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Nanoparticles and microparticles for skin drug delivery
Tarl W. Prow a, Jeffrey E. Grice a, Lynlee L. Lin a, Rokhaya Faye a, Margaret Butler c, Wolfgang Becker d,Elisabeth M.T. Wurm e, Corinne Yoong e, Thomas A. Robertson a,b, H. Peter Soyer e, Michael S. Roberts a,b,a The University of Queensland, School of Medicine, Therapeutics Research Centre, Brisbane, QLD, Australiab The University of South Australia, Therapeutics Research Centre, School of Pharmacy and Medical Science, Adelaide, SA, Australiac Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australiad Becker & Hickl, GmbH, Berlin, Germanye Dermatology Research Centre, The University of Queensland, School of Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia
a b s t r a c ta r t i c l e i n f o
Article history:
Received 21 September 2010
Accepted 31 January 2011
Available online 23 February 2011
Keywords:
Nanoparticle
Drug delivery
Topical
Skin
Percutaneous penetration
Transdermal delivery
Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery
as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are
opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair
follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating
local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on
lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300 nm in diameter, which are now
considered microparticles. Metal nanoparticles are now recognized for seemingly small drug-like
characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical
data on nanoparticle penetration and previously published reports that support the hypothesis that
nanoparticles N10 nm in diameter are unlikely to penetrate through the stratum corneum into viable human
skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake
does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom
construction of complex particulates and delineating their molecular interactions within biological systems.
In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug
delivery to the skin, and future directions currently being explored. 2011 Elsevier B.V. All rights reserved.
Contents
1. Skin as a site for particle delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
1.1. Skin as a natural particle barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
1.2. Barrier properties of the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
1.2.1. Skin structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
1.2.2. The stratum corneum barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
1.2.3. Transport routes of exogenous substances across the stratum corneum . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
1.2.4. Acid mantle maintains the stratum corneum barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
1.2.5. Viable epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
1.2.6. Hair follicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4741.3. Barrier properties of diseased skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
1.4. Skin flexing and massage for enhanced delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
2. Small drug particle delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
2.1. Anti-inflammatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
2.1.1. Corticosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
2.1.2. Flufenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Advanced Drug Delivery Reviews 63 (2011) 470491
This review is part of the Advanced Drug Delivery Reviews theme issue on Nanodrug Particles and Nanoformulations for Drug Delivery.
Corresponding author at: The University of Queensland, Therapeutics Research Unit, School of Medicine, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia.
Tel.: +61 7 3176 2546.
E-mail address: [email protected] (M.S. Roberts).
0169-409X/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.01.012
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2.2. Anti-photoageing drugs and antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
2.2.1. Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
2.2.2. Tocopheryl acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
2.2.3. Multiphoton imaging for in vivo lipid nanoparticle delivery studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3. Other topical nanoparticle drug delivery applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3.1. Antimicrobial agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3.1.1. Antifungal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3.1.2. Silver nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
3.2. Anti-proliferative agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
3.2.1. 5-aminolevulinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4833.2.2. Podophyllotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
3.3. Other topical particulate delivered drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
4. Recent advances in particle-based drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
5. Systemic safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
6. Limitations of nanoparticle and nanocarrier chemical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
1. Skin as a site for particle delivery
The theory and practical aspects of percutaneous penetration of
drugs, particulate material and contaminants have been covered in a
number of excellent reference texts. For comprehensive treatment of
the topics in this section, the reader is referred to chapters by Roberts
et al. [1], Norlen [2], Monteiro-Riviere and Baroli [3], Mller et al. [4]
and other relevant chapters in these books.
Whilst the skin has historically been used for the topical delivery of
compounds, it is only since the 1970s with the advent of transdermal
patches that it has widely been used as a route for systemic delivery [5].
Nanoparticle delivery to the skin is being increasingly used to facilitate
local therapies. The nanoparticle definition designated by the National
Nanotechnology Initiative has been adopted by the American National
Standards Institute as particles with all dimensions between 1 nm and
100 nm [6,7]. Fig. 1 shows that the potential sites for targeting
nanoparticles include the surface of the skin, furrows, and hair follicles.
A recent review by Baroli discusses nanoparticle penetration largely
from the skin structure perspective.The title of this reviewPenetration
of Nanoparticles and Nanomaterials in the Skin: Fiction or Reality?
highlights the ongoing debate of nanoparticle penetration [8]. This
debate is fuelled by the need for more rigorous, multidisciplinary
approaches to shed light on mechanisms of particle penetration and
interactionswith skin. Likewise,Schneider et al. make a compelling case
in their review on nanoparticle skin interactions for more rigorous
studies on the effects of hydration and mechanical stress on skin with
regard to nanoparticleskin interactions [9].
Particles can interact with skin at a cellular level as adjuvants. This
nanoparticleskin interaction can be used to enhance immune
reactivity for topical vaccine applications [10]. Another example of
nanoparticleskin interactions the topical use of silver nanoparticles
as over the counter antimicrobial agents [11], where the nanoparticles
provide a slow release of silver ions that have wound healing and
antimicrobial properties. The silver ions released from nanoparticle
can inhibit microbial proliferation, but also accelerate wound healing.
This controlled release of silver ions while the nanoparticles remainon the skin surface highlights one of the most successful topical
nanoparticle drug delivery strategies.
Generally, the promise of nanoparticle-mediated drug delivery into
the epidermis and dermis without barrier modification has met with
little success. Where the barrier is compromised, however, such as in
aged or diseased skin, there may be potential for enhanced particle
penetration. Ulcerated squamous cell carcinoma is one example. The
opportunities and obstacles for nanoparticle drug delivery are only just
beginning to be explored in ongoing clinical trials. For instance,
capsaicin loaded nanoparticles are being used to treat the pain
associated with diabetic neuropathy [12]. Advances in particle engi-
neering, formulation science and an improved understanding of
nanoparticleskin interactions will undoubtedly lead to important
clinically relevant improvements in topicaldrug delivery. An overridingconcern is the safety of any applied nanoparticle, recognising the
possibility that non-biodegradable nanoparticles could be taken up and
retained by the reticulo-endothelial system [13]. Inaddition, there isthe
potential for local toxicity, shown by a recent report of nanoparticles
inducing keratinocyte apoptosis, wherethe subtlerelationship between
longer and shorter phosphatidylcholine chain lengths makes the
difference between life and death for keratinocytes [14]. This illustrates
the need for toxicity monitoring in vitro and especially in vivo.
1.1. Skin as a natural particle barrier
It is generally recognised that the potential for nanoparticle and
microparticle skin penetration is negligible [15]. Most environmental
Fig. 1. Sites in skin for nanoparticle delivery. Topical nanoparticle drug delivery takes
place in three major sites: stratum corneum (SC) surface (panel a), furrows
(dermatoglyphs) (panel b), and openings of hair follicles (infundibulum) (c). The
nanoparticles are shown in green and the drug in red. Other sites for delivery are the
viable epidermis (E) and dermis (D).
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nanoparticles, be they viruses, bacteria, dust, allergens or materials,
do not penetrate human skin unless the skin barrier is disrupted
[13,16]. Topical drug delivery with nanoparticles, with the aim of
targeting the nanoparticles into the deeper layers of skin, therefore
has to overcome a significant barrier honed over millions of years of
evolution. Human papilloma virus (HPV) is perhaps the best example
of a nanoparticle able to penetrate barrier compromised skin to cause
skin warts [17]. Today, biomimetic nanoparticle engineering is
applying these principles from nature to develop better nanoparticledelivery systems [18] and progress is being made in the area of
nanoparticle interactions with skin [9]. HPV is also in the same size
range [19] as topical nanoparticles for drug delivery in skin [20] and
both utilize lipids to facilitate payload delivery (Fig. 2).
The benefits of drug delivery resulting from topical penetration of
nanoparticles are offset by their potential for toxicity, as discussed
above. This has led to the topic of environmental and synthetic
particle penetration across human skin becoming a contentious
subject that has attracted the attention of regulatory agencies around
the world.
The likelihood of nanoparticle penetration across the skin has
recently been reviewed by the Scientific Committee on Consumer
Products (SCCP) who conclude that in relation to dermal exposure
[21]:
1) There is evidence of some skin penetration into viable tissues
(mainly into the stratum spinosum in the epidermal layer, but
eventually also into the dermis) for very small particles (less than
10 nm), such as functionalised fullerenes and quantum dots.
