Perspectives on percutaneous penetration: Silica nanoparticles.

http://informahealthcare.com/nan ISSN: 1743-5390 (print), 1743-5404 (electronic) Nanotoxicology, Early Online: 1–15 ! 2014 Informa UK Ltd. DOI: 10.3109/17435390.2014.958115

REVIEW ARTICLE

Perspectives on percutaneous penetration: Silica nanoparticles Shohreh Nafisi1, Monika Scha¨fer-Korting2, and Howard I. Maibach1 Department of Dermatology, University of California, San Francisco, CA, USA and 2Institute of Pharmacy, Pharmacology and Toxicology, Freie Universita¨t Berlin, Berlin, Germany

Nanotoxicology Downloaded from informahealthcare.com by Johann Christian Senckenberg on 11/13/14 For personal use only.

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Abstract

Keywords

Nanotechnology is a rapidly expanding area of research involved in developing science-based solutions for innovative therapeutics. Silica nanoparticles (SNPs) have received wide attention in several industries and medicine and are being developed for biomedical and biotechnological applications such as drug delivery, DNA transfection, and targeted molecular imaging of cancer. Recently, they are emerging in the fields of cosmetics and dermal preparations. SNP may offer a revolutionized treatment of several skin diseases by controlled and sustained release of drugs to skin, as well as enhanced skin penetration of encapsulated drug ingredients. SNPs are candidates for transcutaneous vaccination and transdermal gene therapy, too. Yet there exist concerns that whilst the properties of SNPs have enabled numerous industrial and medical applications, their toxicological and environmental safety mandates evaluation. The knowledge of passage of SNPs through skin following skin exposure (intentionally or unintentionally) and subsequent effects is limited. This review surveys the key experiments on SNP-based formulations in the fields of dermatology and cosmetics with the goal of rationalizing data and informing public health concerns related to SNPs’ toxicity among scientists and manufacturers handling them, while highlights the research gaps in dermal absorption of these compounds.

Percutaneous penetration, silica nanoparticles, toxicity

Introduction Nanoparticles are commonly defined 1–100 nm objects or – at least – one dimension being less than 100 nm. The International Organization for Standardization defines the term ‘‘nanomaterial’’ as ‘material with any external dimensions in the nanoscale or having internal structure or surface structure in the nanoscale (EU Commission Recommendation on the definition of nanomaterial, 2011). Other definitions have been proposed. A recent proposal is based on the surface area rather than the size (a nanoparticle should have specific surface area460 m2/cm3), thus reflecting the critical importance of this parameter in governing reactivity and toxicity of nanomaterials (Kreyling et al., 2010). Nanomaterials can be divided into two large groups: ultrafine-nanosized particles not intentionally produced and engineered nanoparticles produced in a controlled, engineered way. Engineered nanoparticles, because of their large surface to-volume ratios, exhibit chemical, physical, and biological properties distinctly different from the same materials in the bulk form, but such properties may lead to adverse effects on human health and environmental systems (Oberdo¨rster et al., 2005). Nanoparticles can enter body through inhalation, absorption through skin or the digestive tract, voluntary injection, or

Correspondence: Howard I. Maibach, Department of Dermatology, 90 Medical Center Way, Surge Building Room 110, University of California, San Francisco, CA 94143-0989, USA. Tel: +1 415 473 9693. Fax: +1 415 673 3533. E-mail: [email protected]

History Received 1 February 2014 Revised 19 August 2014 Accepted 20 August 2014 Published online 1 October 2014

