, et al. Evolution of efficient methods to sample lead sources, such as house dust and hand dust, in the homes of children. Environ Res 38(1):77-95 (1985 Oct).
35. Song Y, Li X, Du X. Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis and granuloma. Eur Respir J34(3):559-67 (2009 Sep).
36. Castanedo-Tardan MP, Nasir A, Jacob SE. Better understanding the chemicals that surround us. Skin and Aging 15:7 (2007 Jul 15). Available at: https://www.skinandaging.com/article/7428. Last accessed: August 25, 2010.

Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

ABSTRACT

Nanotechnology is a relatively new branch of engineering that is making rapid inroads in medicine and 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. Among US patent holders in nanotechnology, the sixth largest is a cosmetics company. Nanotechnology applications have been realized in sunscreens and are being developed for the maintenance of skin health, as well as for the diagnosis and management of skin disease. This article summarizes some of the recent and anticipated advances in nanotechnology for dermatology. In part II, the author addresses the chief concerns of nanotechnology.

Key Words:
nanotechnology, dermatology, drug delivery, sunscreens, safety

The origins of nanotechnology may date back to the 1950’s when physicist Richard Feynman proposed developing machines that made smaller copies of themselves.^1-3 Feynman surmised that multiple iterations of this process could create machines in the subcellular size range from bench-sized starting materials. If the bench-sized machine could perform useful work, then its replica could as well. The tiny products could then be integrated into assembly lines that could generate microminiature replicas manufactured with atomic precision. These miniature factories could then be fed molecular substrates and turn out molecular products at a prodigious rate, a sort of Detroit scaled to the size of a mitochondrion. In the 1970’s, K. Eric Drexler made computer models for some of these processes and designed simple molecular nanomachines consisting of pulleys, gears, and screws; these could self-assemble, based on their charge or polarity into useful devices.

Drexler further realized that matter has unique properties on the nanoscale. For example, as matter becomes smaller, it becomes subject to scaling laws. Scaling laws govern the basic laws of motion and Newtonian physics. When lever arms are smaller, they spin faster, and when incorporated into motors, they can generate more power.

Most nanotechnology bypasses quantum mechanical considerations in atomic behavior and treats atoms and molecules like smooth spheres. On the nanoscale, liquids behave like buckets of billiard balls, gas behaves like a hailstorm, and photons pelt like ping pong balls. Matter on the nanoscale also displays properties that are different from the parent compound on the macroscale. For example, table salt, sodium chloride, is brittle and an insulator in bulk form. On the nanoscale, salt stretches like taffy and conducts electricity. Sunscreens made from titanium microparticles, while effectively blocking UVA and UVB light, require a greasy vehicle for dissolution and leave a chalky residue when applied on the skin (Figure 1). Nanosized titanium particles dissolve more easily in water-based vehicles and leave no residue on the skin.^4-6 They enhance their physical blocking capabilities by coating the skin more evenly.

Figure 1. As nanoparticles shrink in size, they interact with light differently. If they are smaller than the wavelength of visible light, they may become transparent. Smaller nanoparticles also coat the skin more tightly and evenly than their counterparts. Microparticle (left); nanoparticle (right) 1/1000 size of microparticle (not to scale).

Size is not the only critical factor in nanotechnology. Purposeful engineering is also important. It is not enough to make a small nanoparticle. For example, nanoparticles penetrate the skin more readily than their bulk counterparts. Smaller nanoparticles penetrate more readily than larger ones. Discrete particles penetrate more readily than aggregates. These attributes can be useful considerations in drug delivery. Furthermore, therapeutic agents can be made more useful if the synthesis of nanoparticles is controlled to encapsulate or stabilize a drug or target it to the epidermis or dermis.

Since Feynman’s and Drexler’s time, nanotechnology has made great strides.⁷ Consumer products such as sunscreens, shampoos, and cosmeceuticals have been developed. Diagnostic devices and tools are in the early stages of development and treatments for a variety of skin diseases are being explored in the laboratory. It is anticipated that nanotechnology will be the fastest growing area for the maintenance of skin health, as well as for the diagnosis and management of cutaneous disease.