2) When using accepted skin penetration protocols (intact skin),
there is no conclusive evidence for skin penetration into viable
tissue for particles of about 20 nm and larger primary particle size
as used in sunscreens with physical UV-filters.
3) The above statements on skin penetration apply to healthy skin
(human and porcine). There is an absence of appropriate
information for skin with impaired barrier function, e.g. atopic
skin or sunburned skin. A few data are available on psoriatic skin.
4) There is evidence that some mechanical effects (e.g. flexing) on
skin may have an effect on nanoparticle penetration.5) There is no information on the transadnexal penetration for
particles under 20 nm. Nanoparticles of 20 nm and above
penetrate deeply into hair follicles, but no penetration into viable
tissue has been observed.
The statement that nanoparticles N20 nm in diameter do not
penetrate into viable tissue is controversial. There have been reports
showing nanoparticles N20 nm penetrating through the stratum
corneum (SC), to the viableepidermis[22,23]. However, our experience
with gold, silver and quantum dots illustrates that these nanoparticles
do consistently penetrate into the SC, but not into the viable epidermis.
The reasons for this important disparity may be due to differences in
nanoparticle constituents, models, and methodologies.
We have also investigated nanoparticle gene, vaccine, siRNA, and
drug delivery in a variety of systems, including skin [2436]. Our past
and present focus in the field of topical therapeutic nanoparticles is
developing a better understanding of nanoparticle disposition and
toxicity [16,3740]. The most common tool used to evaluate
nanoparticle penetration, delivery, toxicity or localization is the
confocal microscope, illustrating that some primary aspects we areinvestigating are spatial and concentration related. In other words,
where are the nanoparticles and how much is there? The Monteiro-
Riviere, Lademann, Guy and Roberts groups are currently investigat-
ing nanoparticle penetration, delivery, toxicity and species differ-
ences. The Monteiro-Riviere group have made significant
contributions towards understanding nanoparticle penetration, tox-
icity and model systems, and hasgenerated an extensivebody of work
that has largely focused on nanoparticle interactions with skin and
skin cells. These reports have illuminated molecular mechanisms of
nanoparticle uptake, toxicity, and bioretention [22,4164]. The
Lademann group has made significant contributions towards a better
understanding of the role hair follicles play as nanoparticle reservoirs
[16,6576]. The Guy group has also contributed to this are and has
investigated nanoparticle versus model drug localization in skin
compartments, revealing valuable information about drug and
nanoparticle distributions in skin [7781]. The Roberts groups is
using novel fluorescence lifetime imaging techniques to simulta-
neously evaluate NAD(P)H lifetime changes with nanoparticle
penetration [40,82,83].
1.2. Barrier properties of the skin
Among the multiple, complex functions of mammalian skin, one of
its major roles is to prevent invasion of the organism by acting as a
defensive barrier to threats from the external environment. The skin
has evolved defensive mechanisms which give it physical, immuno-
logical, metabolic and UV-protective barriers to allow it to inhibit
attacks by microbes, toxic chemicals, UV radiation and particulate
matter (including nanoparticles, which may occur in the naturalenvironment)[84]. Ontheotherhand, the skincan beusedas a portof
entry for therapeutic substances such as drugs and vaccines if the
mechanisms that confer the barrier properties are understood and
exploited.
1.2.1. Skin structure
Skin consists of two main layers. The underlying dermis contains a
variety of cell types, nerves, blood vessels and lymphatics embedded
in a dense network of connective tissue. Above the dermis and
separated from it by the basement membrane, the epidermis is
Fig. 2. Electron microscopy comparison of size and morphology of a virus (panel a, adapted from [254]) that infects human skin, human papilloma virus, and nanoparticles (panels b
and c) for topical drug delivery are in similar size ranges. The human papilloma virus is 40 nm in diameter, the same size range as smaller drug delivery vehicles like poly(q-
caprolactone)-block-poly(ethyleneglycol) nanoparticles, 40 nm, designed to deliver minoxidil to hair follicles (panel b, adapted from [130]). Solid lipid nanoparticles like these
developed for penciclovir can be several times larger at an average diameter of 250 nm (panel c, adapted from [255]). The bar indicates 200 nm for all panels.
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composed mostly of layers of stratified keratinocytes, where the SC
cells or corneocytes are bathed in a protein-rich envelope with an
outer lipid envelope, surrounded by an extracellular lipid matrix [85].
Keratinocytes undergo a process of keratinisation, in which the cell
differentiates and moves upward from the basal layer (stratum
basale), through the stratum spinosum and stratum granulosum, to
the outermost layer, the stratum corneum (SC or horny layer). On
reaching the SC, cells become anucleated and flattened and are
eventually sloughed off [86]. Interspersed amongst the keratinocytesin theviable epidermisare cells with roles such as melanin production
(melanocytes), sensory perception (Merkel cells) and immunological
function (Langerhans and other cells). In addition to the structured
cellular components of skin, there are appendages including the
pilosebaceous units (hair follicles and associated sebaceous glands),
apocrine and eccrine sweat glands.
1.2.2. The stratum corneum barrier
TheSC represents themain physical barrier of theskin,so that fora
substance permeating across the skin, diffusion through the SC is the
rate limiting step [1]. Conversely, the SC is also the main barrier for
diffusionof water out of theskin [87]. The flattened, anuclear, protein-
rich corneocytes of the SC are densely packed within the extracellular
lipid matrix which is arranged in bilayers [88]. Thisis often referred to
as a bricks and mortar arrangement [89]. The corneocytes are held
together by corneodesmosomes, which help to form a tough outer
layer by maintaining cellular shape and regular packing. Eventual
degradation of the corneodesmosomes by proteolytic enzymes leads
to desquamation [90].
Transport of substances across the SC occurs mainly by passive
diffusion and based on the dual-compartment bricks and mortar
structure of the SC, interrupted by appendages, is considered to occur
via three possible routes. These are the transcellular, the intercellular
and the appendageal routes.
Covering the corneocytes on the SC surface is a thin (0.410 m),
irregular and discontinuous layer consisting of sebum secreted by the
sebaceous glands, along with sweat, bacteria and dead skin cells. This
layer is considered to have a negligible effect as an additional barrier
to permeation through the SC [91].
1.2.2.1. Inter-cellular spacing. For most penetrants, the intercellular
route is favoured. Small molecules are able to move freely within the
inter-cellular spaces and diffusion rates are governed largely by their
lipophilicity, but also physicochemical properties such as molecular
weight or volume, solubility and hydrogen bonding ability [92].
However, the free movement of macromolecules or particles may be
physically restricted within the lipid channels, which have been
estimated by van de Merwe et al. to be 19 nm [93] and by Baroli et al.
to be 75 nm [23]. This suggests that for such materials, the SC could
present an additional barrier that is not present for small molecules.
1.2.2.2. Skin turnover as a moving barrier. The outer layers of the SC
(the so-called stratum dysjunctum) are subject to desquamation,allowing the SC to be completely turned over in a period of about
14 days in humans, depending on anatomical site and age [94]. Thus,
these cells might be regarded as a moving, constantly renewable
barrier, providing an inherent mechanism for preventing foreign
bodies from penetrating the skin and gaining a foothold [95]. The
continuous upward migration and sloughing of corneocytes from the
surface might assist in eliminating pathogens, cancerous cells or solid
particulate matter.
1.2.3. Transport routes of exogenous substances across the stratum
corneum
Polar and non-polar solutes were originally thought to permeate
through the SC via separate routes [96], with polar solutes taking a
transcellular routeand morelipophilic solutes goingvia the intercellular
lipids. However a perception of the difficulty of repeated partitioning
between lipophilic and hydrophilic compartments in the SC led to this
pathway being regarded as unlikely in most cases. This was supported
by histochemical [87] and theoretical [97,98] evidence showing that
diffusion through intercellular lipids was more likely for most solutes.
Despite a recent reaffirmation of importance of the transcellular route,
even for lipophilic solutes, by Wang et al. [99] the transcellular route
remains controversial.
With most work focussing on the hair follicles, delivery of drugs orparticles via the appendageal route is regarded as a realistic
alternative to delivery across the SC, despite the relative sparseness
of these features on the skin surface [100]. The follicles extend deep
into the skin, the thickness of the SC layer is progressively reduced as
it extends into the structure and there is a rich capillary blood supply
available to transport solutes diffusing out of the follicle. There is
considerable interest in targeted follicular delivery with tailored drug
formulations [98] or nanoparticle-bound drugs [101]. There have also
been suggestions that partitioning of drugs into sebum itself may be a
potential delivery route [100].