implantation for drug delivery. Skin, the largest organ, is a primary barrier to nanoparticle exposure from naturally occurring and engineered nanomaterials found in the environment and workplace. Thus, the skin may be an unintended route for localized and possibly systemic exposure to nanoparticles released during manufacture, use, and disposal (Labouta & Schneider, 2013; Proksch et al., 2008; Prow et al., 2011). Nanoparticles may induce a spectrum of adverse health effects ranging from localized damage (e.g. irritant contact dermatitis) to induction of immune-mediated responses (e.g. allergic contact dermatitis and pulmonary responses), or systemic toxicity (e.g. neurotoxicity and hepatoxicity) (Poland et al., 2013). Recently, silica nanoparticles (SNPs) have attracted significant interest because of their unique properties such as hydrophilic surface favoring protracted circulation, following i.v. administration, versatile silane chemistry for surface functionalization, ease of large-scale synthesis, and low cost of NP production (Barbe et al., 2004; Slowing et al., 2008). SNPs are widely applied in chemical industry, agriculture, and cosmetics (Willey, 1982). In addition, they are being developed in medical uses including for diagnosis and therapy (Tang & Cheng, 2013; Tang et al., 2012), probes for biomarkers for optical imaging (Lee et al., 2009), controlled release drug delivery as well as gene transfection carriers (Slowing et al., 2008). Such medical approaches have numerous applications including skin cancer therapy (Benezra et al., 2011; De Louise, 2012; Scodeller et al., 2013), transdermal drug delivery (Prausnitz et al., 2012), transcutaneous vaccination, and gene delivery (Bharali et al., 2005). They can act as a carrier for drugs with low solubility and might improve drug safety,

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stability, and performance (De Villiers et al., 2009). With the growing commercialization of SNPs, human exposure to these materials is increasing, and many aspects related to their toxicity should be studied. The main goal of this review is to organize the current state of the art relating to skin absorption of SNPs based on the 10 parameters of percutaneous penetration, while raising awareness of silica nanomaterials’ toxicity among scientists and manufacturers handling them. The importance of such overview stems from percutaneous penetration research tradition dating back to World War II military studies, focused on a one-step penetration model (Tregear, 1966). Such work corrected misconceptions (i.e., skin being largely impermeable); subsequent chemical, in vivo and in vitro experiments document a far more complex penetration model – whose steps may be highly clinically relevant to the nanotoxicity debate.

Silica Silicon dioxide (SiO2), also known as silica, an oxide of silicon with the chemical formula SiO2 is the most commonly element found in nature and is widely distributed in dusts, sands, planetoids, and planets (Georgia State University, Hyperphysics). Silica can be classified into the main two classes: crystalline and amorphous. Different forms of silica and their properties are in Table 1. Crystalline silica Crystalline micron-sized silica is a basic component of soil, sand, granite, and many other minerals (Iier, 1979; Unger, 1979). Silica exposure is a serious threat to workers and has been classified as a human lung carcinogen (OSHA, 2002). Amorphous silica Amorphous silica are synthetic silica except biogenic diatomaceous earth, composed of ultimate particles or structural unit less than 1 mM in diameter. Synthetic and natural amorphous silica are important materials for their variety of technological applications due to their physico-chemical properties such as surface area, pore properties, and bulk density (Iier, 1979; IMA Europe, 2014). Natural amorphous silica Diatoms are microscopic, eukaryotic, unicellular algae ubiquitously present in almost every water habitat on earth. Diatom cell walls are composed of silica; hydrated SiO2 (Iier, 1979; IMA Europe, 2014). Synthetic amorphous silica (SAS) Different synthetic amorphous (noncrystalline) silica particles (Table 1) have large specific geometric surface ratio (Iier, 1979). SAS particles are generally regarded to be safe, with no, or minimal chronic effects. However, increasing use of various forms of noncrystalline silica particles, and in particular the nano-sized, requires more thorough examination of their possible health effects (Choi et al., 2008; Fruijtier-Po¨lloth, 2012). They can be categorized as mesoporous and nonporous based on their biomedical applications (Tang & Cheng, 2013). Pyrogenic or fumed silica. Pyrogenic or fumed silica, an extremely low bulk density powder with a high surface area and synthesized by thermal process, is consisted of amorphous silica particles fused into branched, chainlike, three-dimensional secondary particles and can agglomerate into tertiary particles (Iier, 1979; Willey, 1982). Fumed silica is not listed as a carcinogen by

