Advance Drug Delivery Reviews

Advanced Drug Delivery Reviews 63 (2011) 470491
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
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, Australia The University of South Australia, Therapeutics Research Centre, School of Pharmacy and Medical Science, Adelaide, SA, Australia Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia d Becker & Hickl, GmbH, Berlin, Germany e Dermatology Research Centre, The University of Queensland, School of Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia
b c
a r t i c l e
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a b s t r a c t
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 We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles N 10 nm in diameter are unlikely to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, signicant 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 eld of nanoparticle drug delivery to the skin, and future directions currently being explored. 2011 Elsevier B.V. All rights reserved.
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
Contents 1. Skin as a site for particle delivery . . . . . . . . . . . . . . . . . 1.1. Skin as a natural particle barrier . . . . . . . . . . . . . . 1.2. Barrier properties of the skin . . . . . . . . . . . . . . . . 1.2.1. Skin structure . . . . . . . . . . . . . . . . . . . 1.2.2. The stratum corneum barrier . . . . . . . . . . . 1.2.3. Transport routes of exogenous substances across the 1.2.4. Acid mantle maintains the stratum corneum barrier . 1.2.5. Viable epidermis . . . . . . . . . . . . . . . . . 1.2.6. Hair follicles . . . . . . . . . . . . . . . . . . . 1.3. Barrier properties of diseased skin . . . . . . . . . . . . . 1.4. Skin exing and massage for enhanced delivery . . . . . . . Small drug particle delivery . . . . . . . . . . . . . . . . . . . . 2.1. Anti-inammatory drugs . . . . . . . . . . . . . . . . . . 2.1.1. Corticosterone . . . . . . . . . . . . . . . . . . 2.1.2. Flufenamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . corneum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 471 472 472 473 473 473 473 474 474 474 475 475 475 476
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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: m.roberts@uq.edu.au (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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Anti-photoageing drugs and antioxidants . . . . . . . . . 2.2.1. Retinoids . . . . . . . . . . . . . . . . . . . . 2.2.2. Tocopheryl acetate . . . . . . . . . . . . . . . 2.2.3. Multiphoton imaging for in vivo lipid nanoparticle 3. Other topical nanoparticle drug delivery applications. . . . . . . 3.1. Antimicrobial agents. . . . . . . . . . . . . . . . . . . 3.1.1. Antifungal drugs . . . . . . . . . . . . . . . . 3.1.2. Silver nanoparticles . . . . . . . . . . . . . . . 3.2. Anti-proliferative agents . . . . . . . . . . . . . . . . . 3.2.1. 5-aminolevulinic acid . . . . . . . . . . . . . . 3.2.2. Podophyllotoxin . . . . . . . . . . . . . . . . 3.3. Other topical particulate delivered drugs . . . . . . . . . 4. Recent advances in particle-based drug delivery . . . . . . . . . 5. Systemic safety . . . . . . . . . . . . . . . . . . . . . . . . 6. Limitations of nanoparticle and nanocarrier chemical methods . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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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 denition 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 review Penetration 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 interactions with 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 remain on 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 modication 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 engineering, formulation science and an improved understanding of nanoparticleskin interactions will undoubtedly lead to important clinically relevant improvements in topical drug delivery. An overriding concern 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]. In addition, there is the potential for local toxicity, shown by a recent report of nanoparticles inducing keratinocyte apoptosis, where the subtle relationship 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.
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).
