Nanodermatology

Claire Fason, BA and Stephen K. Tyring, MD, PhD, MBA^1,2

¹Center for Clinical Studies, Webster, TX, USA
²Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there is no conflict of interest.
Funding sources: None.

Abstract:
Nanodermatology has been an emerging area of research and drug development in the last two decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has yielded potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery. Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been more frequently explored for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been increasingly investigated to improve efficacy of various drugs via enhanced delivery to the target site. Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but these formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to boost drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects. Enhanced drug delivery utilizing nanoparticles has been successfully trialed for treatment of psoriasis, vitiligo, acne vulgaris, and atopic dermatitis in many research studies, however more investigation is needed prior to utilization in humans.

Keywords:nanodermatology, nanoparticles, enhanced drug delivery, nanocarriers

Introduction

Nanodermatology has been an emerging area of research and drug development in the last decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has exhibited potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery.¹

Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been increasingly investigated for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been more frequently explored in order to improve the efficacy of various drugs via enhance delivery to the target site.

Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but topical formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to increase drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects.²

This article will discuss the promising application of nanotechnology as a route of increased transdermal drug delivery in order to treat various common dermatological conditions, including psoriasis, vitiligo, acne vulgaris and atopic dermatitis, as well as nanoparticle utilization in sun protection.

Psoriasis

Psoriasis is a common inflammatory skin disorder, affecting over 125 million people worldwide, that can range in presentation from erythematous plaques to pustules. Traditionally, mild psoriasis can be treated with topical medications, including corticosteroids, betamethasone/calcipotriol, calcineurin inhibitors, and retinoids.³ However, moderate to severe disease often requires systemic treatments such as methotrexate, cyclosporine, and biologic agents. These systemic treatments often come with the risk of significant adverse effects.

Multiple drug‐loaded nanoparticles and nanocarriers have been found to have promising potential in the treatment of psoriasis, while minimizing the risk for adverse effects and maximizing transdermal drug delivery.⁴ Tazarotene (TZ), a topical antipsoriatic retinoid with significant irritation potential, was loaded into fluidized spanlastic nanovesicles that measured about 260 nanometers. When compared to commercially available topical tazarotene, researchers found that the nanovesicles not only showed higher antipsoriatic activity in human subjects but also demonstrated deeper penetration during ex vivo testing.⁵ Tacrolimus, an immunosuppressive agent that has often been used topically to treat psoriasis, exhibits poor cutaneous bioavailability, particularly in hyperkeratotic plaques. Therefore, topical tacrolimus ointment was compared to a micelle nanocarrier tacrolimus formula. The micelle formula showed increased tacrolimus delivery into the stratum corneum and epidermis when compared to the traditional topical tacrolimus ointment.⁶

In addition to improved delivery of classic topical treatments, researchers have been utilizing nanotechnology to investigate the transdermal delivery potential of drugs traditionally used as systemic therapy, such as methotrexate and cyclosporine. Both methotrexate and cyclosporine are typically reserved for severe psoriasis due to the significant risks of toxicity and adverse effects. However, when combined with nanotechnology, these drugs can be applied topically, therefore greatly minimizing the risk for systemic adverse effects.⁴

Cyclosporine, a calcineurin inhibitor, is incredibly effective as a systemic therapy for psoriasis, but unfortunately, its use comes with risks of nephrotoxicity, neurotoxicity, metabolic disruptions, and immunosuppression.⁷ In an imiquimod induced psoriatic plaque on mice, cyclosporine‐loaded liposomes were more effective at reducing psoriatic features than cyclosporine gel.⁸

Like cyclosporine, systemic methotrexate has shown great utility in the treatment of psoriasis, however there is risk of significant side effects. In an in vivo skin deposition study, methotrexate niosomes, or non‐ionic surfactant vesicles, resulted in a greater percentage of drug deposition in the skin when compared to a simple methotrexate topical solution.⁹ Similarly, gold nanoparticles loaded with methotrexate led to improvement of scaling, erythema, epidermal thickness, and parakeratosis in mice models with imiquimod induced psoriasis. The methotrexate‐gold nanoparticles also showed deeper penetration when compared to topical methotrexate. Additionally, after treatment there was no significant difference in the blood count, AST, and ALT of the treatment group when compared to the control.¹⁰

Nanoparticles have not only allowed for greater skin penetration and drug delivery than classical topical treatments, but they have also allowed researchers to create topical formulations of systemic medications that come with risk of significant adverse effects. More research is needed to compare the efficacy of systemic therapy with nanoparticle formulations.

Vitiligo

Vitiligo, an acquired disorder characterized by the development of depigmented macules, is thought to be caused by autoimmune destruction of melanocytes. Treatment is typically focused on preventing progression and inducing some degree of repigmentation. Recent investigation into the utility of nanodermatology has led to exciting treatment potential.