Benefits

There is a great deal of excitement about the potential for novel materials and devices using nanotechnology.8-10 In dermatology, these fall into three broad realms: consumer products, diagnostic products, and therapeutic products (summarized in Table 1). These will be discussed briefly here with examples of potential dermatologic applications for each field.

Figure 2. Some biologically active materials may be too large (botulinum toxin, hyaluronic acid) or polar (γ-aminobutyric acid) to penetrate the epidermis and may require injections for administration (left). Nanoencapsulated versions of these molecules may be stable and penetrate to the dermis (right).

Consumer Products

Sunscreen has already been briefly discussed. A number of manufacturers have developed sunscreens using nanosized titanium, zinc, and iron to allow formulation in vanishing and cosmetically elegant vehicles. Fillers typically require injection to penetrate the skin (Figure 2). Hyaluronic acid in its bulk form is 50,000 nm or larger in size and is unable to penetrate skin.^11,12 Nanosized particles of hyaluronic acid can penetrate the skin and are the basis of a topical delivery system in development. Retinoids suffer from instability and irritability. Nano-encapsulated retinoids are more stable and their release can be controlled and slowed, resulting in less irritation. Solid lipid nanoparticles and nanostructured lipid carriers can be synthesized with an active ingredient in the center of the particle to delay release. Slow release kinetics are important for perfumes, which can yield all-day fragrance.¹⁰ They are also useful for insect repellants, such as N,N-Diethyl-meta-toluamide (DEET), to prolong efficacy.

Fabrics incorporating superhydrophobic ‘nanowhiskers’ (nanosized hair-like projections on individual textile fibers) can repel stains, dirt, and microorganisms. Bulk silver is inert. Silver on the nanoscale is highly toxic to microorganisms, including resistant microorganisms such as Staphylococcus aureus.^9,13 Fabrics impregnated with nanosilver are antimicrobial and may be beneficial to health care workers. Nanosilver is also being incorporated into dressings or bandages to minimize the potential for wound infection. Nanosilver in washing machines allows disinfection at lower temperatures and saves energy.

Diagnostic Devices

One of the great joys of dermatology is the primacy of examination in diagnosis. Most skin conditions reveal themselves to astute and informed observation. Nevertheless, dermatologists still use specialized tools and tests to assist in or confirm the diagnosis of skin disease. The tools of the nanotechnology era will bear little resemblance to our potassium hydroxide slide preparation and will be far less invasive than our punch biopsy.

Quantum dots are small semiconductors.^8,14 They can be made to absorb desired wavelengths of light. Upon absorption, they emit brightly fluorescent color. Quantum dots can be coupled to tags such as antibodies. In animal models, tagged fluorescent quantum dots have proven useful for the visualization of tumors in the skin and for the harvesting of sentinel lymph nodes without the use of radioactivity.¹⁴

A nanopunch is a small, simple biopsy tool consisting of copper, nickel, silicon, and chromium layered in the shape of an origami claw. Differing coefficients of expansion of the layers allow temperature change to cause the claw to close and open, like a Venus flytrap. The nanopunch is paramagnetic and its migration can be controlled by a magnetic field. The nanopunch could be injected into the bloodstream and guided to challenging biopsy sites, such as the nail matrix, the fascia, and the liver. The claw could be activated by temperature and collected from a urine sample by a magnetic trap. Tissue could then be released for analysis.

Figure 3. Carbon nanotubes stretched across a gap conduct electricity. If they are coupled to receptors(antibodies shown here),the conductivity changes if the receptor is free or bound to ligand. This can be detected as a change in current in real time. (Not to scale, the entire ladder of nanotubes could easily fit into a mitochondrion).

Carbon nanotubes conduct electricity, unlike their bulk precursors. Carbon nanotubes can be coupled to macromolecules such as nucleic acids and antibodies. Coupled molecules alter the conductivity of the carbon nanotube as compared with its native state. Conductivity is further altered if the coupled molecules bind their cognate receptors (Figure 3). Carbon nanotube conductivity can therefore be used to make a highly sensitive biomarker sensor on an extremely tiny scale (sub-organellar). Single biomarkers or tandem arrays may be useful for the real time diagnosis of skin infections and possibly malignancies. Carbon nanotube sensors may be able to detect infinitesimally minute quantities of substrate.