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
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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 signicant 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 nanoparticle delivery 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 benets 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 Scientic 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-lters. 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. exing) 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 N 20 nm in diameter do not penetrate into viable tissue is controversial. There have been reports showing nanoparticles N 20 nm penetrating through the stratum corneum (SC), to the viable epidermis [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 eld 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 are investigating are spatial and concentration related. In other words, where are the nanoparticles and how much is there? The MonteiroRiviere, Lademann, Guy and Roberts groups are currently investigating nanoparticle penetration, delivery, toxicity and species differences. The Monteiro-Riviere group have made signi cant contributions towards understanding nanoparticle penetration, toxicity and model systems, and has generated an extensive body 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 signicant 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 uorescence lifetime imaging techniques to simultaneously 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, immunological, 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 natural environment) [84]. On the other hand, the skin can be used as a port of 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(qcaprolactone)-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 stratied 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 attened and are eventually sloughed off [86]. Interspersed amongst the keratinocytes in the viable epidermis are 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 The SC represents the main physical barrier of the skin, so that for a substance permeating across the skin, diffusion through the SC is the rate limiting step [1]. Conversely, the SC is also the main barrier for diffusion of water out of the skin [87]. The attened, anuclear, proteinrich corneocytes of the SC are densely packed within the extracellular lipid matrix which is arranged in bilayers [88]. This is 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 route and more lipophilic solutes going via the intercellular
lipids. However a perception of the difculty 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 reafrmation 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 or particles 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 the skin has long 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 inuenced by sex and anatomical site [103], sweat, sebum and hydration [104]. There is a sharp gradient across the SC, with the pH in the upper viable layers in the stratum granulosum approaching neutral. Using two-photon uorescence lifetime imaging of a pH dependent uorophore applied to the SC of hairless mice, Hanson et al. [103] identied 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 specic biochemical mechanisms have been proposed to account for the acidication per se, including generation of transurocanic acid by histidase-catalysed degradation of histidine [105]. The acid mantle has a number of functions, including antimicrobial defence [106], the maintenance of the permeability barrier by effects on extracellular lipid organisation and processing [107], the preservation of optimal corneocyte integrity and cohesion, regulated by pHsensitive proteolytic enzymes [108] and restriction of inammation by inhibiting the release of pro-inammatory cytokines [109]. There is a clear association between elevated skin pH and diseases such as atopic dermatitis [102], with signicant pH differences between affected and unaffected skin in individual patients [110]. Interestingly, the acidic pH of the skin surface may also support the skin's barrier to nanoparticle penetration in some cases, as carboxylated polystyrene nanoparticles were found to aggregate due to decreasing electrostatic forces as the solution pH was lowered [111]. Aggregates would be less likely to penetrate the SC. On the other hand, 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 pH may 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 identied 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 chemical or metabolic barrier, with enzymes mainly located 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 to their 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 signicant 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 rst-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 (b 100 nm) liposomes, formed from engineered lipid nanovesicles, has been 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 transferred to late endosomes or lysosomes. The uptake of solid lipid nanoparticles (b 180 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 particlebound 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 insignicant 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], minoxidilloaded [130], and uorescent polystyrene [78] nanoparticles has been demonstrated. Lademann discussed the nding 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 efcient reservoir for