Nanotoxicology, Early Online: 1–15

OSHA, ECETOC, or NTP (ECETOC, 2006). Due to its fineness and thinness, it can easily become airborne, making it an inhalation risk, capable of causing irritation (Otterstedt & Brandreth, 1998). Precipitated amorphous silica. Precipitated amorphous silica, consisted of a three-dimensional network of coagulated primary silica particles and prepared by wet process, is not classified as dangerous regarding physical and chemical hazards (ECETOC, 2006; Iier, 1979). Silica gel. Silica gel also referred to as silica aerogel or hydrated silica is a white, fluffy powder, or milky suspension of fine amorphous spherical particles in a liquid phase. It is odorless, tasteless, nontoxic, and can be prepared by wet process (ECETOC, 2006; Iier, 1979; IMA Europe, 2014). Nonporous silica nanoparticles. Nonporous SNPs or monodisperse silica spheres (diameters ranging from 50 nm to 2 mm) was firstly prepared by Sto¨ber process (Sto¨ber & Fink, 1968) in which tetraalkoxysilane was added to an excess amount of water containing a low molar-mass alcohol and ammonia. These particles are porous or nonporous. The pores are not some random accidents but an inherent property of them (Van Blaadern et al., 1992; Xia et al., 2000). Synthesis methods based on the type of silicate ester, alcohol, volume ratios, and reaction condition were developed in order to control size, shape, and surface properties (Tang & Cheng, 2013; Xia et al., 2000; Zhang et al., 2003). Biomedical applications of monodispersed silica spheres for therapy and diagnosis are categorized based on the different active cargoes delivered by silica NPs: drug delivery for small molecule drugs, proteins, or photo sensitizers, gene delivery, molecular imaging by incorporating different contrast agents. Nonporous silica NPs can deliver cargos through encapsulation or conjugation (Tang & Cheng, 2013). Mesoporous silica nanoparticles (MSN). MSN characterized by their meso-pores (2–50 nm pore size) are widely used for delivery of active payloads based on the physical or chemical adsorption. They have been synthesized as ordered or hollow/rattle-type mesoporous silica structures. Ordered MSN with uniform pore size and a long-range ordered pore structure were first reported in the early 1990s using surfactants as structure-directing agents (SDAs) (Kresge et al., 1992). Size, morphology, pore size, and structure of MSNs can be rationally designed and the synthesis process can be freely controlled (Garcia-Bennett, 2011; Hoffmann et al., 2006; Tang et al., 2012; Slowing et al., 2010; Wan & Zhao, 2007). With the abundant availability of various surfactants and a deep understanding of sol–gel chemistry, ordered MSNs with different structures as MCM, SBA, MSU, KIT-1, and FSM have been developed. Until now most research on drug delivery and cancer therapy applications of ordered MSNs are based on MCM41, MCM-48, and SBA-15 (Tang et al., 2012). Lack of toxicity of various ordered mesoporous silica has been deduced from both in vivo and in vitro studies (Chen et al., 2013; Garcia-Bennett, 2011; Vallet-Regi et al., 2007). Hollow/Rattle-type mesoporous silica with interstitial hollow space and mesoporous shell have low-density and high specific area, which are ideal as newgeneration drug delivery systems with extraordinarily high loading capacity. Different synthesis methods (by tuning the composition and concentration of surfactants during synthesis) for preparing hollow and rattle type with various sizes and particle morphology have been reported. Surface chemistry plays a key role in the cellular interactions and toxicity (Tang et al., 2012). They have been actively explored for enzyme immobilization,

2.2. Synthetic amorphous (SAS)

2.2.6. Silica host for other NPs

–

–

– 50–2000 nm - Controllable sphere size – 2–50 nm - Controllable pore size, morphology

Different synthesis methods

2.2.4. Nonporous silica nanoparticles 2.2.5. Mesoporous silica nanoparticles (MSN) Different synthesis methods

30–100 nm

Wet process

2.2.3. Silica gel

5–100 nm

Wet process

2.2.2. Precipitated amorphous silica

5–50 nm

-

-

–

– –

– –

– –

Manufacture of glass, abrasives, ceramics, enamels, scouring, castings in molds Filtration agent, abrasive, absorbent, industrial filler

Applications

–

Medical imaging, drug delivery

Counteracts oily or greasy skin feel, raising sun protection, improving storage, stabilize emulsions temperature and stability 30–500 m2/g Rubber and plastics, cleaning, Porous thickening, polishing agent in toothpastes, food processing, pharmaceuticals additive as anticaking, absorbent, antiblocking agent in polymer films 800 m2/g Abrasives in carbonless papers, Porous finning agent and catalysis, desiccant, stationary phase in chromatography, anticaking agent, filter aid, emulsifying agent, viscosity control agent, antisettling agent Masks in lithography, optical Non-porous and porous sensor, drug delivery, gene Controllable surface delivery, molecular imaging properties High surface area Confined-space catalysis, acoustic, (41000 m2/g) thermal and electrical insulation, enzyme immobilization, drug Porous, high pore volume delivery system, cell marker, (0.5–2.5 cm3/g) gene transfection reagents High drug loading Imaging modality, bone tissue capability regeneration