Berberine, an isoquinoline alkaloid, despite exhibiting potential benefit as a topical vitiligo treatment, has limited utility due to its poor skin permeability. In order to improve delivery, berberine was loaded into hyalurosomes, which are modified nanovesicles that have enhanced skin penetration abilities and are non‐irritating. In human skin studies, berberine hyalurosomes showed greater permeability and greater drug retention when compared to a conventional berberine gel. In a vitiligo‐induced mouse model, the berberine loaded hyalurosomes showed a significant return of normal pigmentation that was greater than the conventional berberine gel.¹¹

Psoralen in combination with ultraviolet light (PUVA) is a common treatment for vitiligo. However, psoralen has weak percutaneous permeability. Resveratrol, a sirtuin activator, has the potential to manage vitiligo by reducing oxidative stress, therefore psoralen and resveratrol were loaded into ultra deformable liposomes and used as combination antioxidants in PUVA therapy for vitiligo. This combination not only demonstrated greater skin penetration but also showed significant melanin stimulation and tyrosinase activity. Administration of a nanocarrier loaded with resveratrol and psoralen in combination with UV light therapy stimulated pigment and reduced oxidative stress, making it a promising potential therapy for vitiligo.¹²

While the mechanism of vitiligo is not completely understood, oxidative stress is believed to play a significant role in the disease. Platinum and palladium have been investigated for their strong antioxidant properties as they are inducers of superoxide dismutase.¹³ PAPLAL, a topical cream consisting of platinum and palladium nanoparticles, has been shown to be an effective treatment for vitiligo that was refractory to first‐line therapies including narrow band UVB and topical corticosteroids.¹⁴

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions, affecting up to 90 percent of adolescents with presentation ranging from mild to severe. The pathophysiology is multifactorial, making treatment complicated. Therapeutic options for mild to moderate acne typically consists of topical agents, including retinoids, antibiotics, benzoyl peroxide, and salicylic acid, whereas treatment for severe acne consists of oral therapy with isotretinoin, antibiotics, or hormonal agents.¹⁵

While topical tretinoin is an effective treatment, its use is limited by low water solubility and high instability in air and heat. Its use also comes with the risk of significant skin irritation and dryness. Therefore, nanocarriers have been investigated to achieve greater photostability and lower irritation potential. Tretinoin was encapsulated into solid lipid nanoparticles which improved its photostability and showed significantly less irritation when compared to the gel formula in an animal model.¹⁶

Similar to tretinoin, adapalene has been widely used in the treatment of acne vulgaris since gaining US FDA approval in 2016, however it has limited bioavailability in the hair follicle and its use also comes with the risk of irritation and dryness. Adapalene was successfully encapsulated into tyrosine derived nanospheres (TyroSphere™). In ex vivo follicular penetration studies, the tyrospheres significantly enhanced adapalene delivery to the pilosebaceous unit, when compared with commercially available adapalene. In vitro irritation studies also demonstrated decreased irritation potential of the tyrosphere formula.¹⁷

Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that presents with dry, eczematous, erythematous patches, and pruritus. AD is likely mediated by a combination of epidermal changes, increased immunoglobulin E levels, and T-helper 1 and 2 proliferation which leads to elevated levels of inflammatory cytokines. Traditionally, topical corticosteroids have been the treatment of choice for acute flares, however long-term use of topical corticosteroids can cause skin atrophy.

Liposomes, composed of phospholipids, have a strong affinity for the stratum corneum, allowing for increased skin permeability and uptake. Both betamethasone 17‐valerate (BMV), a moderate potency corticosteroid, and diflucortolone valerate (DFV), a high potency corticosteroid, were loaded into liposomes. The liposomes showed 2.68 to 3.22 times greater retention in the stratum corneum and epidermis when compared to the commercially available BMV and DFV creams. In pharmacodynamic evaluation, the liposome formula showed greater anti‐inflammatory activity when compared to the commercial creams, despite the liposome gel having 10 percent less active drug than the commercial cream. This result was thought to be due to enhanced delivery and decreased systemic absorption. Finally, in rat models, AD was induced by dinitrofluorobenzene, and the liposomes formulas not only showed lower erythema, edema, and scratching behaviors, but also to the commercial creams.¹⁸

In a similar study, chitosan nanoparticles were loaded with hydrocortisone (HC) and hydroxytyrosol (HT). These nanoparticles exhibited deeper penetration and a higher concentration of drug in the epidermal layer. This could reduce the dose and frequency of drug application needed for effective treatment, which could decrease the risk of adverse effects. Systemic adverse effects of glucocorticoids include hypocalcemia and hyperglycemia. When commercially available hydrocortisone was repeatedly applied to rat models, they showed a significant decrease in serum calcium concentration and an increase in serum glucose concentration, while the HC‐HT nanoparticle solution did not cause any biochemical derangements. This demonstrates that utilizing a nanoparticle drug delivery system could potentially reduce systemic adverse effects of glucocorticoids, while also increasing skin penetration.¹⁹