1.2.4. Acid mantle maintains the stratum corneum barrier
The surface of theskin haslong been recognised to be acidic, with a
pH of 4.25.6 measured in humans by Blank over 70 years ago [102].
This acidic skin surface is described as the acid mantle. The surface pH
is influenced by sex and anatomical site [103], sweat, sebum and
hydration [104]. There isa sharp gradientacross the SC, with the pH in
the upper viable layers in the stratum granulosum approaching
neutral. Using two-photon fluorescence lifetime imaging of a pH
dependent fluorophore applied to the SC of hairless mice, Hanson et
al. [103] identified acidic microdomains in the extracellular matrix,
which became less frequent away from the surface towards the viable
epidermis. This, they suggested, accounted for the pH gradient,
although specific biochemical mechanisms have been proposed to
account for the acidification per se, including generation of trans-
urocanic acid by histidase-catalysed degradation of histidine [105].
The acid mantle hasa numberof functions, includingantimicrobial
defence [106], the maintenance of the permeability barrier by effects
on extracellular lipid organisation and processing [107], the preser-vation of optimal corneocyte integrity and cohesion, regulated by pH-
sensitive proteolytic enzymes [108] and restriction of inflammation
by inhibiting therelease of pro-inflammatory cytokines [109]. There is
a clear association between elevated skin pH and diseases such as
atopic dermatitis [102], with significant pH differences between
affected and unaffected skin in individual patients [110].
Interestingly, theacidic pH of theskin surface mayalso support the
skin's barrier to nanoparticle penetration in some cases, as carbox-
ylated polystyrene nanoparticles were found to aggregate due to
decreasing electrostatic forces as the solution pH was lowered [111].
Aggregates would be less likelyto penetratethe SC.On theotherhand,
by maintaining the integrity and cohesion of the SC, embedded
particles would be less likely to be sloughed off during desquamation.
Further, for certain nanoparticles, such as zinc oxide, the acidic pHmay greatly affect the nanoparticle aggregation and dissolution
kinetics, thereby confounding experiments on skin penetration
[112,113].
1.2.5. Viable epidermis
1.2.5.1. Tight junctions. The existence of functional tight junctions has
been demonstrated in mammalian stratum granulosum [114,115],
although many constituent tight junction proteins have been
identified in other epithelial layers, as well as follicles [116]. Tight
junctions are regarded as important elements of the epidermal barrier
system and localization and expression of tight junction proteins have
been shown to be altered in diseases characterised by a compromised
skin barrier, such as psoriasis [117,118].
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1.2.5.2. Skin deactivation of nanoparticles by skin metabolism and other
mechanisms. As well as acting as a physical barrier, the skin functions
as a chemicalor metabolic barrier, with enzymes mainlylocated in the
basal layer of the viable epidermis [119], as well as the extracellular
spaces of the SC [120] and the appendages in the dermis [119]. A
number of nanoparticles are biodegradable through hydrolysis,
enzyme activity and physical forces causing, for instance, liposomes
to merge with intercellular lipids [86]. Zinc oxide nanoparticles
hydrolyse at neutral pH and even more so at acidic pHs, leading totheir conversion to zinc ions [37,112,113], which is accelerated on
exposure to light [112]. This hydrolysis can be, however, complex and
affected by the local environment. Cross et al. showed that there was
no significant difference in the levels of zinc ions passing through the
human epidermis from nanoparticle zinc oxide formulations relative
to controls [37]. More recently, Gulson and colleagues showed
increased recovery of 68Zn in blood and urine following application
of 68Zn-enriched zinc oxide particles to human volunteers and
concluded that zinc was able to penetrate the skin barrier. They
were unable, however, to distinguish between the penetration of solid
or solubilised zinc oxide,or zinc ions [121]. Skin metabolism following
topical delivery has often been referred to a first-pass effect,
analogous to that seen in the liver [84]. With nanoparticles, a similar
phenomenon applies but arises from the destruction of nanoparticles
not only by enzymatic processes but also by physical and chemical
processes as discussed above. In the same way that skin metabolism
may be exploited in a pro-drug or soft-drug approach to delivery
[122], there is a potential for similar exploitation of nanoparticles in
drug delivery. Indeed, the effective delivery of drugs to the skin by
nanometer scale (b100 nm) liposomes, formed from engineered lipid
nanovesicles, hasbeen suggested to involve the release of drugs in the
intercellular lipid layer [36].
There is also a wide range of protein transporters present in skin
[123] which may assist in active transport of drugs or other
compounds. Nanoparticle uptake in keratinocytes is, however, more
likely to occur through other specialised processes. For instance,
Zhang et al. have shown that 18 nm quantum dots (QD) with a
carboxylic acid surface coating are taken up in human epidermal
keratinocytes by endocytosis on recognition by lipid rafts [57].Transport involved internalizing into early endosomes before trans-
ferred to late endosomes or lysosomes. The uptake of solid lipid
nanoparticles (b180 nm) into keratinocytes has also been studied
with it being suggested that they easily traverse the cell membrane,
distribute throughout the cytosol and localize in the perinuclear
region without any toxic effects [124].
Delivery systems based on drugs, pro-drugs, soft-drugs or particle-
bound drugs may need to be designed to exploit, or to overcome, the
complex array of enzymes and transporters awaiting them in the skin
[125,126]. Particle bound drugs must be able to reach a site where
they can be released and as we have seen, the barriers to particle
penetration of the skin are considerable. One possibility of doing this
is to target the follicular route, to be discussed below.
1.2.6. Hair follicles
Whereas hair follicles were regarded as insignificant as potential
routes for drug delivery, covering only 0.1% of the human skin surface
area, their complex vascularisation and deep invagination with a
thinning SC has led to a reappraisal of this view [101]. Work has been
done on assessing the contribution of the follicular route to drug
penetration [127,128], as well as targeted delivery [98]. Follicular
penetration of solid particles, including liposomes [129], minoxidil-
loaded [130], and fluorescent polystyrene [78] nanoparticles has been
demonstrated. Lademann discussed the finding that 300600 nm
particles penetrated follicles best on massage as a consequence of the
distance between the scales on the hairs, and suggested that the
movement of the hair acted as a geared pump to push the particles
into the follicle [70]. They viewed follicles as an efficient reservoir for
nanoparticle-based drug delivery [101], havingpreviously shown that
titanium dioxide particles did not penetrate beyond the follicle [131]
and would be eliminated in time by outward sebumflow. It is possible
also that some follicles may be blocked by a plug of sebum or closed
leading to particle penetration being impeded. Significant penetration
of 40 nm nanoparticles beyond the follicles into epidermal cells can
occur when the hair sheath has been pulled out [75].
1.3. Barrier properties of diseased skin
As stated in the SCCP nanotechnology report [21], there is limited
data on skin penetration of nanoparticles through diseased skin.
Topical nanoparticle drug delivery for local effects is likely to be used
on diseased skin. Among the most common adult skin diseases are
atopicdermatitis (6.9%) and psoriasis(6.6%) [132]. The effects of these
barrier altering diseases on the penetration of nanoparticles are
unknown.
A report by the Australian Government, Department of Health and
Ageing, Therapeutic Goods Administration (TGA) identifies a single
unpublished report that assessed systemic zinc levels in psoriatic
patients and foundno evidence of an increase in systemic zinc [133].
We have carried out pilot clinical studies with the aim of quantifying
nanoparticle penetration in psoriatic and atopic dermatitis lesions.
We and others have investigated the penetration of nanomaterial
contained in sunscreens, the most commonly applied source of
nanoparticles, [16,134137], but there is a gap in the clinical literature
where the penetration of nanoparticles has not been quantified in
subjects with clinically relevant skin diseases like psoriasis and
dermatitis. Hypothetically, nanoparticles could penetrate these
lesions more efficiently due to an altered SC, inflammation and
increased keratinocyte turnover.
Our investigation included zinc oxide nanoparticle (35 nm)
penetration profiling by quantifying second harmonic generation of
the nanoparticles with non-invasive multi-photon imaging using
time-correlated single photon counting (Fig. 3). There is a low level of
background signal that can be seen in untreated skin images, taken en
face, that may be due to melanin, keratin aggregates, or collagen
(Fig. 3a). We observed concentrated zinc oxide nanoparticle signals inlesion furrows (Fig. 3b, red, Furrow and in Fig. 3c, F). The
nanoparticles penetrated laterally from the furrows into the SC, but
remained outside of the viable epidermis in non-lesional and lesional
tissue (Fig. 3c). There was an intense zinc oxide nanoparticle signal
from alltreated skin optical biopsies,but the imagesshow a punctuate
distribution on the SC. Compared to the signal obtained from the
untreated non-lesional (0.230.17 mg/ml at 0 m) and lesional sites
(0.23 0.13 mg/ml at 0 m), no higher signal for zinc oxide
nanoparticles could be detected within the viable epidermis of
sunscreen treated non-lesional (0.17 0.10 mg/ml at 0 m) or
lesional skin (0.220.09 mg/ml at 0 m). These results are consistent
with previous reports [133] and the lack of nanoparticle penetration
may be a mechanism that explains why applying zinc oxide
sunscreens to subjects with psoriasis does not give rise to an increasein systemic zinc levels.
