Cutaneous drug delivery offers many advantages over alternative routes of administration with regards to target specific impact, decreased systemic toxicity, avoidance of first pass metabolism, variable dosing schedules, and broadened utility to diverse patient populations.
A complicating factor is that the skin has evolved mechanisms to impede exogenous molecules, especially hydrophilic ones, from safe passage. The horny layer of the stratum corneum (the top most layer of the skin) is tightly bonded to an intercellular lipid matrix making the passage of therapeutics a serious challenge1. This strong barrier to molecular activity is quite effective at blocking large drugs (molecular mass > 500 Da), which of course make up the majority of active therapeutics2.
Mechanical abraders and micro-needles can open a limited number of relatively wide (≥ 103 nm) pores in the skin barrier, that can allow for transient passage of small and even large molecules (or even bacteria)3. Disruption with either ultrasound (phonopheresis) or high-voltage electrical pulsing (electroporation) has been used to force larger materials through this complex barrier. Chemical penetration enhancers are also utilized in order to perturb the epidermal barrier, though safety concerns have limited their efficacy4-6.
Furthermore, many substances that could, in theory, be used as topical therapeutics have several disadvantages in that they are:
1. weakly or not soluble in water;
2. degraded or inactivated prior to reaching the appropriate target;
3. nonspecifically distributed to tissues and organs, resulting in undue adverse side effects and limited efficacy at the target site
Nanotechnology and Delivery Vehicles
Novel delivery vehicles generated through nanotechnology is raising the exciting prospect for controlled and sustained drug delivery across the impenetrable skin barrier. Particles 500 nm and smaller exhibit a host of unique properties that are superior to their bulk material counterparts7-9. Small size is a necessary feature but other properties are needed for nanomaterials to achieve efficacy as a topical delivery vehicle.
Optimally these nanoparticles should:
1. carry drugs through cutaneous pores in the primary skin barrier;
2. release the transported drug spontaneously once penetration is achieved; and
3. exhibit low rates of cutaneous drug clearance allowing for deep/targeted deposition and prolonged action of the carrier-transported drugs.
Additionally, these products should be able to adjust to relevant physiologic variations as part of their design and targeting.
Nanotechnology Becoming a Major Focus in Dermatology Research
Given the potential significant therapeutic benefits listed above, it is no surprise that nanotechnology is becoming a major focus of dermatologically oriented product development7, 10-14. The sixth largest patent holder of nanotechnology in the United States is a cosmetics company15,16. In fact, cosmetic companies are above the curve with respect to their nanotechnology research efforts as compared to industry giants like Motorola and Kodak. While nano-manufacturing can be costly and require sophisticated facilities, mass production, decreasing prices, and exponential growth are expected control costs in the future and allow this science to blossom. Some estimates place nanotechnology by 2012 to be a $2 trillion industry, employing two million in the United States alone7. Applications are underway in medicine and dermatology for the early detection, diagnosis, and targeted therapy of disease7,9,10,12,13,17-24.
As can be expected with any technology in its infancy, of the potential and excitement must be tempered with the realization that there are still pitfalls and remaining concerns regarding safety23,25-35. The skin is the first point of contact for most environmental nanomaterials, regardless of medium in which they are delivered. The risks of nanomaterials in the world of dermatology are therefore extensive, ranging from irritant or allergic contact dermatitis to foreign body reactions to tissue death27.
Theoretically speaking, the toxic potential of any material can be predicted to be exponentially proportional to a decrease in particle size. First, smaller size allows for deeper penetration of encapsulated chemicals, and for enhanced intracellular penetration and systemic absorption. Second, just as a greater surface area to volume ratio confer nanomaterials with significant advantages over their macromolecular counterparts, so too does it dramatically increase the availability of surface groups for interaction with tissues and cells. If the surface groups are chemically reactive and are capable of generating reactive oxygen species, the potential for reactivity increases with decreasing particle size28. Lastly, the toxicity of both insoluble and inert nanoparticles in mammalian cells can be directly related to their cellular uptake. Some cells, such as keratinocytes, have the ability to phagocytose small molecules, and when nanomaterial are internalized, they can accumulate in cells and ultimately result in DNA damage and cytotoxicity through the generation of oxidative stress36.
Therefore, it is of the utmost importance that the toxicology of nanotechnologies be appropriately elucidated to both protect the public from potentially harmful materials, but also to allay public fears and media speculation that can prevent this promising technology from being cultivated and utilized.
