NPD

Arch Derm atol Res (2011) 303:533-550 DOI 10.
1007/s00403-011-1163-7
R E V IE W A R T IC L E
Nanoparticles in dermatology
Dimitrios Papakostas Fiorenza Ranean W olfram Sterry Ulrike Blume-Peytavi Annika Vogt
Received: 6 April 2011/R evised: 16 June 2011 / Accepted: 29 June 2011/P ublished online: 12 August 2011 Springer-Verlag 2011
Abstract Recent advances in the field of nanotechnology have allowed the manufacturing of elaborated nanometersized particles for various biomedical applications. A broad spectrum of particles, extending from various lipid nanostructures such as liposomes and solid lipid nanoparticles, to metal, nanocrystalline and polymer particles have already been tested as drug delivery systems in different animal models with remarkable results, promising an extensive commercialization in the coming years. Controlled drug release to skin and skin appendages, targeting of hair follicle-specific cell populations, transcutaneous vaccination and transdermal gene therapy are only a few of these new applications. Carrier systems of the new generation take advantage of improved skin penetration properties, depot effect with sustained drug release and of surface functionalization (e.g., the binding to specific ligands) allowing specific cellular and subcellular targeting. Drug delivery to skin by means of microparticles and nanocarriers could revolutionize the treatment of several skin disorders. However, the toxicological and environmental safety of micro- and nanoparticles has to be evaluated using specific toxicological studies prior to a wider implementation of the new technology. This review aims to give an overview of the most investigated applications of transcutaneously applied particle-based formulations in the fields of cosmetics and dermatology.
Keywords Active targeting Controlled release Drug delivery system Nanoparticles Skin barrier Skin penetration Abbreviations Antigen-presenting cells APC British Standards Institution BSI Cyanoacrylate skin surface stripping CSSS DDS Drug delivery system Epidermal growth factor receptor EGFR HBV Hepatitis B virus HIV Human immunodeficiency virus HPV Human papillomavirus ISCOM Immune stimulating complexes Langerhans cells LC M ajor histocompatibility complex MHC MRI Magnetic resonance imaging P(CL) Poly(s-caprolactone) PDT Photodynamic therapy PLA Poly-lactic acid PLGA Poly(lactic-co-glycolic) acid Polystyrene PS PTT Photothermal therapy Quantum dots QD RSV Respiratory syncytial virus SLN Solid lipid nanoparticles SPF Sunscreen protection factor UV Ultraviolet
D. Papakostas and F. Rancan contributed equally to this work. D. Papakostas F. Rancan W. Sterry U. Blume-Peytavi A. Vogt ( & ) Clinical Research C enter for H air and Skin Science, Departm ent of Derm atology and Allergy, Charite-Universitatsm edizin Berlin, Chariteplatz 1, 10117 Berlin, Germany e-mail: annika.vogt@ charite.de
Introduction Recent advances in the field of pharmacology and nanotechnology have drawn attention on nanoparticles as novel
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Arch Derm atol Res (2011) 303:533-550
drug delivery systems. Drug carriers enable a sustained drug release over a period of time due to their depot function, thus achieving a constant drug level in tissue [47]. Sustained drug release may be beneficial in various clinical situations maximizing the therapeutic effect and minimizing the toxicological concerns about drug overdose and clearance. Moreover, it allows to increases the patients compliance by reducing the frequency of drug administration. Through modification of the particle surface and binding with specific ligands, e.g., monoclonal antibodies, an active targeting of a selected cell population can be achieved [85]. Nanoparticles are not only optimal drug carriers; there is enough evidence that certain nanoparticles possess immunogenic properties and are able to influence the direction of immunological response after the antigen presentation by APCs [56]. Since these advantages of the particulate drug delivery systems could prove valuable for optimizing the current galenical formulations for topical dermatotherapy, extensive research has recently been invested for the manufacture of optimal nanomaterials. One important feature of the skin as an organ is the function, accomplished by the stratum corneum, of a potent barrier to the external environment. The diffusion through the lipid layers of the stratum corneum has long been seen as the sole penetration pathway for topical applied substances. Since the physicochemical properties (e.g., lipophilicity) and the size of topically applied substances are decisive parameters for the degree of penetration within the skin, alternate penetration pathways or shunts gained importance in the case of hydrophilic compounds or supramolecular structures such as proteins or carrier systems. There is indeed evidence that the hair follicle can act as a shunt increasing the penetration and absorption of topically applied substances [17, 61, 66, 83, 84, 116, 128]. Hair follicles also act as a depot for applied substances, thus multiplying the storage capabilities of the stratum corneum [97]. M ost interestingly, it has been shown that particulate formulations penetrate preferentially within the hair follicle canal than through the stratum corneum, thus enabling high concentrations within the reservoir of the follicular infundibulum [105, 139]. Particles can persist in this reservoir ten times longer than in the reservoir of the stratum corneum, thus enabling a sustained drug release, the goal of every modern pharmacotherapy [65, 117]. In case of lipophilic dyes delivered to hair follicles by means of polymer particles, it was shown that the constant dye diffusion from the follicular canal to the perifollicular epidermis and sebaceous gland took place via a transcellular diffusion route [108]. As already mentioned, active targeting is a major advantage of particulate formulations. Particularly in the hair follicle, several cell populations or structures represent possible targets for nanoparticles-based drug carriers, e.g., Langerhans cells of the infundibular
epithelium, stem cells in the bulge region, and matrix cells and melanocytes in the hair bulb, as well as the sebaceous gland [82, 139]. In addition, the selective targeting of specific cells in the dermis, such as mast cells and lymphocytes in case of allergic and inflammatory skin diseases, are actual challenges for nanotechnology applied to dermatology. For these reasons, numerous applications of nanoparticles for local dermatotherapy have been and are currently extensively studied (Table 1), while some of them, e.g., sunscreens and antiseptic products are already commercially available as discussed later in this review.