nanoparticle-based drug delivery [101], having previously shown that titanium dioxide particles did not penetrate beyond the follicle [131] and would be eliminated in time by outward sebum ow. It is possible also that some follicles may be blocked by a plug of sebum or closed leading to particle penetration being impeded. Signicant 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 atopic dermatitis (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) identies a single unpublished report that assessed systemic zinc levels in psoriatic patients and found no 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 quantied in subjects with clinically relevant skin diseases like psoriasis and dermatitis. Hypothetically, nanoparticles could penetrate these lesions more efciently due to an altered SC, inammation and increased keratinocyte turnover. Our investigation included zinc oxide nanoparticle (35 nm) penetration proling 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 in lesion 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 all treated skin optical biopsies, but the images show a punctuate distribution on the SC. Compared to the signal obtained from the untreated non-lesional (0.23 0.17 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 (0.22 0.09 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 increase in systemic zinc levels. 1.4. Skin exing 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 exing 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 exed for 60 min resulted in dermal penetration of the 1 m beads. They also showed rapid penetration through a tear in the skin and signicant 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 MonteiroRiviere group showed that mechanical exion in porcine skin increased the rate of nanoparticle penetration of 3.5 nm modied fullerenes [48]. However, we replicated Tinkle's exing apparatus and conditions, using excised human skin treated with 35 nm zinc oxide nanoparticles, and did not nd penetration (unpublished work). Likewise, Lademann et al. has shown no penetration of nanoparticles into the SC after massaging [72]. Studies on non-massaged and massaged porcine skin revealed that massaging 400700 nm diameter particles 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 m into the 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 inhomogeneous formulations are involved. Noting Lademann's other work showing that 40 nm particles do penetrate deep into follicles when the 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. Together these data suggest that there may be substantial differences between the penetration and interactions of nano- and micro-particles that depend greatly on the skin type, nature of applied exion and massage and formulation used. 2. Small drug particle delivery 2.1. Anti-inammatory drugs Anti-inammatory drugs represent a broad range of molecules, many with potential for topical delivery. Reports on nanoparticledelivered drugs with anti-inammatory properties for topical use include: aceclofenac [140], betamethasone-17-valerate [141], celecoxib [142], clobetasol propionate [143,144], corticosterone [145,146], ufenamic acid [147,148], urbiprofen [149,150], glycyrrhetic acid [151], ketoprofen [152,153], naproxen [153155], nimesulide [156], prednicarbate [141,157,158], and triptolide [159]. These drugs can be divided into steroids, e.g. corticosterone, and nonsteroidal anti-inammatory drugs (NSAIDs), e.g. naproxen. Corticosteroids work to reduce inammation 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 cholesteryl nonanoate), and cubic nanoparticles (glycerol monooleate) to deliver corticosterone to the skin [146]. The SLN, 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 prole 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 autouorescence (green) from zinc oxide nanoparticles (red). The intensity prole of the autouorescence 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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Fig. 4. Particle accumulation in hair follicles after massage. Massaged skin is shown treated with particulate dye and non-particulate dye in panels a and b, respectively. Panels c and d 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].
and differential scanning calorimetry. Nanoparticle skin interactions were monitored with uorescence microscopy. Storage of these nanoparticles for N 15 months did not dramatically change the 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 permeation at 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, and 0.2% for SLN. The permeability coefcients were also calculated and only the cubic nanoparticles showed a distinct improvement over the PBS control, 4.3 10 7 cm/s versus 1.8 10 7 cm/s. Fluorescence microscopy only detected uorescence 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, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, and hydrocortisone21-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-17butyrate, 7.5% for hydrocortisone-17-valerate, and 4.9% for hydrocortisone-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 corticosteroids. 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 controlled anti-inammatory delivery. The major differences in permeation models limit further comparison. 2.1.2. Flufenamic acid Flufenamic acid (FFA) is an anti-inammatory 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 has uorescence properties when in a non-polar environment and excited at 420 nm. This enables microscopic 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
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Fig. 5. AFM images from Luengo et al. showing FFA loaded PLGA nanoparticles for topical anti-inammatory 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-inammatory 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).
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 signicantly 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. The size of the particles ranged from 150 to 182 nm. The size remained at 180 nm after 25 days at room temperature. The encapsulation efciency for both starches was N 95%. A total of 14.8% of drug was released and 4.4 g/cm2 permeated within the rst 12 h. The FFA loaded PLGA particles had 6.7 g/cm2 permeated after 24 h and the starch nanoparticles had 8.3 g/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.