1.4. Skin flexing and massage for enhanced delivery
Nanoparticle skin penetration has the potential for highly
controlled drug delivery in therapeutically relevant concentrations.
The penetration enhancement by skin flexing and massage could
impact topical nanoparticle drug delivery and nanotoxicology. Tinkle
et al. investigated the potential for mechanical stress on skin to
enhance particle penetration [138]. The confocal microscopy results
showed that human skin treated with 1 m beads and then flexed for
60 min resulted in dermal penetration of the 1 m beads. They also
showed rapid penetration through a tear in the skin and significant
penetration into the deeper layers of the SC using scanning electron
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microscopy of SC tape strips. Later, detailed studies by the Monteiro-
Riviere group showed that mechanical flexion in porcine skin
increased the rate of nanoparticle penetration of 3.5 nm modified
fullerenes [48]. However, we replicated Tinkle'sflexing apparatus and
conditions, using excised human skin treated with 35 nm zinc oxide
nanoparticles, and did not find penetration (unpublished work).
Likewise, Lademann et al. has shown no penetration of nanoparticles
into the SC after massaging [72]. Studies on non-massaged and
massagedporcine skinrevealed that massaging 400
700 nm diameterparticles resulted in the highest levels of follicular penetration (Fig. 4)
[72]. An alternative explanation has been advanced by Lekki et al. as
they found 20 nm nanoparticles penetrated as deep as 400 mintothe
follicle [139], a process inconsistent with the much larger sizes of
nanoparticles used by Lademann et al. to support a gearing
mechanism. They suggest that a mechanical process is involved and
is formulation dependent so that certain formulations may be enabling
the mechanical pushing of products into follicles or that inhomoge-
neous formulations are involved. Noting Lademann's other work
showing that 40 nm particlesdo penetratedeep into follicleswhenthe
hair shaft is removed [66], we propose that massaging may push the
hair shaft to one side increasing the available area and depth of the
opening (infundulum). As a consequence, greater penetration of
nanoparticles may be enabled in a formulation, skin type and massage
mechanism dependent manner. Togetherthese data suggest thatthere
may be substantial differences between the penetration and interac-
tions of nano- and micro-particles that depend greatly on the skin
type, nature of applied flexion and massage and formulation used.
2. Small drug particle delivery
2.1. Anti-inflammatory drugs
Anti-inflammatory drugs represent a broad range of molecules,
many with potential for topical delivery. Reports on nanoparticle-
delivered drugs with anti-inflammatory properties for topical use
include: aceclofenac [140], betamethasone-17-valerate [141], cele-
coxib [142], clobetasol propionate [143,144], corticosterone
[145,146], flufenamic acid [147,148], flurbiprofen [149,150], glycyr-
rhetic acid [151], ketoprofen [152,153], naproxen [153155], nime-
sulide [156], prednicarbate [141,157,158], and triptolide [159]. These
drugs can be divided into steroids, e.g. corticosterone, and non-
steroidal anti-inflammatory drugs (NSAIDs), e.g. naproxen. Corticos-
teroids work to reduce inflammation by binding glucocorticoid
receptors, whereas NSAIDs work through inhibiting cyclooxygenase.
2.1.1. Corticosterone
In 2008, Kuntsche et al. investigated the potential for solid lipid
nanoparticles (SLN) (tripalmitate), smectic nanoparticles (cholesteryl
myristate and cholesterylnonanoate),and cubic nanoparticles (glycerol
monooleate)to deliver corticosterone to the skin[146]. TheSLN,smectic
particles, and cubic microparticles were an average of 94 nm, 106 nm,and 361 nm, respectively. The nanoparticles were highly characterized
with electron microscopy, particle sizing, small angle X-ray diffraction,
Fig. 3. Penetration profile of zinc oxide nanoparticles from skin furrows. Panels a and b
show untreated lesional (a) and zinc oxide nanoparticle containing sunscreen treated
lesional sites (b). The inset in panel b is an electron microscopy image of the individual
zinc oxide nanoparticles with a mean diameter of 35 nm, the bar indicates 100 nm.
FLIM measurements were used to differentiate skin autofluorescence (green) from zinc
oxide nanoparticles (red). The intensity profile of the autofluorescence and zinc oxide
nanoparticles is shown in Panel c and is derived from the white lines in panels a and b.
The nanoparticles aggregate in the furrow region (F, Furrow) that is bordered by the
stratum corneum (SC), that protects the viable epidermis (VE). The bar in panel b
indicates 50 m.
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and differential scanning calorimetry. Nanoparticle skin interactions
were monitored with fluorescence microscopy. Storage of these
nanoparticles for N15 months did not dramatically changethe diameter
or polydispersity of any of the formulations. Permeation studies were
carried out in excised human skin and a rat epidermal keratinocyte
organotypic culture model mounted in Franz type diffusion cells.
Cumulative corticosterone in the receptor was measured over 48 h.
These results showed that the PBS control had the highest cumulative
permeationat 1.5%, cubic nanoparticles at 1.0%, smectic nanoparticles at
0.4%, and SLN at 0.1% in human epidermis. In the rat epithelial
keratinocyte organotypic culture the cumulative permeation was 0.7%
for PBS, 0.7% for cubic nanoparticles, 0.6% for smectic nanoparticles, and0.2% forSLN. Thepermeability coefficientswere alsocalculated and only
the cubic nanoparticles showed a distinct improvement over the PBS
control, 4.3107 cm/s versus 1.8107 cm/s. Fluorescence micros-
copy only detected fluorescence with the cubic nanoparticle group. In
conclusion, exposure of skin to the largest particle (361 nm) resulted in
the highest level of drug delivery. This highlights the importance of
interactions of the materials over that of shape and size.
A recent report by Jensen et al. describes topical corticosterone
delivery with SLN using distearate [145]. A series of corticosteroids in
distearate (hydrocortisone, hydrocortisone-12-acetate, hydrocorti-
sone-17-butyrate, hydrocortisone-17-valerate, and hydrocortisone-
21-caprylate) with calculated log P from 1.28 to 4.16 were tested. The
mean diameters of these particles ranged from 180 5 to 220 28 nm.
In vitro release assays using cellulose membranes showed that
permeation was inversely related to lipophilicity. At 12 h, the
cumulative amount of drug released was 23.0% for hydrocortisone,
27.2% for hydrocortisone-12-acetate, 18.3% for hydrocortisone-17-
butyrate, 7.5% for hydrocortisone-17-valerate, and 4.9% for hydrocor-
tisone-21-caprylate.
Although both Kuntsche et al. and Jensen et al. both used SLN
encapsulated corticosteroids for topical delivery, each used different
lipids to construct the nanoparticles. The nanoparticles themselves
were similar in size and both were capable of releasing corticoster-
oids. One possibility for improvement in corticosteroid delivery would
be to explore the glycerol monooleate nanoparticle formulation [146]
to deliver the hydrocortisone derivatives [145] for optimal controlledanti-inflammatory delivery. The major differences in permeation
models limit further comparison.
2.1.2. Flufenamic acid
Flufenamic acid (FFA) is an anti-inflammatory drug that was
chosen as a model lipophilic drug for testing topical nanoparticle drug
delivery by the Schaefer and Lehr group from Saarbrucken, Germany
[147,148]. This model drug also hasfluorescence properties when in a
non-polar environment and excited at 420 nm. This enables micro-
scopic localization studies in addition to traditional pharmacokinetic
studies. In 2006, Luengo et al. described topical FFA delivery with
328 nm poly-lactic-co-glycolic acid (PLGA) particles loaded with FFA
[147]. The particles were characterized with atomic force microscopy
(Fig. 5). Release experiments showed that after 6 h, both the free and
Fig. 4. Particle accumulation inhair folliclesaftermassage. Massaged skin is shown treated with particulatedye andnon-particulate dyein panelsa andb, respectively.Panels c andd
show skin, without massage, that has been treated with particulate dye (panel c) and non-particulate dye (panel d). Panel e and f show the scales on hair follicles for human and
porcine skin which serves as a basis for a geared pump delivery of nanoparticles deep into the opening on massaging. Adapted from [70,72].