W hat are nanoparticles? The term particle derives from the Latin word partcula, which means a small part. A particle is therefore defined as a small object that behaves as a whole unit. Particles on the nanometer scale are generally described as nanoparticles. Currently, there is no worldwide accepted definition regarding their dimensions, although the British Standards Institution (BSI) set 100 nm as the upper limit and 1 nm as the lower limit. Particles with dimension over this limit are considered microparticles. A great variety of materials such as polymers, lipids, metals and ceramics have been used so far, and a variety of shapes have been engineered to create particulate drugs or drug delivery systems (DDS) (Fig. 1). There are a few possibilities to classify and list nanoparticle types. Particles can be divided into organic and inorganic or they can be classified according to their shape, size, surface charge and physicochemical properties. Nevertheless, from the point of view of particle interactions with biological surfaces and barriers like skin, it may be useful to distinguish between soft and rigid particles. In general, soft particles are made of organic materials (e.g., lipids, proteins, polymers) and can temporarily alter their shape by stress or contact with surfaces, while rigid particles are made of inorganic materials and are not deformable. Some of the most common nanoparticles are described below. Soft particles Liposomes are typical soft deformable particles. They are vesicular structures composed of a phospholipid bilayer and a hydrophilic core. Hydrophilic and lipophilic substances can be integrated into the core or the shell, respectively. It has been shown that drugs loaded on liposomes penetrate deeper into the hair follicle canal than drugs applied in other non-particulate formulations [54]. After topical application, liposomes loaded with the antiandrogen RU 58841 were selectively localized in the
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T able 1 Exam ples o f the experim ental application of various nanoparticles in dermatology Application Photoprotection Nanoparticle type Ti2 Ti2 ZnO Liposomes and SLN Lipid nanoparticles Barrier Creams Antiseptic Creams Phototherm al Therapy Photodynamic Therapy Treatm ents o f H air Disorders Silica microparticles TiO2 Gold nanorods QD PEG PLGA P(CL) Liposomes Liposomes Sebaceous Gland Targeting PLGA PLA SLN Liposomes SLN SLN Local Derm atotherapy SLN Liposomes Ethylhexyl methoxycinnamate Antioxidants Zn-protoporphyrin Hinokitiol M inoxidil Finasteride Cyclosporin A Adapalene Fluorescent dyes Retinol Tretinoin RU-58841 RU-58841 Retinoic acid Podophyllotoxin Cyclosporin A M ethotrexate Psoralen Dithranol Clotrimazole Silver nanoparticle SLN Lipid nanoparticles Gene Therapy Gelatine microspheres PEG-PLA Vaccination Nanodiagnostics a. DNA Sequencing b. Sentinel Lymph Node c. M etastase Detection with MRI System ic Drug Delivery Gold Quantum Dots M agnetic Particles CaCO 3 PLGA Insulin Insulin Jain [49] Ballou et al. [11] Rockall et al. [111] Higaki et al. [46] Rastogi et al. [109] PLA PLGA Glucocorticoids Betam ethasone 17-valerate siRNA siRNA Plasmid DNA Peptides Encapsulated drug References Lademann et al. [70] Lekki et al. [75] Pinnell et al. [103] X ia et al. [145] Durand et al. [34] Lademann et al. [67] Tsuang et al. [130] Dickerson [31] Chatterjee et al. [21] Regehly et al. [110] Tsujimoto et al. [131] Shim et al. [121] Kum ar et al. [64] Verm a et al. [135] Rolland et al. [112] Rancan et al. [107] Jenning et al. [52] Patel et al. [100] M nster et al. [89] Stecova et al. [123] Castro et al. [20] Chen et al. [22] Egbaria et al. [35] Ali et al. [2] Fang et al. [38] Saraswat et al. [114] Souto et al. [122] Keck et al. [58] Schlupp et al. [118] Zhang et al. [149] N akam ura et al. [91] Jacobson et al. [48] Panyam and Labhasetw ar [99] Jiang et al. [53]
sebaceous gland [14], an early indication that liposomes could prove useful for a follicular targeting. SLN (solid lipid nanoparticles) and NLC (nanostructured lipid carriers) were developed to create more stable systems. They lack the micelle structure of the liposomes and are therefore more stable in hydrophilic as well as lipophilic
environments, allowing the safe transport and delivery of various substances to skin [63, 115, 117]. ISCOMS (immune stimulating complexes) are matrix constructs of saponine, cholesterol, phospholipids and antigen and are investigated as vaccine delivery vehicles due to their potent adjuvant activity [102]. As their dimensions are similar to
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536 Fig. 1 Nanoparticle types and possible surface modification. A great variety of materials such as polym ers, lipids, metals and ceramics have been used so far for the m anufacture of particulate drug carriers or drug delivery systems (DDS). The most studied particle-based DDS are liposomes, vesicular structures composed o f a phospholipid bilayer and a hydrophilic core. Liposomes are of special interest for local dermatotherapy due to their function as penetration enhancers. The sustained release of particle-encapsulated drugs is another challenge of nanotechnology, with im pact on the therapeutic effect of topically applied substances and on their toxicity due to drug overdose. In this case, the stability of the particulate carrier is requested. Complex polym er nanoparticles are colloidal structures o f various shapes and prepared from various types of polymers or copolymers. Through crosslinking or surface coating, the physicochem ical properties of the nanoparticles can be selectively modified increasing their stability and altering their release properties, thus enabling a sustained drug release. M odified complex nanoparticles offer the possibility o f surface functionalization for the binding of ligands such as m onoclonal antibodies allowing the active targeting of different cell populations. The ability of nanoparticles to carry several drug and detection molecules exclusively to the target cells can revolutionize the therapeutic possibilities offered by local dermatotherapy
Liposomes
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those of many viruses, they are easily taken up from the cells of the immune system. Virosomes are nanoscaled particles which should mimic the nature of viruses. They are hybrids of liposomes and viral proteins and are used as vaccine adjuvants as well [30]. Due to the advances of
modern genetics, virus-like particles that are highly organized spheres made of lipids and viral structural proteins have been engineered. They have been used for a successful vaccination against HBV and HPV [80]. Other types of soft particles are polymer-based particles, e.g.,
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poly-lactic acid (PLA), poly(glycolic-co-lactic acid) (PLGA) and poly(s-caprolactone), P(CL). Numerous polymer-based particles have been studied so far. Since the accumulation and the potential cytotoxicity of non-biodegradable particles constitutes a major problem and limits their use in humans, current attention is being drawn on biodegradable polymers such as PLA or PLGA [81]. PLA is an aliphatic ester of lactic acid, derived from renewable resources such as corn starch or sugarcanes, which has gained not only scientific but also commercial interest due to its easy manufacture [127]. Fullerene derivatives and dendrimers are supramolecular structures with dimension of few nanometers and therefore can be considered as nanoparticles. Fullerenes have been investigated for their ability to absorb UV light and their radical scavenging properties [25, 57]. Dendrimers are highly branched structures, the peripheral groups of which can be used to attach several drug molecules, as well as targeting and solubilizing groups. They are therefore prevalently used as drug carrier systems [136]. However, recently poly(amidoamine) PAMAM dendrimers have also been used as skin penetration enhancers [134]. Rigid particles Typical rigid particles are colloidal structures of various shapes and made of various materials such as metals (e.g., gold, silver), metal oxide (e.g., iron oxide) or ceramics (e.g., silica). The encapsulation of drugs in the nanoparticle core or their adsorption on nanoparticle surface allows the transfer and delivery of various substances avoiding drug metabolism and degradation in tissue. Quantum Dots (e.g., CdSe) are new nanocrystalline semi-conductor materials with unique spectroscopic and optical properties [150] making them good candidates for diagnostic and delivery applications [140].
