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by Dr Adam Friedman
Introduction
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
Copyright AZoNano.com, Dr Adam Friedman (Albert Einstein College
of Medicine)