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gel particulate formulations reached 100% FFA release using human
skin. Cumulative penetration (area under the penetration curve) was
determined for free and gel particle formulations. After 24 h the
particulate group showed significantly more FFA (6.7 g/cm2) in the
deep skin layers than the non-particulate control (3.8 g/cm2) for a
1.8 fold increase.
Santander-Ortega et al. investigated novel starch derivatives, with
two different substitution groups for nanoparticle encapsulation of FFA
[148]. The particles were fully characterized in addition to stability and
pharmacokinetic experiments. Thesize of the particlesranged from 150
to 182 nm. The size remained at 180 nm after 25 days at room
temperature. The encapsulation efficiency for both starches was N95%.
A total of 14.8% of drug was released and 4.4 g/cm2 permeated within
the first 12 h.
The FFA loaded PLGA particles had 6.7 g/cm2 permeated after 24 h
and the starch nanoparticles had 8.3g/cm2 permeated at the same time
point. These data show a substantial improvement when using PLGA or
starch particles to deliver FFA to skin over non-particle controls.
Fig. 5. AFM images from Luengo et al. showing FFA loaded PLGA nanoparticles for topical anti-inflammatory drug delivery [147]. Two formulations are shown, an aqueous
nanoparticle suspension (Panel a) and a gel formulation (Panel b). Multi-photon microscopy images of human skin treated with drug-free nanoparticle gel (Panel c) and FFA
containing nanoparticle gel (Panel d) are shown where the drug is present in the furrows (white arrow heads)." to "AFM images from Luengo et al. showing FFA loaded PLGA
particles for topical anti-inflammatory drug delivery [147]. Two formulations are shown, an aqueous particle suspension (Panel a) and a gel formulation (Panel b). Multi-photon
microscopy images of human skin treated with drug-free particle gel (Panel c) and FFA containing particle gel (Panel d) are shown where the drug is present in the furrows (white
arrow heads).
Table 1
Particle-delivered anti-photoageing drugs and antioxidants. Not determined (ND).
Drug(s) Nanoparticle
material
Diameter range, potential Dose, vehicle Model Ref.
Tretinoin SLN 173406 nm, 2347 mV 0.05%, Hydroxylethyl-cellulose (0.8%) Rhino mice for skin irritation [162]
Tr et inoin SLN 5 2.0 20 .8 t o 6 5.7 28.0 nm, ND 0 .0 5% , C ar bopol Ult rez 1 0 ( 1% , w/w ) Exc ised hairless a bd ominal r at skin [163]
Tretinoin SLN 344 nm, ND 0.05%, Carbopol ETD 2020 Excised hairless abdominal rat skin [166]
Tretinoin Silica 166.5261.6 nm,52.035.6 mV 0.05%, Lecithin or oleylamine in medium
chain triglycerides
Franz type diffusion cells with cellulose
acetate membrane and porcine skin
[160,161]
Tretinoin CaCO3 ND 0.10.4%, Study subjects [167]
Tretinoin CaCO3 1316 nm, ND 0.1%, aqueous ddY mouse [171]
Isotretinoin SLN 31.3 to 50.0 nm,14.1 to17.9 mV 0.06%, Tween 80 and soybean lecithin Excised abdominal rat skin [168]
Retinol SLN 224 nm, 58.10.6 mV 0.5%, glycerol, water and xanthin gum Cellulose membrane in Franz type
diffusion cells
[172,173]
Vitamin A palmitate SLN 350 nm, ND 0.25%, Carbopol 940 (1%) Cadaver skin using Keshary Chien cells [169]
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Importantly, these well controlled and informative studies correlate well
despite having been published 4 years apart thus allowing comparison.
2.2. Anti-photoageing drugs and antioxidants
2.2.1. Retinoids
Retinoids arecommonly usedin topicalacne andanti-ageingproducts
and are one of the most studied drug groups in terms of topical
nanoparticle and microparticle delivery (Table 1) [160
173]. Retinoidswork through nuclear hormone receptors (retinoic acid receptors) and
retinoid X receptors. The molecular responses to receptor binding are
diverse, but in the context of skin disease, topical retinoid treatment
initially reduces inflammation, helps to reduce comedones and wrinkles.
Retinoids are used clinically to treat acne vulgaris [174] and cosmetically
to treat photoageing [175]. Tretinoin (all-trans retinoic acid) is the first
generation retinoid. Instability in the presence of light and oxygen is a
drawback for using Tretinoin and is one of the major focus points for
improvement by nanoparticle encapsulation. In the late 1990s, third
generation retinoids, i.e. adapalene and tazarotene, overcame this
drawback and were approved for clinical use [176], but have not been a
focus for nanoparticle delivery. Theother major issue for retinoid therapy
is local erythema, peeling, dryness, and pain. Skin irritation side effects
have been mitigated by nanoparticle encapsulation, where the mecha-
nism of action is likely to be controlled release.
Improved stability and controlled release have been the primary
focal points of nanoparticles for retinoid delivery. Castro et al. used solid
lipid nanoparticles to encapsulate Tretinoin withan efficiency of 94% by
using a lipophilic amine (stearylamine) [162]. They exploited ion
pairing between Tretinoin and the lipophilic amine to increase the
lipophilicity of the Tretinoin, thus enabling dramatic improvement in
encapsulation efficiency. The microparticles varied in diameter from
2283 to 68226 nm depending on the surfactant to lipid ratio
(0.40.1). Storage of these microparticles at 25 C for 90 days revealed
that samples with stearylamine maintained higher encapsulation
efficiency than SLN without, 975% versus 552%. Skin irritation
studieswere doneby comparing the SLNwith stearylamine to a placebo
gel and a marketed Tretinoin cream containing a completely different
formulation utilizing liposomes. Castro et al. used a rhino mouse modelto test irritation. Although the engineered SLN performed better than
the commercialformulation,the lack of stearylamine controls precludes
further interpretation. Likewise, the lack of skin retention and flux data
hampers comparison of this SLN formulation withother similar studies.
Others including the Patravale group have used SLN to deliver
Tretinoin to skin with similar success [163,166]. In both studies, 0.05%
Tretinoin was formulated with Carbopol to form gels with favourable
spreadability, viscosity, and flow. Two distinct SLN sizes were tested
in these studies: b100 nm [163] and N300 nm [166]. Both reports
utilized excised skin from the abdomen of hairless rats. Both the
smaller and larger SLN had similar, but not identical skin retention at
4.2% and 6.4%, respectively. The encapsulation efficiency of the small
and large SNL was similar at 46% and 49%, respectively. The flux
differed with the larger SLN being exactly twice that of the smallermicroparticle at 75.6 ng/cm2 h versus 37.7 ng/cm2 h. These were
compared to a commercial formulation with a flux of 64.5 ng/cm2 h,
which contained a completely different formulation but had the same
Tretinoin level (0.05%) as the SNL formulations. It is not possible to
identify any potential stability benefits of nanoparticle encapsulation
between the nanoparticles (b100 nm) and microparticles (N300 nm)
because photostability was only investigated with the N300 nm SLN.
Inorganic microparticles have also been used as Tretinoin carriers,
including silica [177] and calcium carbonate [167,171]. Tretinoin coated
silica microparticles were developed by the Prestidge laboratory and
found to be 166 to 261 nm in diameter depending on whether the
microparticles were formulated with lecithin or oleylamine, respec-
tively. The zeta potential of the microparticles was 50 and +34 mV
for lecithin and oleylamine, respectively. Neither the diameter nor the
zeta potential was dramatically altered by oil or water phase
formulation. The microparticle formulations were compared to lecithin
or oleylamine formulations and the controlled release properties were
investigated. The silica microparticle groups showed a significant
reduction in the steady state flux to 90% for lecithin emulsions and
50%for oleylamine emulsions. The72 h cumulative release was13.4 and
7.4 g/cm2 for lecithin and oleylamine emulsions with silica micro-
particles, respectively. However, the skin integrity after 72 h of
treatment is questionable. There was a maximum of 30% and 76%reduction in the cumulative release by the silica microparticle groups
compared to the non-microparticle containing controls. The 12 h skin
retention with silica microparticle formulated with lecithin in oil phase
wassimilar to that ofb100 nm SLNat 3.9% and4.2%,recognizingthat the
silica studies were done with porcine skin [177] and the SLN studies in
rat skin [163]. Clinical studies [167] have been carried out in Japanwith
CaCO3 nanoparticles (1315 nm) coated with Tretinoin at high doses
(0.1%). These studies do not include skin retention or flux measure-
ments, but do describe favourable murine [171] and clinical outcomes.