Surface modifications and functionalization Surface functionalization of particles improves particle properties such as surface charge and colloidal stability, bioavailability as well as drug-carrying and targeting abilities. The surface of particles can act after functional ization as a platform for the binding o f ligands such as monoclonal antibodies, thus enabling an active targeting (Fig. 1). Terminal carboxyl groups, along with avidinbiotin or chitosan coating, have already been used to bind functional units. The biotinylation of polymer nanoparticles or liposomes increases drastically the ligand binding capacity or even enables the construction of molecular superstructures [42]. Coating with a second polymer featuring additional functional groups is another approach
[85]. For example, Cruz et al. [28] could achieve targeting of dendrocytes using particles loaded with antibody fragments. The detailed discussion of all the different methods offered by the advances of biomedical engineering exceeds the goals of this review. Nonetheless, modern nanotechnology offers unlimited possibilities of modifying nanoparticles size and surface charge as well as their functional groups. This will allow achieving control over particle penetration depth into the hair follicle canal, the modulation of drug release kinetics and the specific targeting of certain cell populations. Through modification of the particle surface, particle stability against degradation and aggregation can be improved. This is an important feature for all novel drug delivery systems designed to achieve a controlled and constant drug release. Various methods have been developed so far, such as protein coating, covalent linkage to polyethylene glycol (pegylation), coating with stable polymers or manufacture of hybrids, e.g., silica-PLGA particles [85, 95]. Particle surface functionalization (e.g., pegylation) has also been shown to prevent opsonization and subsequent recognition by the macrophages of the reticulo-endothelial system, thus enhancing their bioavailability. Cross linkage or surface coating with a second polymer creates a barrier to the drug diffusion, thus eliminating the effect of burst release and enabling a sustained release over a prolonged time period. Chen et al. and Rancan et al. observed, respectively, a disassembly or a destabilization of PLA particles in lipophilic environments with formation of conglomerates [23, 108]. Coating and adding a protective shell to the particles could enhance their stability and thus deter their destabilization. Particle surface charge can influence both particle penetration within the hair follicle canal and the intracellular uptake. Experiments of Jung et al. [54] demonstrated that cationic liposomes can penetrate deeper into the hair follicles than their anionic counterparts. Positive charge influences cellular uptake since it allows interactions with the negatively charged cell membrane. The in vitro internalization of microparticles is higher for positively charged particles than for negatively charged particles of the same size. Although Foged et al. [39] set 500 nm as the particle size limit for intracellular uptake in vitro, they showed that cationic particles bigger than 500 nm could get internalized as well. On the other hand, a negative surface charge is very important for certain applications of nanoparticles, such as their use as carriers of antigens and as adjuvants in vaccine formulations. For instance, adsorption of HIV-1 p24 capsid peptide on the particle surface is favored for their negative charge [9]. Since the encapsulation of the antigen could cause its partial degradation, adsorption is crucial for the development of novel vaccination strategies [126].
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Health, risk and safety considerations The wide use of nanoparticles in biomedical and cosmetic applications in recent years has raised major concerns about their safety and toxicity, particularly carcinogenicity, and systemic and cellular toxicity. Especially, press reports on the internet or in consumer addressed magazines are currently nurturing a phobic atmosphere in everything concerning the use of nanoparticles, from food and clothes to drugs and cosmetic products. Nevertheless, considering the enormous potential of nanotechnology-related applications and the prospect of mass commercialization in the coming years, a thorough analysis of environmental and toxicological risks of nanoparticles on a scientific basis is required before their wider implementation. Particle-associated toxicity is relevant for both environmental and human exposure to engineered particles. The major concerns about nanoparticles toxicity are related to their dimensions. These are similar to those of biologically active molecules or their subunits and might give nanoparticles the ability to cross biological membranes and interfere with biological processes. Although current discussions focus on nanomaterials, i.e., particles with one dimension below 100 nm, hazardous effects may also occur after exposure to larger particles and agglomerates, where destabilization and disintegration can cause release of smaller fragments and toxic components. For example, recently it has been reported that small amounts of zinc from topically applied zinc oxide particles were absorbed through human skin, although it was not clear whether the detected zinc had been absorbed as ZnO particles or as soluble Zn [43]. Accumulation and prolonged retention of nanoparticles, albeit useful for drug delivery purposes, further increase the risk of particle destabilization or the extent of protein adsorption on particle surface as a result of particle-tissue interactions, with consequent changes of particle surface morphology and charge. In addition, engineered particles may also be contaminated with solvents, side products, organics, endotoxins, etc. Translocation of ambient or incidental nanoparticles through body barriers other than the skin, such as the respiratory tract, and possible systemic consequences have been studied for many years [18]. A large variety of acute and chronic effects including inflammatory reactions, exacerbation of asthma, genotoxicity and carcinogenesis have been attributed to particle inhalation. Besides the chemical composition, particle surface area, particle concentration, charge and surface coatings appear to be major determinants of particle-associated toxicity [142]. In pulmonary toxicity studies, for example, ultrafine particles enhanced inflammatory responses when compared to larger-sized particles of identical chemical composition at equivalent mass concentrations [33, 96]. Particle size may
also be relevant for cardiovascular effects [143]. Cardio vascular toxicity in response to inhaled nanoparticles has been described in animal models and in humans, but in most cases the exact component causing those effects was not identified. Kainthan et al. [55] reported that cationic, but not anionic nanoparticles, including gold and polystyrene particles, may cause hemolysis and blood clotting. Several authors reported that nanoparticles are even capable of crossing the blood-brain barrier. Transsynaptic transport through the olfactory epithelium after inhalation was also suggested as nanoparticle translocation mechanism to the brain. Kreuter et al. proposed uptake via receptor-mediated endocytosis as one possible delivery mechanism. In this case, nanoparticles could mimic lipoproteins [62, 88]. Oxidative stress-related inflammatory reactions have been observed for various types of nanoparticles [8, 32, 60, 76]. On the cellular level, dose-dependent cytotoxicity and oxidative stress-related reactions have already been observed for a number of nanoparticles in different cell culture systems [77, 145]. Considering the large number of newly emerging applications of nanomaterials, further research looking into both particle-associated effects on living organisms and particle alterations as a result of particle-tissue interaction is crucial. The large body of data available from multiple experimental studies using different models and particle types further suggests that risk assessment has to be done for each particle type or nanomaterial of interest. In fact, particle characteristics such as composition, surface modifications and the manufacturing process itself may influence the behavior of these materials in biological tissues. The effects of UV light on TiO2 particles as key component of sunscreen products, for example, was intensively studied and revealed particle-mediated increase in oxygen radicals as well as mutagenic properties [90]. Coating of TiO2 particles, however, resulted in the quenching of the produced radicals and could significantly reduce photocatalysis and eliminate the threat of carcinogenicity [3]. Nevertheless, further studies are required to elucidate the effects of nanoparticles penetration and longterm deposition in the skin with regard to integrity of particle coating and skin biological functions. The insight that in certain conditions nanoparticle translocation might occurs via human skin is rather new and was significantly promoted by our own results [137]. The great potential of these findings for the design of particle-based therapeutic systems is obvious. However, with regard to unintended exposure to nanoparticles in the environment or cosmetic products, the results also underline the importance of further risk assessment, especially in the light of the increasing number of individuals suffering from those skin disorders characterized by a significant reduction of the skin barrier integrity, e.g., eczema.