While corticosteroids have been considered the first‐line for AD, other topical calcineurin inhibitors, like tacrolimus and pimecrolimus, are being increasingly utilized in AD. Calcineurin inhibitors are often considered safer for long‐term use and use on sensitive areas like the face, but they often cause an uncomfortable burning sensation at the site of application. Tacrolimus has a high molecular weight and poor water solubility which limits its permeability. To reach therapeutic dosing, larger quantities of topical tacrolimus must be applied, which increases the risk of irritation. Chitosan nanoparticles were used as the carrier for tacrolimus. The nanoparticle solution led to greater drug retention in the stratum corneum, epidermis, and dermis than the commercially available cream. In AD induced rat models, AD was successfully managed with the nanoparticle solution containing one‐third the dose in the commercially available cream.²⁰

Sunscreen

Sunscreen commonly contains minerals like zinc oxide and titanium dioxide as the primary active sun protection agents. However, sunscreens with these ingredients are typically opaque and white, which lends cosmetic concerns to many users. Many cosmeceutical companies have begun incorporating nanoparticles into their sunscreens in an attempt to create a more desirable and better tolerated formula.

Sunscreens with zinc oxide and titanium dioxide nanoparticles have been shown, in an in vitro study, to provide enhanced sun protection. Additionally, sunscreen containing nanoparticles demonstrated improved texture with no residual white cast when compared to creams with zinc oxide and titanium dioxide particles.²¹

However, some studies have shown that zinc oxide and titanium dioxide nanoparticles lead to an alteration in the recommended UVA/UVB ratio. Currently, the FDA recommends that at least one‐third of the overall sun protection factor should be against UVA. Reducing the size of the zinc oxide and titanium dioxide particles confers an increased UVB protection at the expense of UVA protection. In order to mitigate this, some researchers have recommended that using various sizes of particles in one formulation, for example using micro and nano zinc oxide (20‐ 200 nanometers) particles and nano titanium dioxide (20‐35 nanometers) particles may remedy this discrepancy. However, more research is needed to determine the ideal size of particles to adhere to the recommended 3 to 1 UVB/UVA ratio.²²

Concerns

As nanoparticle use increases both in treatment of skin disease and in cosmetics, there are concerns regarding the long-term health effects and potential toxicities. The potential for nanoparticles to accumulate in the skin and contain harmful impurities are important considerations regarding toxicity.²³

Due to rising concerns that nanoparticles are depositing into deeper layers of the skin and causing cellular damage, multiple studies have sought to determine the long-term effects of utilizing nanoparticles in various formulations. One study found that both coated and uncoated zinc oxide nanoparticles localized primarily in the stratum corneum with limited penetration into viable epidermis. This study also found that the nanoparticles did not alter the skin barrier function or the redox state of the viable epidermis.²⁴ There are also concerns regarding the ability of titanium dioxide to induce DNA damage and potentially act as a carcinogen.²⁵ However, the carcinogenic effects of titanium dioxide are typically seen after subcutaneous injection or inhalation of nanoparticles.²⁶

There is conflicting data regarding the penetration of zinc and titanium nanoparticles, and thus the ability for these nanoparticles to cause damage. However, despite the conflicting data, the consensus appears to be that nanoparticles in sunscreens and skin care do not pose a health risk, however more research and collaboration is needed between the scientific and cosmetic communities as many cosmetic companies do not advertise their products as containing nanoparticles.^25,27

Conclusion

Nanoparticles, defined as a particle ranging from 1 to 1000 nanometers, have shown extremely encouraging potential in targeted drug delivery systems in the treatment of various dermatologic diseases and conditions. Not only do nanoparticles or nanocarriers exhibit increased penetration and retention of existing topical drugs, but they also have been employed to create topical formulations of drugs that are primarily given as systemic therapy. This allows drugs like methotrexate and cyclosporine to be used topically and without the risk of severe adverse effects. Overall, the utilization of nanoparticles as an enhanced drug delivery system is an incredibly promising area of research with exciting implications in the treatment of many common dermatologic conditions. Nanocarriers appear to be safe, however more research and development is needed as the majority of current research is being done in animal models. It is also important for cosmeceutical and scientific communities to collaborate on research, particularly when it comes to utilization of nanoparticles in sunscreens. Cosmetic companies should also be encouraged to publish or advertise the use of nanoparticles in their products.

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