The lack of pharmacokinetic data, among other discontinuities with the
more recent literature, restricts comparisons with silica and SLN
delivered Tretinoin, however.
Tretinoin derivatives, isotretinoin [168], retinol [172,173], and
vitamin A palmitate [169], have also been delivered to skin with SLN.
The isotretinoin loaded SLN described by Liu et al. [168]were in the
same size range as the tretinoin loaded SLN described by Mandaw-
gade et al. [163], 3050 nm and both studies used excised abdominal
rat skin to investigate the pharmacokinetics. Isotretinoin loaded
nanoparticles were capable of encapsulation efficiencies of up to
99.7% depending on the surfactant concentration (8% soybean lecithin
and 4.5% Tween 80). Stability wastested over 3 monthsat 28 C with
no changes in isotretinoin levels noted. The steady state flux for the
non-SLN control (0.06% isotretinoin) was 0.76 0.3 g/cm2 h, but
there was no isotretinoin found in the receptor chambers after 8 h.
However, the skin retention of the control (2.81 g) and maximum
SLN (3.65 g) formulation were comparable. This was an increase of
30% from the non-SLN control.
Retinol was also delivered by drug loaded SLN, but these studies
utilized particles N220 nm in diameter [172,173]. The skin retentionof retinol was 0.68% (over 6 h) in porcine skin, an improvement of
0.9 g over a nanoemulsion control group. The in vitro flux from the
retinol loaded SLN was 150 ng/cm2 over 6 h, or 25 ng/cm2 h.
Vitamin A palmitateis converted into retinol in theskin andfinally to
tretinoin. Vitamin A palmitate has been formulated into SLN of
approximately 350 nm in diameter by Pople and Singh [169]. The
pharmacokinetics of thisformulationwas exploredusing humancadaver
skin with Keshary Chien cells. After 24 h the SLN drug release was 67.5%
and the gel control was 54.4%, implying that the flux was unusually
higher with the SLN formulation, SLN formulation usually results in
lower flux with longer term release. Pople and Sing also evaluated the
effects of treatment on SC thickness in rats. SLN formulation treatment
resulted in an increasein SC thickness of almost 3 times comparedto the
conventional gel. The conventional gel control was a formulation thatcontainedthe samecomponentsas theSLNformulations. Thisincrease in
SC thickness is likely to be due to a hydration effect.
In summary, a number of SLN and inorganic particles have been
used to improve retinoid pharmacokinetics and stability. SLN were the
most common particles tested and two major size ranges were tested,
b100 nm and N200 nm. This could be interpreted as a broad
comparison of nanoparticle versus microparticle retinoid delivery,
given the definition of nanoparticles as b100 nm in diameter. Both
nanoparticles and microparticles could be formulated with near 100%
encapsulation efficiency and both showed improved stability and
pharmacokinetics (depending on controls used). Together, no real
benefits of nanoparticle(b100 nm) formulation are evident compared
to microparticle (N100 nm) data, but encapsulation appears to have
advantages over free drug formulations.
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2.2.2. Tocopheryl acetate
Zhao et al. explored thebenefitsof a hydrofluoroalkane foam to aid
tocopheryl acetate release from lipid nanoparticles upon contact with
the skin [178]. The uncharged lipid nanoparticles were formulated
with an oil-in-water emulsion and the size range of the loaded
nanoparticles was from 53 1 to 57 0 nm. Maximal encapsulation
efficiency was 90.13.7% and 100% of the drug was recoverable.
Delivery to human skin was evaluated by treating skin with 400 g/
cm
2
tocopheryl acetate for 24 h. Saturated silicone oil was comparedto the aqueous nanosuspension and nanoparticle containing foam. No
tocopheryl acetate was found in the receptor fluid for any group and
the estimate for skin retention was 1.70.4% for the oil control and
0.70.4% for the foam with nanoparticles, while no drug was
delivered to the SC by aqueous nanoparticles. These data suggest no
major differences between the groups and no major benefit of
nanoparticle formulations in terms of total delivery. However, studies
showed improved stability over a 4 week trial with the foam
formulation.
Similar studies from the same group used solid lipid nanoparticles
to deliver tocopheryl acetate with hyalauronic acid gels [179,180],
with similar results. The nanoparticles in this study were comparable
in size to those described by Zhao et al., at 50 1 nm. No tocopheryl
acetate was released over 24 h when permeability tests were carried
out with synthetic membranes treated with SLN formulations [180].
Synthetic membrane permeation studies revealed that the saturated
silicone oil formulation gave a maximal flux of 836.2 137.9 g/
cm2 h. Penetration studies were carried out with porcine and human
skin using tape stripping to extract material from the skin surface.
These experiments showed that porcine skin treated with silicone oil
saturated with tocopheryl acetate or SLN gel retained 1.320.57%
and 1.650.90% respectively of the total dose applied. Interestingly,
in human skin, the saturated silicone oil delivered 1.700.36%, while
tocopheryl acetate could not be detected after SLN gel treatment.
These species differences could be due to a number of reasons
including differences in SC lipid orientation and thickness, supporting
the hypothesis that human skin is less permeable than pig skin [181].
Another difference described by Lademann was the shrinking of hair
follicles in human skin which may prevent penetration of nanopar-ticles [71]. These well controlled and coordinated studies show no
substantial delivery benefit of nanoparticle formulation delivered
tocopheryl acetate over saturated silicone oil, regardless of vehicle.
2.2.3. Multiphoton imaging for in vivo lipid nanoparticle delivery studies
Photoageing severity is significantly associated with skin cancer
(pb0.05) [182]. Photoageing can result in collagen damage, DNA
damage and metabolic changes due to reactive oxygen species and
inflammation. Epidermal and dermal antioxidant enzymes are
powered by NAD(P)H. NAD(P)H is an endogenous fluorophore that
can be investigated with fluorescence lifetime imaging. These data
have direct implications for the metabolic state of the skin.
Our hypothesis was that commercial topical products containing
lipid nanoparticle components and tretinoin, niacinamide, ubiqui-none and folic acid as active agents would alter the NAD(P)H
fluorescence lifetime. This is especially relevant for niacinamide
containing products, as niacinamide is a precursor to NAD(P)H. Other
products include folic acid which is a form of vitamin B that is
essential for cell growth and metabolism.
We applied Nivea Visage Q10 Plus Day cream (Product A,
ubiquinone), Nivea Visage DNage Day cream (Product B, folic acid),
L'Oreal Revitalift Day cream (Product C, retinol) and Olay Regenerist
Microsculpting Cream (Product D, niacinamide) at 2 mg/cm2 every
day for up to 6 days. In vivo NAD(P)H changes pre- and post-
treatment were investigated with multiphoton microscopy using
fluorescence lifetime imaging microscopy on days 2 and 6.
All multiphoton images were collected using DermaInspect system
(JenLab GmbH, Jena, Germany). Excitation emission of 740 nm was
used, and theaverage incident optical power was30 mW at therear of
the objective. The light going to the FLIM detector was filtered with a
band pass filter transmitting 350450 nm light for NAD(P)H. Images
were analysed with SPCImage 2.9.4 software. Two component decay
matrices were calculated and the region of interest of each image was
selected for analysis. The mean value of each NAD(P)H component
(i.e. 1, 2, a1%, a2% and a1%/a2%) were analysed to assess any
metabolic changes. Stratum basale treated with folic acid (Product B)
for 6 days is shown in Fig. 6.The a1%/a2% ratio is inversely related to the metabolic rate and so
was used to evaluate any anti-ageing cream induced changes. At
stratum granulosum and stratum spinosum, all treated sites were
observed to have decreases in relative amounts of free NAD(P)H over
the course of the experiment. Interestingly, ubiquinone-, folic acid-
and retinoic acid-treated sites had increases in free NAD(P)H at the
stratum basale level, indicating lower metabolic states. The only
significant increases in NAD(P)H levels were found in the retinol
treated group on day 2 in the stratum spinosum (Fig. 7, *).