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Skin penetration properties of partiles and carried drugs As previously discussed, it has been shown that particulate formulations penetrate preferentially into the hair follicle canal but not through the stratum corneum, thus enabling high concentrations within the reservoir of the follicular infundibulum [139]. Hence, the use of nanoparticles as carrier system changes the penetration pathway and kinetics of topically applied substances. The skin penetration of a substance carried on particles is the result of the particles accumulation within the infundibulum, the release of the carried substance within the hair follicle canal and its diffusion gradient. It has been found that the use of nanoparticles as drug delivery systems for topically applied substances significantly increases not only the maximum penetration depth, but also the drug permeation rate. Preliminary experiments of Rolland et al. [112] showed that the use of 5 im adapalene-loaded PLGA particles resulted in the increased permeation of adapalene and a better therapeutic effect. Similar observations were made by Shim et al. [121] with minoxidil-loaded P(CL) 40-130 nm nanoparticles. The increased penetration depth of substances loaded on nanoparticles was demonstrated by Lademann et al. [68] using dye-loaded nanoparticles, confirming previous works of Mordon et al. [86] and Alvarez Roman et al. [5, 6]. Lademann et al. [68] showed that a nanoparticle formulation of a fluorescent dye penetrated deeper than a particle-free formulation of the same dye only when the formulations were applied with a massage. W ithout massage, similar hair follicle penetrations were detected for both formulations. These results were explained with a geared pum p mechanism: the movement of the hairshaft would work as a ratchet pump pushing micro and nanoparticles deeper into the hair follicle canal [68]. There is enough evidence that the size of the applied nanoparticles plays a key role in the penetration depth and the selective targeting of certain compartments within the hair follicle. Toll et al. [129] showed that the penetration depth in terminal hair follicles increases when smaller particles (polystyrene 0.75 im > 1.5 im > 3 im > 6 im ) are used. Similarly, Alvarez Roman et al. [6] demonstrated with animal models that 20-nm polystyrene particles penetrate deeper than polystyrene 200-nm particles. Obviously, there are other mechanisms besides the ratchet pump mechanism that could explain this size-dependent penetration of particles on the nanometer scale. The accumulation of nanoparticles within the hair follicle canal can take advantage of their depot function allowing a sustained drug release over a period of time. Thus, a constant drug level in tissue could be achieved opening the way for topical delivery of active compounds to specific targets within the hair follicle [47, 139]. The
accumulation of particles within the follicular ducts could also be followed by the rapid release of the incorporated drug and its diffusion to the viable epidermis or adjacent target structures such as the sebaceous gland [108]. In certain cases, not only the released drug but the nanoparticles themselves could be able to translocate through the skin barrier and find their way to the viable epidermis. Vogt et al. [137] demonstrated, with experiments on excised human skin pre-treated with cyanoacrylate skin surface stripping (CSSS), that 40-nm PS nanoparticles were able to translocate through the barrier of the follicular infundibulum to the viable epithelium of the hair follicle and to get internalized by LCs, whereas 750- or 1500-nm particles were not. This was the first hint of nanoparticle translocation through the skin barrier and raised toxicological concerns, but also opened new perspectives for the field of transcutaneous vaccination as LCs are potent antigen-presenting cells (APC). However, one important issue is that the nanoparticles were applied on skin surface after barrier disruption with CSSS [138]. Skin barrier disruption may be a necessary precondition since, interestingly enough, previous experiments with nanoparticles of similar or even smaller size showed penetration within the stratum corneum, but no translocation of particles to the deeper layers of the viable epidermis and dermis. Titanium dioxide nanoparticles (17 nm) have been shown to penetrate only in the upper stratum corneum and to accumulate in hair follicles infundibula [70]. This was supported by studies using scanning transmission X-ray microscopy on human skin, showing that topical application of gold particles resulted in the formation of layers of single particles on the skin surface without signs of deeper penetration across the layers of the stratum corneum [41]. Baroli et al. [12] reported on the penetration of rigid metallic nanoparticles smaller than 10 nm through the stratum corneum down to the first layer of the viable epidermis of undamaged skin. Recently, polyvinylpyrrolidone-coated silver NPs (25 7.1 nm) have been detected by means of TEM within SC and in the upper keratinocyte layers [71]. All these findings confirm the need for further toxicological studies prior to wide commercialization of nanoparticlebased drug carriers. Summarizing the previous observations, three different therapeutic strategies taking advantage of the selective follicular penetration of topically applied nanoparticles have currently emerged (Fig. 2): firstly, the use of the follicular infundibulum as a reservoir for the sustained release of therapeutic substances encapsulated in nanoparticles; secondly, the use of hair follicles as a shunt taking advantage of the ability of certain types of particles to accumulate within hair follicle infundibula and release rapidly the loaded drug; thirdly, the use of skin barrier disruption methods or penetration enhancers to favor
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Fig. 2 Nanoparticle-based carrier systems in dermatology. One important feature o f the skin as an organ is the function o f the stratum corneum as a potent barrier. Since there is evidence that vellus and term inal hair follicles can act as a shunt increasing the penetration and absorption of topically applied substances, the selective follicular penetration o f topically applied nanoparticles could significantly reform m odern dermatotherapy offering a variety of innovative therapeutic strategies: a Penetration enhancement by nanoparticles o f the liposome type. After skin contact and follicular penetration the liposomes dissociate, enabling the diffusion o f the released drug with proper physicochem ical properties through the skin barrier o f the hair follicle as well as the interaction with target cell populations o f the follicular epithelium and the dermis or even
systemic targets after absorption and blood circulation. b Use o f drugloaded m icrospheres for hair follicle targeting and treatm ent o f hair follicle and sebaceous gland associated disorders. After topical application, particles accumulate within the hair follicle canal, which acts as a depot for the sustained release o f the incorporated drug, achieving a constant drug level within the hair follicle and the sebaceous gland. c Delivery o f particles across the skin barrier and interaction with cell targets. The translocation o f small nanoparticles after skin barrier disruption into the viable epidermis and dermis followed by the interaction with cell populations such as the antigenpresenting cells o f the follicular epithelium could prove beneficial for new therapeutic strategies, e.g., particle-based transcutaneous vaccination
particle translocation to the viable skin and their interaction with important cell populations. The last strategy could be used to design novel therapeutic procedures in cases where particle-based drug delivery and the particle uptake by certain cell populations could prove to be of advantage. A good example for this is the emerging strategy of particlebased transcutaneous vaccination [137], as later discussed in this review article.