Therapeutic Agents

One of the great areas for advance in dermatologic disease will be epicutaneous drug delivery. Some agents developed by nanotechnology will be recognizable, but some will defy and completely upend our current paradigms of dermatologic therapy. Drugs encapsulated in polymers or nanoparticles will be stabilized, and their release and activity will be targeted.

Volatile antimicrobial gases, such as nitric oxide, have been trapped in nanoparticulate chitosan,¹⁵ a carbohydrate polymer found in arthropod exoskeletons. When the polymer dissolves, nitric oxide is released. Biologically active forms of trapped nanoparticulate nitric oxide have shown utility in the treatment of skin infections and have proven highly effective at penetrating abscesses.

Botulinum toxin has been stabilized and encapsulated in a form that allows penetration of the skin and apparent effacement of rhytides in early clinical trials.^16-18 Topical paralytic agents, such as ã-aminobutyric acid, are being used to transcutaneously relax muscles of facial expression to similar effect.

Encapsulated topical steroids are being developed, which accumulate in the epidermis, but do not penetrate the dermis, where collagenolysis associated with atrophy and telagiectases occurs. These types of agents will be useful for the management of spongiotic dermatoses and will carry a reduced risk of corticosteroid-mediated side-effects.
Bulk soybean oil is not toxic. Nanoemulsions of soybean oil are antimicrobial and are being incorporated into disinfectants. Nanoemulsions of other compounds that can penetrate the nail and the pilosebaceous unit are being used to treat onychomycosis and acne, respectively.

Polymeric nanoparticles encapsulating small inhibitor ribonucleic acids (siRNAs) can selectively inactivate gene expression. Nanoencapsulated siRNAs have been used for the management of a genodermatosis (pachyonychia congenital)19 and for the successful targeted delivery and inhibition of a test gene expressed in melanoma in human trials.²⁰

Thermosensitive polymers encapsulate drug below a critical temperature and dissolve to release the drug above the critical temperature. These are being used for drug delivery at sites of inflammation (calor is one of the hallmarks of inflammation) and are also being developed to target release wherever external heat is applied. For example, methotrexate could be encapsulated in a thermosensitive polymer for psoriasis. It could be inactive in the polymer and released by endogenous (calor) or externally applied heat to treat individual or generalized psoriatic lesions. This type of delivery would be very useful and convenient for difficult to treat areas, such as the nails and scalp.

Topical nanoparticles can be engineered to elicit humoral and cell-mediated immunity.^21,22 Microneedle patches have been shown to painlessly target delivery of vaccines to the epidermis and reticular dermis, where the bulk of Langerhans cells and dermal dendritic cells reside, inducing a potent immune response.^22-24

Nanoparticulate drug delivery agents have been developed, their release can be controlled by magnetism, laser light of any frequency, and radio waves (Figure 4).

Figure 4. a. Materials encapsulated within nanoparticles can be designed to have prolonged release kinetics. This is useful for fragrances, insect repellents, and for once daily dosing. b. Nanoparticles can be coupled to receptors for targeting. For example, in animal models, the melanocyte stimulating hormone has been used to target gold nanoshells to melanoma. c. Nanoparticles can be coated with polymers that degrade in the presence of free radicals (O2-), radiofrequency (RF), temperature change (T), or magnetic fields (H), which allows for release to be both controlled and localized.

Conclusion

Nanotechnology capitalizes on the unique behavior of atoms and molecules on the nanometer scale. Nanomaterials depart from their parent compounds in their stability, reactivity, and ability to assemble into useful products. Nanomaterials are already being used in consumer products such as sunscreens, antimicrobial surfaces, and clothing. Nanotechnology is being utilized in cutaneous drug delivery to stabilize compounds, allow controlled release, and to enable targeted drug localization to maximize activity and minimize toxicity. The next generation of diagnostic tools using nanotechnology will be unlike any dermatology has ever seen.