3. Other topical nanoparticle drug delivery applications
3.1. Antimicrobial agents
There are several recent studies thatdescribe topical nanoparticles for
anti-microbialdelivery applications [11,183190]. These studiesexamine
two types of nanoparticles, SLN for imidazole anti-fungal drugs
[183,188190] and silver nanoparticles [11,184187] that have broad
anti-microbial applications. The most prominent topical antimicrobial in
consumer productsis nanoparticle formulated silver.Silver nanoparticles
possesses antimicrobial properties [191,192] and the mechanism by
which silver functions as a disinfectant is not yet fully understood, but
may be related to silver ion induced metabolic inhibition. Alternately,
imidazole antifungal agents inhibit the synthesis of ergosterol, an
important part of fungal cell membranes [193].
3.1.1. Antifungal drugs
Econazole nitrate was loaded into SLN by Sanna et al. and the
particles characterized and permeation studies done to validate thesystem [189]. The particles had diameters ranging between 14013
and 154 5 nm and the encapsulation efficiency ranged between 97
and 102%. The cumulative econazole release from non-particle
containing gel into porcine skin was 124.7221.6 g/cm2 after 24 h
and the particle containing gel was 48.460.8 g/cm2. This could be
explained by the drug leaving theouter particle surface, leaving a high
concentration of drug in the core [20,194,195].
Passerini et al. have also investigated SLN made of glycerol
palmitostearate loaded with econazole nitrate for topical delivery,
but importantly this study compared SLN to solid lipid microparticles
using identical formulations [188]. The microparticles hada size range
of 18.03.17 to 44.75.16 m and the SLN had the same size range
described above (150 nm). Permeation experiments conducted with
porcine skin revealed a flux of 2428 g/cm2
/h1/2
for microparticlesand 1520 g/cm2/h1/2 for SLN, with no statistically significant
difference between the groups. The cumulative amount of econazole
nitrate that permeated after 24 h was 124.20.12 g/cm2 for non-
particulate econazole compared to 78121 g/cm2 for microparticles
and 4881 g/cm2 for SNL. These results show that there is no
significant difference between micro and nano-particle formulation
and econazole delivery kinetics in porcine skin, suggesting no size
dependent effects on drug delivery.
3.1.2. Silver nanoparticles
Topical silver nanoparticles, having antibacterial and antifungal
effects, are some of the most studied therapeutic nanoparticles
[11,184187,192], but important questions remain regarding topical
use. Silver nanoparticles are similar to solid drug nanoparticles in that
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the active agent appears to be the breakdown product of the particle.
Silver nanoparticles exhibit minimal penetration into skin and are
consequently considered safe. Studies of long term occupational
exposure to silver ions and silver nanoparticles conclude that they are
relatively non-toxic. The sub-milligram levels of silver present in burn
dressings are considered low risk [196].
Samberg et al. recently described an in vivo study in porcine skin
[61]. The skin was dosed topically with 2080 nm silver nanoparticles
for 14 days. The authors explored the effects of washing the
nanoparticles and carbon coating the nanoparticles prior to applica-
tion. Their results showed that none of the groups penetrated the SC
and that the sites of application showed focal inflammation. Finally,
Fig. 6. Metabolic state of stratum basale treated with folic acid cream for 6 days. In vivo multiphoton images show untreated (left) and folic acid-treated (right, Product B) stratum
basale. Free NAD(P)H lifetime contributionover protein-bound NAD(P)H contribution ratios (a1%/a2%)are inversely related to the metabolic rate.The 1 component is related to free
NAD(P)H in the cytosol, while the 2 component changes when NAD(P)H protein-binding changes.
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the authors showed through in vitro and in vivo systems that washed
or carbon coated silver nanoparticles were the least toxic form of
silver nanoparticles.
Tian et al. investigated the relationship between topical silver
nanoparticle delivery and wound healing in mouse models. The silvernanoparticles in thewounddressings were 14 10 nm in diameter,as
measured by transmission electron microscopy. Silver nanoparticle
impregnated dressings were changed daily, making treatment
continuous for the course of the experiments. Thermal injury took
35.41.29 days to heal without intervention and took 9 days less
with silver nanoparticle treatment (26.50.93 days). Interestingly,
injury treated with the same concentration of silver, but without
nanoparticles (silver sulfadiazine) took 37.43.43 days to heal, or
10 days longer than with the nanoparticles. Tian et al. also saw
improvements in cosmesis in thermal injury, improved healing time
in diabetic mice, and protection from microorganisms in wound areas.
All of these experiments were conducted in mouse models.
There is a knowledge gap in topical silver nanoparticle treatment in
study subjects. We investigated silver nanoparticle penetrationin intact
and tape stripped skin, while simultaneously monitoring NAD(P)H
metabolic rate. We also used reflectance confocal microscopy to
visualize silver nanoparticle aggregate bio-retention in intact and tape
stripped skin. An aqueous commercial product containing silver
nanoparticles with a size range of 1345 nm based on 100 nanoparticlemeasurements (Fig. 8a) was applied under occlusive conditions for 4 h
(180 l, containing 0.040.045 mg/ml silver). The silver nanoparticles
were characterized by transmission electron microscopy, FLIM, and
reflectance confocal microscopy. Skin barrier integrity was assessed by
TEWL.
Our results show that the commercial topical silver nanoparticle
spray was composed of silver nanoparticles b50 nm and that 740 nm
excitation could be used to excite the silver nanoparticle and NAD(P)
H simultaneously (Figs. 8a, b and 9). Skin penetration of silver
nanoparticles was not dramatically enhanced by tape stripping 20
times compared to silver nanoparticle treated intact skin (Fig. 8c).
This is likely to be due to the incomplete removal of the stratum
corneum. While silver nanoparticle treatment for four hours de-
creased metabolism, as determined by increased a1%/a2%, no
Fig. 7. Summary of NAD(P)H effects from antioxidants delivered with lipid nanoparticle formulations in commercial products. The total NAD(P)H fluorescence was measured by
FLIM photon counting by summing the free and protein-bound NAD(P)H signals weighted by intensity after 2 and 6 days of daily anti-ageing cream treatment formulated with lipid
particles. Optical sections were taken of stratum granulosum, stratum spinosum andstratumbasalefromthe volar forearms ofthreestudysubjects. Theactive ingredients areshown
on the x-axis of each graph.Initial increases in NAD(P)H at 2 days were not observed after 6 days of treatment. Two-tailed Students t-test revealed statistical significance (*)for only
the Retinol treated stratum spinosum after 2 days of treatment.
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statistically significant differences were detected (Fig. 8d.). Differ-
ences between untreated and silver treated groups decreased with
depth, suggesting a depth dependent effect. Fig. 9 shows a1% color
coded images illustrating the difference between the NAD(P)H
(green/yellow, a1% 4585) and silver nanoparticle second harmonic
generation (orange/red, a1% 90100).
Silver nanoparticle aggregates (Fig. 10, arrow heads) were tracked
in furrows up to 10 days after treatment with reflectance confocal
microscopy (Fig. 10, Video 1). Aggregate formation could be due to
protein/nanoparticle binding [197]. After 10 days, no silver nanopar-
ticle aggregates could be detected in intact skin, but aggregates
persisted in tape stripped skin. Similar results were observed in hair
follicles (data not shown). These results show that even relatively
brief treatment with silver nanoparticles can last longer than 10 days
on treated skin, agreeing with previous work by Lademann et al. [71].
This suggests that the treatment benefits of silver nanoparticle
treatment may last longer in damaged skin and that toxicity issues
may need to be studied over longer time courses.
Fig. 8. Characterization of silver nanoparticles and in vivo human skin penetration. Nanoparticles were characterized with TEM (panel a) and MPM (panel b) for size and second
harmonic generation characteristics, respectively. A study subject with intact (non-Tape) and tape stripped (Tape) skin was exposed to a commercial silver nanoparticle containing
antimicrobial solution under occlusive conditions for 4 h prior to MPM imaging. FLIM was used to isolate and measure the silver nanoparticle second harmonic signal. Non-furrowcontaining sites were analysed for silver nanoparticle signal (Integrated Density) and depth plots were generated from FLIM z-stacks. Silver nanoparticle signal was simultaneously
measured with NAD(P)H fluorescence. Fluorescence lifetime analysiswas used to measure the free/protein bound NAD(P)Hratio (a1/a2). This ratio is thought to be inversely related
to the metabolic rate [256,257]. Application of silver nanoparticles was associated with an depth dependent increase in the free/protein bound NAD(P)H contribution which is
consistent with previous reports of silver inhibition of metabolism. However, this trend was not statistically significant when compared to the untreated data.
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3.2. Anti-proliferative agents
Hyperproliferative skin disease is not limited to cancer, but also
precancerous lesions. It can also be caused by inappropriate
inflammatory responses. Several anti-cancer and anti-proliferation
drugs have been delivered with dendrimers and nanoparticles,
including 5-aminolevulinic acid (ALA), 5-fluorouracil (5FU), paclitax-
el, podophyllotoxin, and Realgar [198
204].