Table 1 Particle-delivered anti-photoageing drugs and antioxidants. Not determined (ND). Drug(s) Tretinoin Tretinoin Tretinoin Tretinoin Tretinoin Tretinoin Isotretinoin Retinol Vitamin A palmitate Nanoparticle material SLN SLN SLN Silica CaCO3 CaCO3 SLN SLN SLN Diameter range, potential 173406 nm, 2347 mV 52.0 20.8 to 65.7 28.0 nm, ND 344 nm, ND 166.5261.6 nm, 52.035.6 mV ND 1316 nm, ND 31.3 to 50.0 nm, 14.1 to 17.9 mV 224 nm, 58.1 0.6 mV 350 nm, ND Dose, vehicle 0.05%, Hydroxylethyl-cellulose (0.8%) 0.05%, Carbopol Ultrez 10 (1%, w/w) 0.05%, Carbopol ETD 2020 0.05%, Lecithin or oleylamine in medium chain triglycerides 0.10.4%, 0.1%, aqueous 0.06%, Tween 80 and soybean lecithin 0.5%, glycerol, water and xanthin gum 0.25%, Carbopol 940 (1%) Model Rhino mice for skin irritation Excised hairless abdominal rat skin Excised hairless abdominal rat skin Franz type diffusion cells with cellulose acetate membrane and porcine skin Study subjects ddY mouse Excised abdominal rat skin Cellulose membrane in Franz type diffusion cells Cadaver skin using Keshary Chien cells Ref. [162] [163] [166] [160,161] [167] [171] [168] [172,173] [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 are commonly used in topical acne and anti-ageing products and are one of the most studied drug groups in terms of topical nanoparticle and microparticle delivery (Table 1) [160173]. Retinoids work 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 inammation, 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 rst 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. The other major issue for retinoid therapy is local erythema, peeling, dryness, and pain. Skin irritation side effects have been mitigated by nanoparticle encapsulation, where the mechanism 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 with an efciency 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 efciency. The microparticles varied in diameter from 228 3 to 682 26 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 efciency than SLN without, 97 5% versus 55 2%. Skin irritation studies were done by comparing the SLN with stearylamine to a placebo gel and a marketed Tretinoin cream containing a completely different formulation utilizing liposomes. Castro et al. used a rhino mouse model to test irritation. Although the engineered SLN performed better than the commercial formulation, the lack of stearylamine controls precludes further interpretation. Likewise, the lack of skin retention and ux data hampers comparison of this SLN formulation with other 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 ow. Two distinct SLN sizes were tested in these studies: b 100 nm [163] and N 300 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 efciency of the small and large SNL was similar at 46% and 49%, respectively. The ux differed with the larger SLN being exactly twice that of the smaller microparticle at 75.6 ng/cm2 h versus 37.7 ng/cm2 h. These were compared to a commercial formulation with a ux 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 benets of nanoparticle encapsulation between the nanoparticles (b 100 nm) and microparticles (N 300 nm) because photostability was only investigated with the N 300 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, respectively. 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 signicant reduction in the steady state ux to 90% for lecithin emulsions and 50% for oleylamine emulsions. The 72 h cumulative release was 13.4 and 7.4 g/cm2 for lecithin and oleylamine emulsions with silica microparticles, 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 was similar to that of b 100 nm SLN at 3.9% and 4.2%, recognizing that 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 Japan with CaCO3 nanoparticles (1315 nm) coated with Tretinoin at high doses (0.1%). These studies do not include skin retention or ux measurements, 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 Mandawgade et al. [163], 3050 nm and both studies used excised abdominal rat skin to investigate the pharmacokinetics. Isotretinoin loaded nanoparticles were capable of encapsulation efciencies of up to 99.7% depending on the surfactant concentration (8% soybean lecithin and 4.5% Tween 80). Stability was tested over 3 months at 28 C with no changes in isotretinoin levels noted. The steady state ux 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 N 220 nm in diameter [172,173]. The skin retention of retinol was 0.68% (over 6 h) in porcine skin, an improvement of 0.9 g over a nanoemulsion control group. The in vitro ux from the retinol loaded SLN was 150 ng/cm2 over 6 h, or 25 ng/cm2 h. Vitamin A palmitate is converted into retinol in the skin and nally to tretinoin. Vitamin A palmitate has been formulated into SLN of approximately 350 nm in diameter by Pople and Singh [169]. The pharmacokinetics of this formulation was explored using human cadaver 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 ux was unusually higher with the SLN formulation, SLN formulation usually results in lower ux with longer term release. Pople and Sing also evaluated the effects of treatment on SC thickness in rats. SLN formulation treatment resulted in an increase in SC thickness of almost 3 times compared to the conventional gel. The conventional gel control was a formulation that contained the same components as the SLN formulations. This increase 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, b 100 nm and N 200 nm. This could be interpreted as a broad comparison of nanoparticle versus microparticle retinoid delivery, given the denition of nanoparticles as b 100 nm in diameter. Both nanoparticles and microparticles could be formulated with near 100% encapsulation efciency and both showed improved stability and pharmacokinetics (depending on controls used). Together, no real benets of nanoparticle (b 100 nm) formulation are evident compared to microparticle (N 100 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 the benets of a hydrouoroalkane 