– 50–600 m2/g – Non-porous – Low bulk density

High porosity

0.5–2 mm

Thermal process

9.4 m /g

2

Surface area

0.5–3 mm

Size

2.2.1. Pyrogenic or fumed silica

–

2. Amorphous silica

2.1. Natural amorphous

–

Synthesis method

1. Crystalline silica

Silica forms

Table 1. Different forms of silica, including crystalline silicas, natural amorphous. and synthetic amorphous.


Sto¨ber & Fink (1968), Tang & Cheng (2013), and Xia et al. (2000) Garcia-Bennett (2011), Hoffmann et al. (2006), Lou et al. (2008), Liu et al. (2011), Slowing et al. (2010), Tang et al. (2012), Vallet-Regi et al. (2007), and Wan & Zhao (2007) Piao et al. (2008)

ECETOC (2006), Iier (1979), and IMA Europe (2014)

ECETOC (2006) and Iier (1979)

Iier (1979), Unger (1979) and http://www. crystallinesilica.eu/ Iier (1979), ECETOC (2006), and IMA Europe (2014) ECETOC (2006), Iier (1979), and Willey (1982)

Reference

DOI: 10.3109/17435390.2014.958115

Percutaneous penetration of silica nanoparticles 3

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Figure 1. Simplified representation of skin and routes of penetration.

confined-space catalysis, acoustic, thermal, and electrical insulation (Liu et al., 2011; Lou et al., 2008). Silica host for other nanoparticles. Silica can be used as a host material for other types of functional NPs (e.g. gold NPs, QDs, and iron oxide NPs) to form hybrid NPs. This important class of silica-based hybrid nanomedicines has been thoroughly reviewed by Piao group (Piao et al., 2008). Ultrasmall multimodal SNPs (Cornell dots, C dots) has been FDA approved for the firstin-human clinical trial for targeted diagnostics of advanced melanoma (Benezra et al., 2011; Friedman, 2011).

Percutaneous penetration of silica nanoparticles Skin, a unique barrier composed of several highly organized and heterogeneous layers, also includes a number of appendages such as hair follicles, sweat, and sebaceous glands. It is composed of three layers from outside to inside: epidermis, dermis, and hypodermis. However, from a penetration perspective, epidermis and dermis are most important. The outermost layer of the epidermis is the stratum corneum (SC), to which the main barrier function of the skin is attributed (Bouwstra et al., 2003; Prausnitz et al., 2012). Four pathways of penetration across skin have been identified depending on the physicochemical properties of the compound: intercellular, transcellular, and two transappendageal; through hair follicles and sweat glands (Scheuplein, 1967). Simplified representation of skin and routes of penetration are shown in Figure 1. Percutaneous absorption, a dynamic process, has many components with which a penetrant interacts before possibly gaining systemic access. Accurate assessment of nanoparticle penetration is challenging, with results dependent on 10 parameters of percutaneous penetration: (1) physiochemical properties of nanoparticle; (2) vehicle effects; (3) surface area, dose, duration, and frequency of exposure; (4) distribution; (5) sub-anatomical pathways (skin appendages); (6) skin surface conditions; (7) additional factors of skin penetration and permeation; (8) loss from skin surface, exfoliation, and wash effect; (9) elimination and photochemical transformation; (10) finally the method of determining absorption and toxicity is of high relevance, too. These are issues considered from the perspective of nanoparticles and the potential risks of dermal exposure. Understanding the potential for SNPs dermal penetration and possible toxicological outcomes is of great importance