The Current State of Nanotechnology in Dermatology
Many areas of medicine, such as oncology37 and diagnostic radiology38 have been incorporating nanotechnology into their teaching, education, and research. Dermatology has been lagging in this area despite the seemingly paradoxical observation that a significant proportion of new developments in nanotechnology have been in consumer skin care. Recent data from a pilot study (Friedman and Nasir, unpublished) revealed that there is a strong agreement among dermatologists nationwide that nanotechnology teaching, education, and research are both necessary and important facets of Dermatology.
Furthermore, respondents indicated that there is a need for improved and more rigorous oversight and regulation of these technologies, though it was unclear either how this could be accomplished or how dermatologists can get involved. In fact, until recently, there have not been any dermatology organizations or groups in the United States dedicated to addressing these issues.
The Nanodermatology Society (NDS)
The Nanodermatology Society was founded in 2010 to bring together individuals from a broad array of linked disciplines who share a common interest in nanotechnology as it relates to dermatology.
The society and members are charged with the following mission:
1. to closely monitor developments in nanotechnology as they relate to dermatology;
2. to meet informally and formally at congresses, scientific conferenceand teaching events with the purpose of educating and informing members on developments in nanotechnology and dermatology;
3. to exchange research and ideas on nanotechnology advances;
4. to sponsor research and education in nanotechnology; and
5. to develop policies and positions to benefit consumers, academia, regulatory bodies, and industry11.
The primary focus of the NDS will be monitoring nanotechnology, studying new developments in the field, and evaluating their potential. The NDS will focus on potential beneficial uses of this new technology, as well as potential dangers. NDS members will critically question the suggested benefits and risks of available and developing nanotechnologies based on the latest available data. The impact on consumers, workers, medical personnel, society, and the environment will all be considered. Most importantly, findings will be shared and distributed as part of the NDS's educational mission through various outlets.
As part of its regulatory mission, the NDS will develop safety guidelines based on current medical and dermatologic understanding and reports from toxicology testing agencies. The NDS will communicate these findings to the society, regulatory bodies, and to law and policy makers.
The dermatologic community is not yet aware of all the benefits and drawbacks to nanotechnology. Yet, dermatology is a vibrant discipline poised to yield new discoveries in the diagnosis and management of disease utilizing nanotechnology. This is the perfect time to educate dermatologists, colleagues, consumers, and workers about nanotechnology.
Hybrid Nanoparticles as a Vehicle for the Delivery of Nitric Oxide
Interest in the therapeutic potential of nitric oxide (NO) has been growing exponentially over the past few decades39-51. This interest is a direct result of findings demonstrating an ever-expanding range of functionalities associated with NO under physiological conditions. These established properties not only have direct therapeutic implications for the treatment of infections, modulation of vasoactivity, angiogenesis, and wound healing, but also provide a basis for our understanding of many diseases ranging from asthma to psoriasis52-55.
Harnessing this potential has proven difficult as reflected by the intense but relatively unsuccessful efforts to develop therapeutically useful NO delivery devices/vehicles56. Clinical use of these materials has been limited due to cost, cytotoxicity, instability of the chemical compounds, potential carcinogenicity, and development of tolerance to the NO releasing substances56. The hybrid nanoparticles overcomes many of the existing limitations associated with the current NO releasing strategies.
It combines the beneficial features of two distinct materials. Firstly, polysaccharide-derived glassy matrices that support the conversion of nitrite to NO as well as retention of NO within the matrix57; Secondly, silane-derived, porous hydrogel that provides a relatively rigid skeleton. Alone, glassy matrices suffer from the limitation that they rapidly dissolve following exposure to water. The hydrogel matrix, though more stable in water, is highly porous, allowing a rapid escape of contents. The hybrid platform overcomes these limitations by using the glassy matrix not only to generate the NO, but also to plug the pores of the hydrogel. The hydrogel component provides structure and stability, slowing the breakdown of the glass in solution58.
The nanoparticle skeleton is formed using alkoxysilanes, which have two key benefits. First, they are already widely used in the production of self-forming nanoparticles. That is, products based on alkoxysilanes do not require any particle size reduction steps in order to create the nanoparticle: they are created during the manufacturing process itself. Second, the physical structure of these types of nanoparticles is that of a highly porous network or skeleton59-63. The NO glassy matrix is a unique concept that capitalizes on well-known chemistries and comprises three main components. Sodium nitrite in the presence of glucose in a glassy matrix undergoes a redox reaction that generates NO gas57,64,65.
In the current platform, the glassy properties are believed to be derived from the strong hydrogen bonding network forged from the interaction between chitosan, a cationic polysaccharide, and the anionic hydrogel side chains. It is this strong hydrogen bonding network that both allows for the glucose-mediated generation of NO, as well as the entrapment of the NO gas. Polyethylene glycol (PEG) polymers of different molecular weights are used to regulate the rate of NO release. As mentioned previously, upon exposure to an aqueous environment, the glassy matrix dissolves allowing release of the NO.