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 efciency was 90.1 3.7% and 100% of the drug was recoverable. Delivery to human skin was evaluated by treating skin with 400 g/ cm2 tocopheryl acetate for 24 h. Saturated silicone oil was compared to the aqueous nanosuspension and nanoparticle containing foam. No tocopheryl acetate was found in the receptor uid for any group and the estimate for skin retention was 1.7 0.4% for the oil control and 0.7 0.4% 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 benet 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 ux 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 1.32 0.57% and 1.65 0.90% respectively of the total dose applied. Interestingly, in human skin, the saturated silicone oil delivered 1.70 0.36%, 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 nanoparticles [71]. These well controlled and coordinated studies show no substantial delivery benet 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 signicantly associated with skin cancer (p b 0.05) [182]. Photoageing can result in collagen damage, DNA damage and metabolic changes due to reactive oxygen species and inammation. Epidermal and dermal antioxidant enzymes are powered by NAD(P)H. NAD(P)H is an endogenous uorophore that can be investigated with uorescence 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, ubiquinone and folic acid as active agents would alter the NAD(P)H uorescence 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 posttreatment were investigated with multiphoton microscopy using uorescence 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 the average incident optical power was 30 mW at the rear of the objective. The light going to the FLIM detector was ltered with a band pass lter 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 acidand retinoic acid-treated sites had increases in free NAD(P)H at the stratum basale level, indicating lower metabolic states. The only signicant 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 that describe topical nanoparticles for anti-microbial delivery applications [11,183190]. These studies examine 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 products is 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 the system [189]. The particles had diameters ranging between 140 13 and 154 5 nm and the encapsulation efciency ranged between 97 and 102%. The cumulative econazole release from non-particle containing gel into porcine skin was 124.72 21.6 g/cm2 after 24 h and the particle containing gel was 48.46 0.8 g/cm2. This could be explained by the drug leaving the outer 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 had a size range of 18.0 3.17 to 44.7 5.16 m and the SLN had the same size range described above (150 nm). Permeation experiments conducted with porcine skin revealed a ux of 2428 g/cm2/h1/2 for microparticles and 1520 g/cm2/h1/2 for SLN, with no statistically signicant difference between the groups. The cumulative amount of econazole nitrate that permeated after 24 h was 124.2 0.12 g/cm2 for nonparticulate econazole compared to 78121 g/cm2 for microparticles and 4881 g/cm2 for SNL. These results show that there is no signicant 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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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 contribution over 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.
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 application. Their results showed that none of the groups penetrated the SC and that the sites of application showed focal inammation. Finally,
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Fig. 7. Summary of NAD(P)H effects from antioxidants delivered with lipid nanoparticle formulations in commercial products. The total NAD(P)H uorescence 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 and stratum basale from the volar forearms of three study subjects. The active ingredients are shown 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 signicance (*) for only the Retinol treated stratum spinosum after 2 days of treatment.
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 silver nanoparticles in the wound dressings 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 35.4 1.29 days to heal without intervention and took 9 days less with silver nanoparticle treatment (26.5 0.93 days). Interestingly, injury treated with the same concentration of silver, but without nanoparticles (silver sulfadiazine) took 37.4 3.43 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 penetration in intact
and tape stripped skin, while simultaneously monitoring NAD(P)H metabolic rate. We also used reectance 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 nanoparticle measurements (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 reectance confocal microscopy. Skin barrier integrity was assessed by TEWL. Our results show that the commercial topical silver nanoparticle spray was composed of silver nanoparticles b 50 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 decreased metabolism, as determined by increased a1%/a2%, no
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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-furrow containing 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 uorescence. Fluorescence lifetime analysis was used to measure the free/protein bound NAD(P)H ratio (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 signicant when compared to the untreated data.
statistically signicant differences were detected (Fig. 8d.). Differences 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 reectance confocal microscopy (Fig. 10, Video 1). Aggregate formation could be due to
protein/nanoparticle binding [197]. After 10 days, no silver nanoparticle 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 benets of silver nanoparticle treatment may last longer in damaged skin and that toxicity issues may need to be studied over longer time courses.