Nanoparticles in dermatology where are we? Applications in prevention, diagnosis and therapy Photoprotection Since sun exposure and UV radiation have been correlated with the increased incidence of epithelial skin cancer and melanoma, sunscreens have become important skin cancer prevention tools. Further, thanks to their protective effect against UV radiation-induced oxidative stress, sunscreens are also important components of cosmetic anti-aging
products. There are currently three different types of photoprotecting methods available: antioxidants, stimulators of repair mechanisms and physical photon blockers [40]. The latter are organic chemical compounds adsorbing UV radiation or particles on the nanoscale such as titanium dioxide (TiO2) and zinc oxide (ZnO) with the ability to scatter, absorb or reflect UV radiation. The wide commercialization of such products aroused major concerns regarding their safety and resulted in extended studies on their penetration properties as well as their photochemical activity on the skin. There is enough evidence that, although nanoparticles can penetrate into the human hair follicle upper regions or the superficial layers of the stratum corneum, they cannot penetrate the barrier of intact skin and reach the viable epidermis [27, 70, 92]. However, UV radiation can weaken this barrier function, as measured by transepidermal water loss, which is believed to result from a disorganization of the intercellular lipid lamellae [53]. In addition, the expression of tight junction related proteins (ZO-1, claudin-1 and occludin) was found to be perturbed following UVB exposure [146]. Based on these
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findings, Mortesten et al. used quantum dot nanoparticles similar in size to particles in sunscreen formulations (30 nm) to simulate the behavior of TiO2 nanoparticles after cutaneous application on UV-exposed skin [87]. Depending on their size and surface chemistry, a penetration into the viable epidermis and dermis has been shown, raising safety concerns. However, the TiO2 particles used in sunscreen formulations are surface-modified by coating with dimethicone or silica to improve their stability and prevent possible photochemical reactions, which otherwise would influence the cellular homeostasis, damage the DNA or impair DNA functions [133, 141]. Nevertheless, there is not enough knowledge about the stability of the coating once the particles have penetrated and accumulated in the viable tissue and this issue should be further addressed. Apart from their direct function as photon blockers, other nanoparticulate structures such as liposomes or SLN have been used in sunscreen formulations as penetration enhancers [34, 144]. They are able to improve not only the stability, but also the tolerance for the active ingredients [4, 98]. Another advantage of the particulate sunscreen formulation is the homogeneity of the distribution on skin surface after topical application. UV filters loaded on microparticle formulations can form a homogenous film on the skin surface and maximize protection. On the contrary, the distribution of substances formulated in O/W cream was shown to be heterogeneous because the lipophilic components distributed predominantly in the hydrophobic regions of the stratum corneum [67]. Earlier studies have already shown that homogeneity of the distribution on skin surface is a necessary precondition for increasing SPF [69]. Nonetheless, particulate formulations remain longer on the skin surface in contrast to non-particulate formulations, which are faster depleted, thus resulting in a prolonged effect of the sunscreen and enabling less frequent application of the sunscreen [67]. Daylong Actinica is a novel liposome-based sunscreen developed for the needs of transplanted and immunocompromised patients. The liposomal formulation enables the application of the sunscreen once daily before sun exposure, thus improving the patients compliance and reducing the risk of epithelial carcinomas of the skin [132]. Barrier creams and cosmetics Since the barrier function of the stratum corneum could prove insufficient in protecting the skin from certain irritants such as chemotherapeutics or allergens, a boost of this function may be required. The same applies to certain pathological conditions where the function of the skin barrier is impaired, such as dermatitis. Emulsions (O/W or W/O) have been used so far to satisfy this need, since they may contain active ingredients that presumably work by
trapping or transforming allergens or irritants [148]. The better homogeneity of substances distribution achieved with the use of particulate formulations, enabling the coverage of the skin with a thin protective film, resulted in new applications of nanoparticles, e.g., nanoparticles loaded with antioxidants that could effectively protect the skin from doxorubicin excreted from the sweat glands [67]. Early studies had already proved that particulate barrier creams are more effective than moisturizers with a high lipid content in protecting the skin from water loss and thus minimizing the potential threat of irritant hand eczema [29]. The better distribution of the solid microparticle formulation on skin surface might have resulted in a better occlusive effect than those achieved using moisturizers. In addition, certain nanoparticles possessing antioxidative properties have been proposed as components of anti-aging cosmetic products. In a clinical trial, a formulation of fullerene (C60) dissolved in squalene has been tested for its anti-wrinkle efficacy [57]. Diverse cosmetic products taking advantage of the use of nanoparticles in galenical formulations to improve the barrier function of the skin are already in the market, e.g., Eczemel cream (DERMAVIDUALS USA) containing nanoparticles loaded with primrose oil and urea. Another example for a nanoparticlebased barrier cream with regenerative properties is Regenerationscreme Intensiv. The list of commercially available products is continuously expanding, indicating the significance of nanoparticles for the cosmetic industry. Leading companies in the cosmetic industry have already launched high and mass market products containing microand nanoparticles. Industry experts see the use of nanotechnology and the incorporation of nanoparticles into skin care formulations as an area of enormous potential for a category that continues to witness some of the largest annual sales growth. Antiseptic properties Antisepsis is another important application of nanoparticles. Chlorhexidin-loaded nanoparticles (Nanochlorex ) have not only an immediate antibacterial effect due to rapid desorption of chlorhexidine from the capsule wall, but a prolonged effect as well, based on sustained release from the particle core [73, 74]. The efficacy of particulate formulations is comparable to that of 2-propanol 60%, thus representing a reliable alternative to alcohol-based hand rubs which exhibit certain drawbacks such as skin dryness after repeated exposure [44, 93]. Other nanoparticles, such as uncoated TiO 2, possess antibacterial properties due to their photocatalytic action. After UV-irradiation, uncoated TiO 2 acts as a photocatalyst and promotes peroxidation of the polyunsaturated phospholipid component of the lipid membrane of prokaryotes such as bacteria [130]. The most