(Ngo et al., 2012). The following passages overview experiments related to transcutaneously applied SNPs based on the relevant properties which affect percutaneous penetration. Summary of the literature data is in Table 2. Physiochemical properties of silica nanoparticles Physiochemical properties of the penetrant may be the most pervasive factor influencing penetration since they influence interactions with the skin components (cell layers, cell membranes, and lipids) and the extent to which nanoparticles penetrate or release associated ingredients into skin. Physiochemical properties influencing nanoparticle penetration resemble the major factors influencing the penetration of chemicals across skin. It is generally viewed that nanoparticle size, agglomeration/ aggregation state, shape, crystal structure, chemical composition, surface chemistry, surface charge, porosity, dose, exposure time and applied formulation, are major factors which influence nanoparticle dermal penetration and toxicity (Ngo et al., 2012; Poland et al., 2013; Thurn et al., 2007). There exist experiments which relate the physicochemical properties of SNPs to their percutaneous penetration (Table 2). Relationship between different sizes of SNP ranging from 291 ± 9 to 42 ± 3 nm (single unit size) with positive and negative surface charges and skin penetration have recently examined. Despite partial silica particle aggregation occurring after transfer in physiological media, particles were taken up by skin cells in a size-dependent manner and SNPs above 75 nm in size did not penetrate human skin. Functionalization of the particle surface with positively charged groups enhanced in vitro cellular uptake, despite the fact that a large fraction of the positively charged particles were aggregated leading to lower internalization ratios especially by primary skin cells (Rancan et al., 2012). Hair follicles represent important shunt routes into skin for drugs and chemicals (Otberg et al., 2008). In vitro studies of nanoparticles sized from 122 to 1000 nm suggested that particles in the size range of 400–700 nm had optimal penetration depth in porcine hair follicles compared with those smaller or larger. Depending on the nanoparticles size, different depths and thereby different target structures within the hair follicle can be reached (Patzelt et al., 2011). For single silica oxide particles ranging in size from 300 to 1000 nm, follicle penetration depth increased between 300 and 646 nm sized particles, and then decreased for


DOI: 10.3109/17435390.2014.958115

particles larger than 646 nm (Lademann et al., 2009). It can be concluded that the optimal particle size for the deepest penetration corresponds approximately to the rough surface structure of the hair. Having overcome the skin barrier, amorphous SNPs can induce various immunological effects and allergic diseases such as AD as intradermal injection of mite antigen (Dp) plus silica particles (diameter of single units size: 30–1000 nm) into the ear of NC/Nga mice resulted in AD-like skin lesions. DP-induced sensitization and signs of AD were aggravated by SNP in a sizedependent manner compared with that of Dp alone. Clinical signs were correlated with excessive induction of total IgE and Dp specific IgE and were associated with induction of IL-18 and thymic stromal lymphopoietin (TSLP) which led to systemic Th2 response in the skin lesions (Hirai et al., 2012; Takahashi et al., 2013) (Table 2). Park et al. (2013) studied cytotoxicity on keratinocytes and ROS generation by negatively charged NC and weakly negatively charged WNC-SNPs (20 and 100 nm in size). Smaller sized NCSNPs appeared more toxic than the larger sized (100 nm) and NC-SNPs (20 nm) showed more toxicity than the respective WNC-SNPs (20 nm). Skin irritation and contact sensitization were not detected (Park et al., 2013). Compared with larger SNPs (single unit 300 and 1000 nm), the SNPs of 70 nm diameter induced an elevated level of reactive oxygen species (ROS), leading to DNA damage of HaCaT cells, a spontaneously transformed human keratinocyte cell line (Nabeshi et al., 2011a). Proliferation of HaCaT cells was inhibited in a doseand size-dependent manner (Nabeshi et al., 2011b). Viability and mitochondrial membrane potential of human dermal fibroblasts were more strongly affected by SNPs 80 nm in size, but adhesion and migration ability of the fibroblasts were impaired by SNPs, single units being 80 and 500 nm in diameter (Zhang et al., 2010). Moreover, cellular uptake and localization of amorphous SNPs (30, 48, 118, and 535 nm) in mouse keratinocytes (HEL-30) appeared to be independent of particle size. Dose-dependent LDH leakage and significant cytotoxicity at high concentrations (100 mg/mL), however, were seen with exposure to 30 and 48 nm nanoparticles. No LDH leakage was observed for the larger nanoparticles. Redox potential of cells (GSH level) was reduced significantly only with SNP 30 nm in size at concentrations of 50 mg/mL and higher (Yu et al., 2009). Fate of fluorescent nonporous-SiO2 nanoparticles (single unit diameter: 10–200 nm) varying in charge (negative and positive) was studied in normal human dermal fibroblasts. Uptake of SNPs was determined by fluorescence spectroscopy and TEM. Largest particles did not impact on cellular function. Outside and inside the fibroblasts, extensive aggregation was seen with smaller SNPs, either negatively or positively charged. Small SNPs of either charge induced major detrimental effects on fibroblast viability and exposure to negatively charged particles 10 nm in diameter resulted in genotoxic effects. Fluorescence reading revealed that positively charged SNPs (440 nm) were taken as aggregates followed by a significant decrease in the size of the SNPs located in endocytic vesicles and both colloidal and soluble species were released without an impact on cellular function (Quignard et al., 2012). In summary, size and charge of amorphous SNPs are critical for biological effects and particles below 100 nm in size are more toxic (Table 2). In addition, particle surface area may play a crucial role in the toxicity of SNPs which can be related to their surface interfacing with the biological milieu (Elias et al., 2000; Napierska et al., 2010; Waters et al., 2009) and forming a protein corona. Even a minor surface modification can change biological effect, surface functionalization, such as for binding of specific ligands, allows nanoparticle targeting of specific cell populations and subcellular