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Fig. 9. In vivo z-stack of FLIM images color coded from a1% 0 to 100%, blue to red, respectively. The images are 214 214 m2 and show untreated and silver nanoparticle treated skin that was intact (No tape strip) or tape stripped. The yellow/green indicates NAD(P)H autouorescence and orange/red indicates silver nanoparticle second harmonic generation. Bar indicates color code and 50 m.
3.2. Anti-proliferative agents Hyperproliferative skin disease is not limited to cancer, but also precancerous lesions. It can also be caused by inappropriate inammatory responses. Several anti-cancer and anti-proliferation drugs have been delivered with dendrimers and nanoparticles, including 5-aminolevulinic acid (ALA), 5-uorouracil (5FU), paclitaxel, podophyllotoxin, and Realgar [198204].
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 nonmelanoma skin cancers. Topical delivery has not been optimized.
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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.
There are signicant gaps in knowledge regarding the relationship between photodynamic response and dose parameters. Both drugs have poor skin penetration proles (0.26% methylaminolevulinate penetration/24 h). MAL is faster acting at 3 h versus ALA at 46 h. Importantly, 19% of those treated do not respond [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 efcacy by mitigating the hydrophilic nature of ALA and characterized porphyrin production and photosensitivity [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 benet over methylaminolevulinate. The lack of topical data in this area could be due to insufcient 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 conjugate that has been shown to work well in an excised porcine skin model [206]. Treatment efcacy 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 rst-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 the potential 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 uorescent and can be excited at 290 nm with emission at 633 nm, so the endogenous uorescence was used to visualize podophyllotoxin localization after treating excised porcine ear skin (Fig. 11). Podophyllotoxin uorescence 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, FFA loaded PLGA microparticles are shown in Fig. 5d and the silver nanoparticles in Figs. 9, 10 and Video 1. Encapsulation of podophyllotoxin in SLN resulted in an increase in the cumulative podophyllotoxin compared to the tincture, 23.38 0.55 g and 6.08 0.31 g, respectively. However, no podophyllotoxin could be detected in the receptor 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 eld of nanoparticle drug delivery to the skin is fragmented in terms of the drugs investigated. Some examples of molecules and
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Fig. 11. Podophyllotoxin was loaded into SLN nanoparticles and imaged in porcine ear skin by Chen et al. [199]. Atomic force microscopy (panels a and b) show two distinct size ranges of the SLN. The uorescent nature of podophyllotoxin enables direct drug tracking by confocal microscopy (panel d). The drug appears to accumulate in the furrows (arrow) and hair follicles in addition to coating the surface of the skin.
combinations of molecules that have been investigated for topical nanoparticle delivery that have not been discussed are: diethyltoluamide and ethylhexyl p-methoxycinnamate [209]; udrocortisone acetate and umethasone pivalate [210]; hinokitiol, glycyrrhetinic acid and 6-benzyl aminopurine [211]; tolterodine tartrate [212]; JSH18 [213]; acyclovir [214]; amlodipine [215]; ascorbyl palmitate [216]; benzyl nicotinate [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]; temoporn [237]; thrombin [238]; and triamcinolone 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 surfactant vesicles (proniosomes) [225]; polymer [77,211,226,240]; solid drug [221]; and solid lipid nanoparticles [209,213,216,222,224,228,229,231236,239]. We recognize that many reports use more than one type of nanoparticle material and some of these carrier categories overlap. This integration of nanoparticle 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 dendrimers 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 signicantly higher cumulative amounts of penetrated 5FU (ranging from 1952 to 2597 g/48 h) than the control (1421 g/ 48 h). The ux 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 modied 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). Together, 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 delivery systems focuses on solid lipid nanoparticles. Kuchler et al. from the Shfer-Korting group in Germany, have reported the use of SLN for a variety of drugs and applications [243245]. Recently, they also reported a comparison of dendrimer nanoparticle versus SLN drug delivery to skin [246]. Detailed particle analysis showed that the SLN were 150170 nm and the dendrimer aggregates were 2030 nm. Both particles were used to deliver nile red, a uorescent marker, at 0.004% to porcine skin for up to 6 h at 32 C. A nile red containing cream (oil-inwater emulsion: glycerol monostearate 60, cetyl alcohol, medium chain triglycerides, white vaseline, macrogol 20-glycerol monostearate, propylene glycol, and water) was used as a reference control. Confocal microscopy images and image analysis showed clearly enhanced inltration of nile red from the dendrimer nanoparticles, compared to the SLN and cream (Fig. 12). The dendrimer nanoparticles showed
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Fig. 12. Penetration of nile red loaded cream (Panel a), SLN (Panel b), and dendrimer nanoparticles (Panel c) as seen by uorescence microscopy. Comparisons between delivery vehicles are necessary to select the most appropriate delivery vehicle for a given drug. In this case the dendrimer nanoparticles enabled more nile red to penetrate deeper into porcine skin than the cream or the SLN. Adapted from [246].