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commercialized nanomaterial with antibacterial properties so far is nanosilver, used not only for the coating of wound and burn dressings, but also as a water disinfectant and room spray as well. Its antibacterial effect is presumably the result of its mitochondrial toxicity due to interaction with thiol groups of internal membrane proteins causing oxidative stress [24]. Many products are already in the market, e.g., Actisorb Silver 220 wound dressing. Laser ablation and phototherapy Short laser pulses have already been used in ophthalmology and dermatology to target melanosomes and thus treat hyperpigmentation disorders of the skin or retinal disorders. To use the same principle for the specific targeting of cell populations that lack endogenous pigments, immunoconjugates of iron oxide microparticles or gold nanoparticles have been tested as light absorbers. Since both particle types can absorb visible light and release part of the absorbed energy in the form of heat, after a laser pulse, high temperatures are achieved resulting in microscopic tissue disruption and cell damage [104]. Photothermal therapy (PTT) with the use of pegylated gold nanorods can inhibit tumor growth in mice with squamous cell carci noma with minimal damage in surrounding tissue, thus making further clinical curative applications feasible [31]. By conjugation of nanoparticles with monoclonal antibodies or numerous other ligands such as hormones, an active targeting of malignant cell populations can be achieved. Previous experiments with various epithelial cell lines have already demonstrated that gold nanoparticles conjugated with anti-EGFR antibodies could kill malignant cells after using half the laser energy required to kill benign cells, thus ensuring the safety of PTT [36]. Recently, hollow gold nanospheres conjugated with melanocyte-stimulating hormone analog were developed to evaluate their potential use for selective photothermal ablation in murine melanoma, promising a wide spectrum of novel therapeutic strategies in the near future [79]. Photodynamic therapy (PDT) has been seen as a promising treatment strategy of skin cancer and various skin diseases, but its use has been limited due to the costs and patient compliance (pain). It is based on the principle of optical activation of a photosensitizing agent and subsequent conversion of local tissue oxygen into various tissue damaging radicals [45]. The use of nanoparticles as passive carriers for photosensitizing substances or as active participants has renewed the interest for PDT applications. Passive carriers enable a sustained release optimizing the therapeutic effect. Furthermore, they counter the side effect of photosensitivity since they can specifically accumulate in the target cells sparing surrounding healthy tissues from the undesirable effects of PDT. The preferential
accumulation of nanoparticles in the target tumor tissue also improves the efficacy of the drug because, at the same dose, a higher photosensitizer concentration in the target cells is reached using NPs than when administrating the photosensitizer alone. Coupling nanoparticles with both a photosensitizer and a tumor-specific antibody can further enhance the selectivity of the carrier system [107]. Certain nanoparticles such as the semiconductive quantum dots (e.g., CdSe) can generate oxygen radicals after photosensitization without the need of photosensitizing molecules and may therefore be used as new active agents for PDT [21]. Recently, evidence has been shown about the efficacy of nanoparticles for combinational treatments, e.g., chemotherapy and PDT. Nanoparticle-mediated combination of chemotherapy and photodynamic therapy using doxorubicin and methylene blue had significant therapeutic effects against drug-resistant tumors. The use of nanoparticles resulted in enhanced tumor accumulation of both the chemotherapeutic substance doxorubicin and the photosensitizer methylene blue, significant inhibition of tumor cell proliferation and increased induction of apoptosis [59]. Treatment of hair diseases Particulate drug delivery systems are gaining importance in the treatment of hair disorders since they increase drug penetration into the hair follicle openings and can act as a depot for a sustained drug release within the hair follicle. Thus, nanoparticle formulations are believed to be more appropriate than the aqueous alcohol solutions used so far for the treatment of hair disorders such as alopecia androgenetica and alopecia areata. Indeed, encapsulating hair-growing ingredients in PLGA particles increased their permeation within hair follicle regions 2.0- to 2.5fold more than in the case of the control aqueous solu tions. Hinokitiol encapsulated in the same particles enhanced the transition of hair follicles from the telogen to anagen phase substantially more than the simple solution of the same substance [131]. Encapsulation of minoxidil in 40-130 nm of poly(s-caprolactone)-blockpolyethylene glycol nanoparticles improved its permeation within the hair follicle region [121]. Taking advantage of the preferential penetration of particle-based drug delivery systems within the hair follicle canal, Jain et al. could demonstrate an enhanced delivery of minoxidil encapsulated in neutral liposomes into pilosebaceous units compared to conventional formulations of the same drug [50]. The other major drug in alopecia androgenetica treatment, finasteride, has also been loaded on liposomes for a more effective localized drug delivery, attempting to replace the oral administration with a topical treatment [64]. Antiandrogens such as RU 58841 myristate encap sulated in solid lipid nanoparticles have also been
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reported to increase penetration and delivery of the active substance [89]. The use of nanoparticulate drug delivery systems could be very helpful for a more successful treatment of alopecia areata, since the treatment of this autoimmune disease of the hair follicle remains a great challenge and its frequent failure can be frustrating for both patients and physicians. The incorporation of immunomodulatory agents in nanoparticles or nanoparticulate delivery systems could allow replacing the oral administration of drugs causing severe adverse side effects with more selective and effective topical treatments. Promising enough, liposomal formulations of cyclosporine A induced visible hair re-growth in rats, thus showing a potential for new topical treatments of alopecia areata in humans as well [137]. Recently, Nakamura et al. demonstrated an effective controlled delivery of small interfering RNA using biodegradable cationized gelatin microspheres in a murine model of disease, resulting in remission of the alopecia areata [91]. Due to lack of other therapeutic options, gene therapy of hair is gaining importance and the last results emphasize the role of novel particle-based drug delivery systems for a promising active follicular targeting of disease-related cell populations in the hair follicle. Sebaceous gland targeting The sebaceous gland is a key component of the pilosebaceous unit. The sebaceous duct opens into the hair follicle canal, i.e., targeting strategies for hair follicleassociated diseases benefit particularly from the follicular penetration of topically applied particles. Early experiments of Schaefer et al. with adapalene-loaded PLGA particles demonstrated already the beneficial role of particulate drug delivery systems for intrafollicular drug delivery and for a more successful treatment of sebaceous gland disorders such as acne or rosacea [112]. These first indications for a specific targeting of the sebaceous gland using biodegradable PLA or PLGA particles were confirmed recently by Rancan et al. [108]. After follicular penetration of the particles, the encapsulated fluorescent dyes were released from PLA particles and selectively stained the sebaceous gland [108]. Recently, Taglietti et al. [125] reviewed the various particulate DDS already used for acne therapy. Interestingly enough, a wide spectrum of nanoproducts with different physicochemical properties, such as liposomes, SLN and polymer nanoparticles, have been shown to increase follicular penetration, achieve higher drug local concentrations and optimize therapeutic effect. Besides adapalene encapsulated in PLGA particles, other retinoids have been tested as well, such as retinol in SLN or tretinoin in liposomes [52, 100]. A major advantage of