Percutaneous penetration of silica nanoparticles

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components. Moreover, adsorbed proteins forming the corona can change extent and depth of penetration as well as cytotoxicity (Oberdo¨rster et al., 2005). In order to target M21 melanomas in a xenograft mouse model, multimodal SNPs were coated with bifunctional methoxy-terminated polyethylene glycol (PEG) chains (0.5 kDa; 7 nm). Neutral charged PEG functionalized SNPs were poorly uptaken by noncancer cells, and the bifunctional group enabled attachment of the integrin targeting RGDY peptide labeled with 124I (Benezra et al., 2011). In another study, functionalized mesoporous silica (FMS) with a rigid, uniform, open nanopore geometry of tens of nanometers was used for loading of a monoclonal antibody (mAb) binding to CTLA4- an immunoregulatory molecule overexpressed in melanoma (Leach et al., 1996). Protein spontaneously entrapped in FMS and release of the entrapped proteins from FMS was controlled based on the functional groups and pore sizes. This strategy enhanced inhibition of tumor growth compared with the free antibody given systemically (Lei et al., 2010) (Table 2). Further study is needed to assess the effect of surface modification of nanoparticles on mAb penetration and toxicity following topical use as peptides which are rapidly degraded in human skin by proteinases (Do et al., 2014). Vehicle effects One general approach to overcoming the barrier properties of the skin is to use penetration enhancers or nanoparticles that help to promote drug diffusion through the stratum corneum to viable epidermis and dermis. Dermal absorption of a compound will be influenced by vehicle solubility and partitioning of the compound between vehicle and skin. Agents that are more soluble in an aqueous vehicle may tend towards limited absorption into the lipid-rich SC. Vehicle pH may influence the ionization state of the compound and the rate of partitioning into stratum corneum (Ngo et al., 2012). It also affects colloidal stability and agglomeration status which may alter penetration dynamics. Vehicle-dependent effects on penetration behavior of drugs following topical application have been widely examined (Smith & Maibach, 2006). There is also an increasing understanding of the effects of nanoparticles on penetration enhancement in general (Alnasif et al., 2014; Korting & Scha¨fer-Korting, 2010). Oil-based microemulsions, solvents or surfactants, referred to as penetration enhancers, accelerants, adjuvants, or absorption promoters, act by reducing drug binding and interactions with skin components (Ngo et al., 2012). For silica particles, skin penetration studies showed that silica microparticles (3 mm) could penetrate living epidermis and when formulated in the 65% ethanolic medium, even reached the dermis. This demonstrated the relevance of the vehicle in which silica microparticles were presented (Boonen et al., 2011). Nanoemulsions are oil dispersed in water and have used for penetration enhancement of hydrophilic and lipophilic substances. Nanoemulsions are transparent and their small size and hydrophilic exterior may facilitate transport of active ingredients across the stratum corneum of the epidermis (Nohynek et al., 2007). Eskandar and coworkers investigated SNPs coated submicron oilin-water emulsions for stabilization and skin penetration of lipophilic agents, retinol and a fluorescent dye, namely acridine orange 10-nonyl bromide. Lecitin and oleylamine addition, respectively, was used for the induction of negative and positive charge to the emulsion. Both formulations improved retinol resistance towards UV-induced degradation, controlled release, and significantly enhanced the penetration of both agents into excised porcine skin compared with free agent used for control. With the positive charged formulation, penetration was even seen in the upper dermis without major penetration of the agents