enhanced delivery over the cream and SLN in the SC, epidermis, and dermis by image intensity analysis of nile red uorescence. In the epidermis, the dendrimer nanoparticle group (4449 corrected absorbance units, ABU) showed more than double (2.1 times) the uorescence than the SLN group (1959 ABU), with the cream (490 ABU). These data support the hypothesis that stepwise improvements can be made by engineering the size, composition, and surface chemistry on small nanoparticles for topical drug delivery. The chemical composition of SLN is generally restricted to include only biodegradable chemicals that are approved for use in applications on human skin [247]. For example, Kuntsche et al. used the common endogenous molecules: non-hydroxy fatty acid ceramides, -hydroxy fatty acid ceramides, cholesterol, stearic acid and cholesterol-3-sulfate. By providing a high local concentration of drug close to the desired site of action, nanoparticles minimise the drug dose and consequently the risk of side-effects in other tissues when compared with alternative administration methods. A recent report from Zhao et al. shows that solid drug particles can successfully treat melanoma in a mouse model [204]. The particles, containing Realgar, a traditional Chinese drug with tetraarsenic tetrasuldes as the active ingredient, were produced by cryogrinding. The particles had a mean size of approximately 150 nm and were capable of inhibiting the proliferation of B16 cells at 0.1 5.0 M for 48 h. Cell death occurred through apoptosis and necrosis, i.e. at 1 M for 48 h there were averages of 8.2% apoptotic and 16.9% necrotic cells. B16 cells were dosed via intradermal injections on the backs of mice and tumors were allowed to grow to 4060 mm3. Then 100 l of a cream, glycerylmonostearate, hydroxylpropylmethyl cellulose, isopropylmyristate, methylparaben, propylparaben, polyoxyl (40) stearate, and water (10:1:10:1:1:11:66, w/w), containing 25 mg Realgar microparticles was applied to the tumor. One control group of mice received intraperitoneal injected Realgar particles at the same dose, 100 l of 250 g/l. Another control group received the cream without Realgar. Missing from this experiment was a Realgar cream group without particles. The Realgar particle cream and injection groups were treated every other day for 14 days. The tumor volume and survival rates were dramatically improved with Realgar treatment. By far the most effective treatment was the topical Realgar cream. Fourteen days after treatment began the non-drug control cream group had developed 500 mm3 tumors, the intraperitoneal Realgar particle group had on average 300 mm3 tumors, but the topical Realgar microparticle cream group only had 100 mm3 tumors on average. This dramatic retardation of tumor proliferation is an exciting development. Follow up studies will undoubtedly clarify the role of nanoparticulates in the formulation and dose response relationships in human subjects. Likewise, combinational therapy, i.e. photodynamic therapy, has the potential for an even better outcome. 5. Systemic safety Nanoparticles can be classied as either: i) soluble and/or biodegradable, which disintegrate upon application to skin into molecular species (e.g. liposomes, microemulsions, and nanoemulsions), or ii) insoluble and/or biopersistent (e.g. titanium dioxide,
fullerenes, and quantum dots). In general, conventional risk assessment methodologies can be applied for the rst group whereas more detailed evaluation is required for the second group [21]. In particular, insoluble particles may lead to health concerns if taken up by the skin as a consequence of their translocation/transportation and eventual accumulation in secondary target organs, especially on repeated application. There is also an issue of environmental burden [21]. More details on safety of various nanoparticles in given in a recent review we have undertaken in this area [83] as well as our earlier work [16]. 