3.2.1. 5-aminolevulinic acid
Photodynamic therapy is based on the delivery of photosensitive
drugs to skin lesions followed by targeted light exposure. ALA and
methylaminolevulinate (MAL) are commonly used as they both
induce the production of the photosensitiser protoporphyrin IX in
skin cells. Photodynamic therapy is now being used for an increasing
number of skin conditions, including actinic keratosis and non-
melanoma skin cancers. Topical delivery has not been optimized.
Fig. 9. In vivo z-stack of FLIM images color coded from a1% 0 to 100%, blue to red, respectively. The images are 214214 m2 and show untreated and silver nanoparticle treated skin
thatwas intact (No tapestrip) or tape stripped. The yellow/green indicates NAD(P)H autofluorescence and orange/red indicates silver nanoparticle second harmonic generation. Bar
indicates color code and 50 m.
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There are significant gaps in knowledge regarding the relationship
between photodynamic response and dose parameters. Both drugshave
poor skin penetration profiles (0.26% methylaminolevulinate penetra-tion/24 h). MAL is faster acting at 3 h versus ALA at 46 h. Importantly,
19%of those treated do notrespond [Australian clinical trial,PC T305/99]
and MAL (Metavix, US$225/g) is nine times more expensive than ALA.
Therefore, enhanced ALA delivery could improve non-responder rates,
recurrence rates, and decrease the cost of therapy.
Battah et al., from the MacRobert group, have used dendrimers
conjugated to ALA for improved efficacy by mitigating the hydrophilic
nature of ALA and characterized porphyrin production and photo-
sensitivity [198,200]. However, these compounds have not been
reported for topical use, only reports of systemic application are
available [205]. The practical problem with systemic ALA application
is that the entire person would become photosensitive and much
more drug would likely be needed, thus eliminating any benefit over
methylaminolevulinate. The lack of topical data in this area could bedueto insufficient skin penetration levels of the large dendrimers-ALA
molecules or premature ALA cleavage by esterases in the skin. This
issue may be resolved with the development of a peptide-ALA
conjugatethat hasbeen shown to work well in an excised porcine skin
model [206]. Treatment efficacy of this prodrug has the potential to be
enhanced by nanoparticle delivery in the future.
3.2.2. Podophyllotoxin
Podophyllotoxin is a topical antiproliferative drug that is extracted
from the roots and rhizomes of Podophyllum species [207]. This toxin
is used clinically to treat HPV induced warts in a 0.5% gel called
Condylox. Typical therapy would include twice daily application for
three days and then no treatment for four days before treating again.
No more than 10 cm2
should be exposed and a maximum of 0.5 ml
applied per day. Although this drug is a first-line treatment for genital
warts, there are severe side effects and systemic absorption can be
dangerous [208]. This toxicity issue led Chen et al. to explore thepotential for SLN-podophyllotoxin delivery to the skin surface [199].
SLN were prepared from tripalmitin, soybean lecithin, poloxamer 188,
and polysorbate 80 in an aqueous solution. The control tincture
contained podophyllotoxin in 75% ethanol and water. The resulting
SLN had two populations of particles with mean diameters of 44 nm
and 194 nm and all had negative zeta potentials that ranged from
48 to 17 mV. Atomic force microscopy, differential scanning
calorimetry, and X-ray diffraction were used to further characterize
the formulations. Podophyllotoxin is fluorescent and can be excited at
290 nm with emission at 633 nm, so the endogenous fluorescence
was used to visualize podophyllotoxin localization after treating
excised porcine ear skin (Fig. 11). Podophyllotoxin fluorescence
accumulation can be seen in a furrow and hair follicle, in a manner
similar to the zinc oxide nanoparticles in Figs. 3, 9 and Video 1, FFAloaded PLGA microparticles are shown in Fig. 5d and the silver
nanoparticles in Figs. 9, 10 and Video 1. Encapsulation of podophyllo-
toxin in SLNresulted in an increase in thecumulative podophyllotoxin
compared to the tincture, 23.380.55 g and 6.080.31 g, respec-
tively. However, no podophyllotoxincould be detected in thereceptor
chamber of SLN treated skin, suggesting that the majority of the drug
was contained in the SLN on the outer layers of the skin. The
podophyllotoxin activity was not measured, so the therapeutic value
of SLN delivery cannot be assessed.
3.3. Other topical particulate delivered drugs
The field of nanoparticle drug delivery to the skin is fragmented in
terms of the drugs investigated. Some examples of molecules and
Fig. 10. In vivo RCM images of untreated and silver nanoparticle treated skin that was intact (No tape strip) or tape stripped. Silver nanoparticle aggregates (arrow heads) were seen
2 days and 6 days (data not shown) after application but not at 10 days after application in intact skin. In contrast, silver nanoparticle aggregates were still seen 10 days after
application, but only in discrete areas. Each image is 0.5 0.5 mm2.
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combinations of molecules that have been investigated for topical
nanoparticle delivery that have not been discussed are: diethyltolua-
mide and ethylhexyl p-methoxycinnamate [209]; fludrocortisone
acetate and flumethasone pivalate [210]; hinokitiol, glycyrrhetinic acid
and6-benzylaminopurine [211]; tolterodine tartrate [212]; JSH18[213];
acyclovir [214]; amlodipine [215]; ascorbyl palmitate [216]; benzylnicotinate [217]; buprenorphine [218]; calcipotriol with methotrexate
[219]; ceramide-3 [220]; coenzyme Q10 [221]; cyclosporin A [222,223];
cyproterone acetate [224]; frusemide [225]; insulin [226,227]; lidocaine
[228]; methoxycinnamate[77]; minoxidil [229,230]; nitrendipine
[231,232]; oxybenzone [233]; progesterone [234]; psoralen [235]; RU
58841-myristate [236]; temoporfin [237]; thrombin [238]; and triam-
cinolone acetonide acetate [239]. These reports describe the use of
several different nanoparticle carriers: chitosan [214]; invasomes [237];
iron oxide [238]; lipid [218220,223,230]; micro- and nano-emulsions
[210,212,215,217,218,227]; non-ionic surfactantvesicles(proniosomes)
[225]; polymer [77,211,226,240]; solid drug [221]; and solid lipid
nanoparticles [209,213,216,222,224,228,229,231236,239]. We recog-
nize that many reports use more than one type of nanoparticle material
and some of these carrier categories overlap. This integration ofnanoparticle drug delivery technologies has helped to cross validate
studies.
4. Recent advances in particle-based drug delivery
Materials advances are critical for the advancement of topical
nanoparticle drug delivery and have the potential to dramatically
improve drug delivery kinetics, but also reveal new biological
information on skin function. Poly(amidoamine) or PAMAM dendri-
mers have been used as effective delivery devices for some time,
reviewed by Jain et al. and Nishiyama et al. [241,242]. Dendrimers are
considered to be nanoparticles, but are composed of highly branched
polymers. Recent advances by Venuganti et al. have shown that
engineering the surface charge on dendrimers can regulate dendrimer
skin penetration for enhanced small drug delivery [202,203].
Venuganti et al. manipulated the surface charge of the dendrimers
by the addition of multiple amine groups (x16, 64, and 256),
carboxylic acid (x64), and hydroxyl (x64) groups, with isopropyl
myristate as the control. The antiproliferative drug 5FU was used as
the model for skin permeation studies in separated porcine ear skin.Dendrimers were used to pre-treat skin, at 0.1 to 10 mM, with 1 mM
as the chosen concentration, for 24 h. Interestingly, all dendrimer
groups had significantly higher cumulative amounts of penetrated
5FU (ranging from 1952 to 2597 g/48 h) than the control (1421 g/
48 h). The flux of the dendrimer groups (96236 g/cm/h) also
increased well above the isopropyl myristate control (67 g/cm/h).
Pre-treatment with the hydroxyl modified dendrimer resulted in the
highest 5FU levels in skin (23.7 g/mg skin), more than twice that of
the isopropyl myristate pre-treated group (11.9 g/mg skin). Togeth-
er, these data suggest that engineering dendrimer surface chemistry
to match the drug and desired skin penetration characteristics has the
potential to improve nanoparticle drug delivery.
Dendrimer drug delivery is currently being explored on many fronts
and the majority of the knowledge about nanoparticle drug deliverysystems focuses on solid lipid nanoparticles. Kuchler et al. from the
Shfer-Korting group in Germany, have reported the use of SLN for a
v