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(Ghouchi-Eskandar et al., 2009a,b). Moreover, solid state nanoparticle-coated emulsion prepared by freeze-drying significantly enhanced retinol stability (Ghouchi-Eskandar et al., 2012) (Table 2). Flavonoids such as quercetin and rutin are used in topical cosmetic and pharmaceutical products because of antioxidant and radical scavenging properties, but its use is limited by its poor physico-chemical stability. In human volunteers, addition of colloidal silica (average particle diameter: 486 nm) to an emulsion significantly increased the quercetin penetration into stratum corneum to 26.7 ± 4.1% of the applied dose, the enhancement being more marked in the deep stratum corneum sampled by tape stripping. Silica particles were detectable in the intermediate region of human stratum corneum and hence could act as a carrier for quercetin (Scalia et al., 2013). Mesoporous silica (MCM-41) has widely been proposed as a vehicle able to improve the penetration and performance of drugs. Complexes of quercetin with plain or octyl-functionalized MCM-41 was formed based on the host/guest interaction due to the formation of Si–OH/quercetin hydrogen-bonded adducts, and strengthened by octyl functionalization. Immobilization of quercetin, particularly on octylfunctionalized silica, increased stability without undermining the antioxidant efficacy of quercetin opening the way for an innovative employment of mesoporous composite materials in the skincare field and topical products (Berlier et al., 2013a). Moreover, immobilization of rutin in the pores of in aminopropyl silica (NH2–MCM-41) stabilized the agent against UV degradation and enhanced the accumulation in porcine skin ex vivo while maintaining rutin0 s antioxidant properties (Berlier et al., 2013b). Octyl methoxycinnamate is an efficient and widely used UV filter, yet shows light susceptibility (photoinstability) and potential skin permeation which is not wanted with sunscreen products. For improvement of photostability and safety, octyl methoxycinnamate was entrapped in the pores of the mesoporous silicate MCM-41, pore openings were plugged and the loaded nanoparticles incorporated into a lipid-based cosmetic formulation allowed a broader photoprotection range and remarkable improvement of sunscreen photostability (Ambrogi et al., 2013). In addition, inclusion of Trolox (a water soluble analog of vitamin E) in the MCM-41 matrix, retarded in vitro release and increased photostability for complexed agent particularly in O/W emulsion. Importantly, the radical scavenging activity of Trolox was maintained after immobilization (Gastaldi et al., 2012) (Table 2). Recently, hyaluronidase (degrading enzyme of hyaluronic acid) was immobilized on 250 nm SNP as adjuvants of carboplatin (CP), peritumorally injected in A375 human melanoma bearing mice. Enzyme activity was maintained, SNP-immobilized hyaluronidase cleaved hyaluronic acid over-expressed by the tumor cells and tumor volume was significantly more declined compared with nonimmobilized Hyal used for comparison (Scodeller et al., 2013) (Table 2). In cases where skin penetration is not desired, penetration reducers can inhibit the compound from entering the systemic circulation (Trommer & Neubert, 2006). Barrier-enhancing emulsions have reduced the penetration of exogenous proteins into the hair follicles to varying degrees (Meinke et al., 2011). Caffeine loading to a silica nanocomposite resulting in the formulation of both core–shell and multilayered caffeine–silica structures, reduced and delayed caffeine permeation of pig skin in comparison with the reference gel, independently from the amount of the tested formulation (Pilloni et al., 2013) (Table 2). Surface area, dose, duration, and frequency of exposure Following skin contact, the amount of chemical absorbed, which is often expressed as dose per area (cm2), depends greatly on