For example, such advances may allow real time visualization of molecular markers of skin disease in vivo and in situ, rapid diagnosis of infections and malignancies using minute quantities of tissue, and minimally invasive skin biopsy in challenging locations. The theoretical concerns of the toxicity of nanomaterials will be discussed in part II of this series.²⁵

References

1. Drexler KE. Machine-phase nanotechnology. Sci Am 285(3):74-5 (2001 Sep).
2. Drexler KE. Nanosystems: molecular machinery, manufacturing, and computation. New York, NY: John Wiley & Sons, Inc. (1992).
3. Hall JS. Nanofuture: what’s next for nanotechnology. Amherst, NY: Prometheus Books (2005).
4. Sadrieh N, Wokovich AM, Gopee NV, et al. Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci 115(1):156-66 (2010 May).
5. Sayes CM, Wahi R, Kurian PA, et al. Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 92(1):174-85 (2006 Jul).
6. Schilling K, Bradford B, Castelli D, et al. Human safety review of “nano” titanium dioxide and zinc oxide. Photochem Photobiol Sci 9(4):495-509 (2010 Apr).
7. Bhushan B, editor. Springer handbook of nanotechnology, 2nd ed. Heidelberg, Germany: Springer-Verlag, (2007).
8. Nasir A. The future of nanotechnology in dermatology. US Dermatology 3(1):9-13 (2008).
9. Nasir A. Nanotechnology and dermatology: part I–potential of nanotechnology. Clin Dermatol 28(4):458-66 (2010 Jul-Aug).
10. Nasir A. Nanovehicles: topical transportation of the future. Skin & Aging 18(5):36-40 (2010 May 6).
11. Jenning V, Gohla SH. Encapsulation of retinoids in solid lipid nanoparticles (SLN). J Microencapsul 18(2):149-58 (2001 Mar-Apr).
12. Katz LM. Nanotechnology and applications in cosmetics: general overview. ACS Symp Ser 961:193-200 (2007).
13. Lee HJ, Yeo SY, Jeong SH. Antibacterial effect of nanosized silver colloidal solution on textile fabrics. J Mater Sci 38(10):2199-204 (2003 May).
14. Kim S, Lim YT, Soltesz EG, et al. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 22(1):93-7 (2004 Jan).
15. Martinez LR, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infection. J Invest Dermatol 129(10):2463-9 (2009 Oct).
16. Chajchir I, Modi P, Chajchir A. Novel topical BoNTA (CosmeTox, toxin type A) cream used to treat hyperfunctional wrinkles of the face, mouth, and neck. Aesthetic Plast Surg 32(5):715-22; discussion 23 (2008 Sep).
17. Collins A, Nasir A. Topical botulinum toxin. J Clin Aesthetic Dermatol 3(3):35-9 (2010 Mar).
18. Flynn TC. Update on botulinum toxin. Semin Cutan Med Surg 25(3):115-21 (2006 Sep).
19. Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther 18(2):442-6 (2010 Feb).
20. Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464(7291):1067-70 (2010 Apr 15).
21. Mahe B, Vogt A, Liard C, et al. Nanoparticle-based targeting of vaccine compounds to skin antigen-presenting cells by hair follicles and their transport in mice. J Invest Dermatol 129(5):1156-64 (2009 May).
22. Nasir A. Nanotechnology in vaccine development: a step forward. J Invest Dermatol 129(5):1055-9 (2009 May).
23. Gill HS, Soderholm J, Prausnitz MR, et al. Cutaneous vaccination using microneedles coated with hepatitis C DNA vaccine. Gene Ther 17(6):811-4 (2010 Jun).
24. Peterson TA. Microstructured transdermal systems for intradermal vaccine and drug delivery. Pharm Tech Eur 18(12):21-36 (2006 Dec).
25. Nasir A. Nanodermatology: a glimpse of caution just beyond the horizon – part II. Skin Therapy Lett. In press 2010.