such delivery systems is the better tolerability of irritating retinoids improving patient compliance as well as the avoidance of systemic absorption and side effects [106]. Elaborated new encapsulation techniques are currently being developed to improve the therapeutic index of retinoid formulations. Castro et al. showed that the SLNs loaded with all-trans retinoic acid (RA) were significantly less irritating than the marketed RA cream. These new particle-based formulations represent a promising alternative for topical treatment of acne with retinoids [19, 20]. The current research on encapsulating acne drugs into particle-based drug delivery systems is not confined to retinoids. Since Bernard et al. demonstrated that liposomal formulations of the antiandrogen RU-58841 penetrate deeper into the hair follicle canal and target specifically the sebaceous gland, various antiandrogens have been loaded to novel SLN for maximized effect [14, 89]. The extended research in recent years has led to the commercialization of certain particle-based anti-acne products of benzoyl peroxide (BP, such as a BP microsphere cream 5.5% (NeoBenz M icro(R), SkinMedica, Inc.) and a BP microsphere wash 7% (NeoBenz Micro Wash Plus Pack(R), SkinMedica, Inc.). Clinical studies showed high levels of skin tolerability, esthetic attributes and patient satisfaction after treatment with BP-loaded microsphere creams [16]. Topical dermatotherapy Since nanoparticulate DDS had been developed in the first place for controlled drug release, it could be easily postulated that their use would prove beneficial for local therapy of inflammatory skin diseases as well. Glucocorticoids are key drugs in dermatology, but certain side effects such as skin atrophy can limit their chronic use. It has lately been shown that a targeting of the epidermis, where the inflammatory process takes place, instead of the dermis, can be achieved by using liposomal formulations, thus minimizing skin atrophy [113]. The use of podophyllotoxin encapsulated in SLN for the treatment of genital warts had similar effects [22]. Liposomal formulations of T cell inhibitors such as cyclosporine A and tacrolimus have been tested with promising results. Several other studies indicate that various drugs such as methotrexate, psoralen, dithranol, clotrimazole and other antifungal drugs could be incorporated in nanoparticles to achieve a better tolerability, an increased safety and an optimal therapeutic effect [2, 35, 37, 38, 114, 122]. Recently, solid lipid nanoparticles have been designed for the topical delivery of an antifungal agent [51], antiinflammatory drugs [78] and glucocorticoids [118, 149], while silver nanoparticles were tested for the treatment of atopic dermatitis skin [58].
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Cell-targeted drug delivery Gene therapy As previously mentioned, the hair follicle and more precisely the bulge region and the hair matrix accommodate a substantial population of stem cells. Since nanoparticles can penetrate selectively into the hair follicle canal, nanoparticulate formulations could be used for gene delivery, creating new possibilities in the now emerging field of gene therapy. The follicular way would thus constitute a convincing alternative to establishing methods such as gene gun, direct injection and electroporation [99]. Encapsulation in the hydrophilic core of nanoparticles with a lipophilic shell could solve the problem of limited cutaneous delivery of DNA due to its hydrophilic nature. For example, topical gene delivery in mice using gemini surfactant-based nanoparticles provided increased gene expression confirming the theoretical postulations while, as already mentioned, Nakamura et al. reported the effective controlled delivery of small interfering RNA using biodegradable cationized gelatine microspheres in an animal model for the treatment of alopecia areata [10, 91]. More recently, Jacobson et al. [48] used pegylated PLA particles for sustained release of functional siRNA in mouse skin. Targeting o f antigen-presenting cells A great number of vaccines and vaccine carriers have been developed in recent years for the prevention of infectious diseases. Intramuscular administration, the use of live, attenuated, fragmented or dead pathogens and the generation of a potent humoral immunologic response are their common important features. The prevention of chronic infectious diseases with intracellular persistent pathogens or the treatment of various tumors, however, requires a potent cellular immunologic response. Since the use of living or attenuated viruses (e.g., measles and rubella vaccine) for such purposes is not without risk, new approaches are being sought. The dense network of APCs, the dermal DCs and the Langerhans cells (LCs), which are especially accessible in the lower infundibulum of the hair follicle, could be a more appropriate target for vaccination purposes than the scarce population of muscle DCs [139]. Mahe et al. [81] demonstrated recently that 40-nm fluorescent polystyrene nanoparticles, after topical application on murine skin, penetrated into hair follicle openings and translocated into the viable tissue, where they were internalized by skin APCs. W ithin 24 h, nanoparticles migrated to the proximal lymph nodes, m ost likely in association with migrating APCs. These results strengthen the concept of transcutaneous (TC) targeting of skin APCs of the perifollicular tissue and could contribute to the development
of advanced vaccination protocol using nanoparticles as carriers [81]. Since APCs are capable of MHC-I presentation of particulate- and cell-associated antigens, a promising C D 8+ T cell activation can be achieved [138]. As previously discussed, most of the nanoparticle formulations cannot penetrate the intact skin barrier of the stratum corneum, even in the infundibulum of the hair follicle. Hence, various techniques such as cyanoacrylate skin surface stripping (CSSS), chemical enhancers, microneedles, electroporation and ultrasound have been developed [72, 138]. Current research is focused on the use of nanoparticles as vaccine carriers due to their additional adjuvant function. Besides enhancing the immunologic response, they are able to modulate it as well. Due to their particulate nature, they are recognized by the cells of the immune system and promote the uptake of the antigen along with an activation of the immune system [124]. Modification of particle physicochemical properties can help to tailor the immunologic response. It has been shown that nanoparticles provoke a stronger cellular response, whereas