The composition of the nanoparticles allows both for retention of the NO within the dry particles, as well as for slow sustained release of therapeutic levels of NO over long time periods when exposed to moisture/water58. Unlike many of the current NO releasing materials, NO release from nps requires neither chemical decomposition nor enzymatic catalysis. Instead, release of NO from the nps requires only exposure to water56. The release profile for the NO is found to be easily tuned through straightforward manipulation of the relative concentrations of the components used in preparing the hydrogel/glass composites that is basis for the np platform58.
The Application of Nitric Oxide as a Drug Delivery Vehicle
The potential for broad applicability for this NO releasing nanoparticulate platform is emerging though a series of translational projectsa. First and foremost, cutaneous penetration and safety of the hybrid nanoparticles in vivo has thus far been demonstrated. Penetration of fluorescent nanoparticles was visualized both using total body infrared imaging up to twenty four hours following initial application and by histologic sectioning of involved skin in animal models as well nails from human subjects . Repeated applications of the nanoparticles to murine skin demonstrated no pathologic changes to the involved skin, such as thickeneing of the epidermis or increased inflammatory infiltrate. Though these initial studies are promising, continued investigations are underway to fully appreciate any issues with safety.
Because the role of NO in wound healing and antimicrobial activity is well established42,54,66-70, it is a major focus of this work. Treatment with NO-nps results in accelerated wound closure both in fibroblast migration assays and in vivo splinted murine wound model71-73. Antimicrobial in vitro efficacy against Methicillin Resistant S aureus (MRSA)74, Mycobacterium tuberculosis, Acenitobacter baumannii75 has been established .
Topical application of NO nanoparticles to in vivo MRSA and A. baumannii infected excision models results in acceleration of wound healing and clearance of bacterial burden as compared to controls clinically and histologically74,75. To extend these results further, topical application of NO nps in an induced in vivo MRSA abscess model, demonstrating a dose dependent impact on lesion resolution based on wound size, histology, and cytokine profiling from abscess sites76. Therapeutic comparative studies are underway, and preliminary studies have demonstrated that topical and intralesional treatment with NO nps in the MRSA abscess model was significantly more effective than topical Retapamulin and intravenous Vancomycin following four days of treatment based on clinical assessment and wound cultures.
The important role of NO in maintaining vascular health lead to our testing the efficacy of NO nps in addressing conditions associated with endothelial dysfunctions. NO nps increased erectile function when applied topically to the penis of rats that were developed as a model of erectile dysfunction77. In a dose-dependent manner, intravenously (IV) administered, circulating NO nps increased exhaled NO concentrations, decreased mean arterial blood pressure (MAP) and increased microvascular flow over several hours, without inducing an inflammatory response as compared to control nanoparticles78.
When compared to two well known NO donors, DETA NONOate and DPTA NONOate, similar decreases in MAP were witnessed. However, the impact on vascular tone following NONOate use was highly inefficient as compared to NO nps, requiring 30 times more NO release to induce a similar physiological response. This pitfall manifested as a significant effect on methemoglobin formation by NONOate administration with subsequent decrease in hemoglobin oxygen carrying capacity.
Translating these findings, the potential role of the NO-nps in vascular disorders of hemodynamic distress has been investigated. Intravenously administered NO nps are observed both to counteract systemic hypertension following infusion of an NO scavenging hemoglobin based oxygen carrier, improving systemic and microvascular function. Furthermore, IV NO-nps were able to correct the negative, potentially life threatening hemodynamic changes during hemorrhagic shock - the continuous NO released by the NO-nps reverted arteriolar vasoconstriction, recovered functional capillary density and microvascular blood flows, and prevented cardiac decompensation. These data suggests that the NO nps have a clear potential to replenish NO in situations were NO production is impaired, insufficient or consumed (e.g. endothelial dysfunction, metabolic disorders and hemolytic diseases).
Together these data demonstrate the clear potential of the NO nps not only as a therapeutic agent for inflammatory, infectious, and vascular/cardiovascular, but also as a promising tool to promote our understanding of NO signaling mechanisms.
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aThe pre-clinical investigations discussed would not have been possible without the following collaborators: George Han, PhD, Luis Martinez, PhD, Joshua Nosanchuk, MD, Moses Tar, PhD, Kelvin Davies, PhD, Pedro Cabrales, PhD, Parimala Nacharaju, PhD, Joel Friedman, MD,PhD
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