6. Limitations of nanoparticle and nanocarrier chemical methods There are several limitations associated with the design and characterization of these materials. These include our ability to reproducibly fabricate specic nanoparticle shapes and sizes, to achieve optimal drug loading of carriers, to control drug release and delivery and to design stable materials which do not release harmful degradation products. It has been suggested [248] that particle shape may play an important role in nanoparticle action transport and intracellular uptake. However, due to a reliance on emulsion-based methods which generally produce spherical, polydisperse particles, our ability to synthesize specically shaped particles has been limited. Another developing area is the ability to cause triggered release of drugs from particulate carriers [248] at a specic target site, for instance, in response to pH change [249]. Such an application may be useful in skin, to exploit the pH gradient existing in that tissue [103]. Enzyme or protein nanocarrier conjugates have received attention, but a limitation has been the potential loss of function due to changes in bound protein structure [250]. Improved nanoparticle design to allow conjugation without loss of function will improve the ability to deliver these materials with wide systemic and topical application. The architecture of some polymeric nanocarriers and dendrimers can now be specically controlled [251] and this has improved our ability to control stability, solubility and drug carrying capacity. 7. Conclusions The eld of nanoparticle drug delivery to the skin has progressed over the last dozen years to a point where there are well characterized tools, i.e. SLN, lipid nanoparticle, and increasingly dendrimers, that have the capacity for customized pharmacokinetics. There are nanoparticles to increase or decrease the ux, customize the drug depot location and size, and even to selectively permeabilize the SC. Understanding the interactions of nanoparticles with the common structures of skin, i.e. furrows, hair follicles, eccrine ducts, etc., are absolutely critical to the improvement of percutaneous drug delivery. Rening the chemistry of nanoparticles will help to enable an atom by atom approach to particle synthesis that takes advantage of nanoparticlebiological interactions. Equally important is an understanding of the importance of skin differences between species when analysing and interpreting data. Likewise, long term, in vivo, nanoparticle and contaminant toxicity are important because of the potential medical application. Bioretention has been an area of focus for inhaled nanoparticles by Kreyling [252,253] for some time and
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skin clearance studies are receiving increased attention by researchers in the eld of topical nanoparticle therapeutics. Dening how long carrier substances remain on the skin and how are they eliminated, especially from reservoirs like furrows (Video 1) and hair follicles could have important delivery and regulatory impact. Two of the most widely studied drugs delivered by nanoparticles are retinoic acid and tocopheryl acetate, both of cosmeceutical interest. New techniques to non-invasively detect drug altered metabolic activity by time-correlated single-photon counting in study subjects were discussed. We also discuss the underlying technology that is currently being widely exploited to enhance drug delivery, lipidSC interactions. Established skin permeation studies using diffusion cells and confocal microscopy are the most common tools used to evaluate nanoparticle drug delivery. Preclinical and clinical studies have shown that nanoencapsulation can reduce side effects and improve delivery of certain drugs. Studies also show that both micro and nanoparticle systems give similar benets, given identical formulations. The eld is fragmented with regard to the types of drugs delivered with nanoparticles, suggesting that a better understanding of nanoparticleSC interactions are critical for the success of this eld. The number of nanoparticle skin delivery publications has dramatically risen over the last 5 years making this an exciting and promising area of science. Supplementary materials related to this article can be found online at doi:10.1016/j.addr.2011.01.012.
Acknowledgments Queensland Cancer Council, National Health and Medical Research Council grant 569694, and the United States Air Force grant AOARD 084024 are funding for this research.
References
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Advanced Drug Delivery Reviews 63 (2011) 470491

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Advanced Drug Delivery Reviews

Nanoparticles and microparticles for skin drug delivery

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

T.W. Prow et al. / Advanced Drug Delivery Reviews 63 (2011) 470491

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