microparticles provoke a humoral one [56]. The basic or acid nature of the particles is crucial for immunomodulation due to their impact on the pH of the endosomes [147]. The addition of PAMPs (pathogen associated molecular patterns) promotes their adjuvant function and conjugation with monoclonal antibodies and the targeting of specific cell populations [119, 147]. Currently, only a handful of transdermal vaccines is commercially available, but diverse nanomaterials such as liposomes, ISCOMs, non-degradable particles (e.g., latex, silica, gold, polystyrene) and biodegradable particles like PLA and PLGA are being tested, promising new challenging results in the emerging field of particle-based transcutaneous vaccination [26, 72]. Transdermal drug delivery Several opiates are already commercially available as a patch. The therapeutic effect follows upon transdermal penetration and systemic absorption of the drug. Unfortunately, the strong lipophilic stratum corneum hinders the permeation of hydrophilic molecules and retains high lipophilic drugs, thus limiting the transdermal delivery of strong lipophilic or hydrophilic molecules. Hair follicles could play an important role as a shunt for the systemic absorption of topically applied drugs. Recent studies have drawn interest on nanoparticles as drug carriers for transdermal drug delivery as well. There is evidence that encapsulation of substances in nanoparticles enhances their transdermal penetration and permeation as a result of the follicular targeting, nanoparticles deeper penetration into the hair follicle canal and their depot function for a sustained drug release as previously discussed. Due to the
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nanoparticles small size, close contact to the stratum corneum is insured, thus facilitating drug permeation by enhancing the partition coefficient between carrier and stratum corneum [5]. Nimesulide-loaded nanocarriers delivered the drug transdermally more efficiently than the non-particulate formulation [7]. Shakeel et al. [120] had similar results with nanoemulsions of indomethacin, which enabled the improved transdermal penetration of the carried anti-inflammatory drug. Calcium carbonate (CaCO3) nanoparticles successfully delivered insulin transdermally to diabetic mice resulting in significant decrease in blood glucose [46]. More recently, polymeric nanoparticles and electroporation were successfully used for the transdermal delivery of insulin [109]. Particulate carrier systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carrier (NLC) have been tested for transdermal delivery of nitrendipine (NDP) with promising results [15]. Considering the disadvantages of subcutaneous drug administration, such as discomfort for the patient, hygienic considerations and localized drug reactions, e.g., lipoatrophy and granuloma formation, this could revolutionize future treatment strategies of diabetes and chronic pain leading to a much better patient compliance. The increasing interest in transdermal applications, not only of the scientific community but of the financial world as well, can be clearly perceived in the latest report on the potential of commercial transdermal applications in the decade 2008-2018 issued by the leading market research company Research and M arkets [13]. Nanodiagnostics Various nanoparticles have lately been tested in new diagnostic applications due to certain advantages such as the higher sensitivity of related detection methods, which allow performing analysis on small amounts of tissue samples. Furthermore, a high specificity can be achieved through conjugation with monoclonal antibodies as modification of particle surface prevents aggregation and optimizes the cellular uptake. Gold nanoparticles have already been used for DNA sequencing as they are very good labels, and a variety of analytical techniques, such as optical absorption, fluorescence emission, Raman scattering, and atomic and magnetic force can be used to detect them, providing non-PCR methods for DNA sequencing [49]. Gold nanoparticles have also been used as contrast enhancer in photoacoustic imaging of cancer in a mouse model [94]. The various advantages of quantum dots, such as excitation with simple light sources without the need of lasers, high and stable fluorescence intensity and the availability of red and infrared fluorescence emissions
enabling whole blood analysis have resulted in their experimental use for diverse diagnostic applications, most importantly cancer diagnostics. By using monoclonal antibodies, various tumor markers can be fluorescently labeled with QD allowing visualization of cancer cells [49]. Of particular interest for dermatological oncology is the use of QD for sentinel lymph node imaging. After injection into tumors in mice, they were used to define the sentinel lymph nodes. Using non-specific QD, a labeling of the sentinel lymph nodes could be achieved, while QD conjugated with appropriate ligands could be used for the detection of metastases in the same lymph nodes [11]. Besides cancer diagnostics, QD could be used for the detection of viruses such HPV or RSV. It has already been shown that antibody-conjugated QD detect sensitively RSV [1]. Another group of nanoparticles used for diagnostic applications are those with magnetic properties. Superparamagnetic nanoparticles (2-3 nm) were used for detection of lymph node metastases with magnetic resonance imaging (MRI). Furthermore, monoclonal antibodies conjugated with magnetic nanoparticles can be used to label specific molecules and microorganisms, thus broadening the spectrum of their diagnostic applications [49].
Conclusion Several studies in the past decades have shown that the use of nanoparticles is of great advantage in many dermatological applications. Besides the biological activity of certain nanomaterials, micro- and nanoparticles are widely investigated as carriers or drug delivery systems. Their variable shape, size, functionalization and loading capabilities confer to the carrier-drug system new pharmacological properties such as special internalization routes, selectivity, targeting and delayed clearance. Since nanomaterials represent a great group of structurally, physically and chemically variable substances, specific toxicological studies are required for each product prior to commercialization. Furthermore, a distinctive line has to be drawn between in vitro and in vivo studies, as the results of the first should not necessarily be generalized to predict the consequences of in vivo exposure. Nonetheless, current research is focused on biodegradable nanomaterials, which are thought to constrain toxicological and environmental concerns and increase safety. The wide spectrum of dermatological applications for particle-based formulations could revolutionize the therapeutic and diagnostic strategies of modern dermatology, offering solutions to old challenges but also opening new perspectives for the treatment and prevention of diseases such as cancer and chronic infections.
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Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

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complex polymer nanoparticles

modified complex nanoparticles

G ene Targeting Ligand S pacer

P a ram agn etic S m all M o le c u le s

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

Arch Derm atol Res (2011) 303:533-550

32. 33. 34.

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