several conditions of exposure (Ngo et al., 2012). Increasing surface area over which a chemical is in contact will increase absorption. Percent absorption also depends upon the concentration and dose applied per unit area. For many compounds, percent absorption at relatively high concentrations is inversely related to applied dose (Wester et al., 1980). In other words, percent absorbed increases as skin loading decreases, and the function is nonlinear. This is attributed to saturation of the absorptive skin capacity. Despite a decrease in efficiency of absorption, in terms of percent absorption, a continued increase in total penetration, in mass, can be observed with increased dose. Similarly, with multiple applications and frequency of exposures, skin may become saturated and resist penetration from subsequent doses (Wester et al., 1977, 1980). Moreover, dermal penetration tends to increase with the duration of contact or exposure and compounds retained in the skin layers may become released available after the contact material had been removed from skin surface. Experimental protocols often set periods of exposure and sample collection that may not be relevant. It is often necessary to extrapolate long-term exposure from short-term data. In general, the total absorption of a compound appears to be linearly correlated with the amount of penetration into the stratum corneum observed shortly after application (Rougier et al., 1987). While many studies investigate dermal absorption of a compound following a single dose, multiple or repeated exposures are more clinically relevant to real life (Ngo et al., 2012). Synthetic amorphous SiO2 nanoparticles have been widely used in a glass cleaner formulation (spray application). Workers and consumers are frequently exposed to it during production and using as spray application. Percutaneous penetration of SiO2 is unlikely as the hydrophilic character of uncoated SiO2 does not favor skin penetration (Michel et al., 2013) (Table 2). Engineered nanomaterials are incorporated into textile products; nanotextiles, include nanosilica, nano-layered silica, nano-silver, nano-TiO2, nanoZnO, nano-alumina (Al2O3), carbonblack, and carbon nanotubes (Som et al., 2011). These nanomaterials are used to improve textile properties such as wrinkle resistance, water repellency, antimicrobial and antistatic properties, and UV- and flammability resistance. Since there is continuous and intimate contact between clothing and skin, transfer and absorption of nanomaterials under these conditions should be considered (Ngo et al., 2012). Distribution Once stratum corneum has been breached, interactions with the deeper components of the permeability barrier and finally access to the vascular system and thus systemic availability will again depend on the physiochemical properties of the penetrant in question (Menczel & Maibach, 1970). Perfusion of the dermis promotes absorption and creates a sink for chemicals that have traversed the epidermis. Subsequent distribution of a chemical to target sites or organs within the body will also depend on the blood flow. By reducing the local blood flow, such as with the use of a vasoconstrictor, systemic absorption can be inhibited. At the same time, drug penetration into deeper tissue layers adjacent to the application site may be enhanced by reduced blood flow (Higaki et al., 2005). Local and systemic toxicities following dermal absorption of drugs or chemicals across skin have been widely evaluated (Alikhan & Maibach, 2011). Proposed toxic effects of nanoparticles entering the systemic circulation include perturbation of the immune system, as well as other organ systems. Once more, size and surface physico-chemical properties of SNPs contribute decisively to their biological effects. Following 3 days of topical application to mouse, SNPs (70 nm in size) were observed in keratinocyte layer including Langerhans cells, dermis,

DOI: 10.3109/17435390.2014.958115

and lymph node (Tsunoda, 2011). Application of SNP (single unit size) to the ears of mice (250 mg/ear/d) for 28 days resulted in particles being detected in skin, regional lymph nodes, parenchymal hepatocytes present in liver, cerebral cortex, and hippocampus (Nabeshi et al., 2011b) (Table 2). Yet analysis was based on the murine skin and TEM analysis with no confirmation that the electron dense regions were, in fact, particles of interest. More experimental data – including those generated in the human skin – are needed to confirm the results.


Sub-anatomical pathways (skin appendages) Although the Stratum Corneum plays a critical role in the function of permeability barrier, there are many components with which a penetrant interacts before entering the body. In recent years, it has been suggested that skin appendages represent important shunt routes into skin for drugs and chemicals. Skin appendages include hair follicles, sebaceous glands, and sweat gland, which originate in the dermis (Ngo et al., 2012; Poland et al., 2013). Particle size influences the penetration depth, with different follicle structures interacting with particles of particular size (Patzelt et al., 2011; Toll et al., 2004; Vogt et al., 2006). For silica oxide particles ranging in size from 300 to 1000 nm, follicle penetration depth increased up to about 650 nm sized particles, and then decreased for larger particles. It can be suggested that the optimal particle size for the deepest penetration corresponded approximately to the structure of hair and follicles (Lademann et al., 2009) (Table 2). Skin surface condition Surface conditions including hydration, occlusion, pH, and temperature are the factors which affect skin absorption (Ngo et al., 2010). The degree of interactions with the different skin components determines the time and the chemical residues persist or accumulate in skin as well as the time required to traverse the different layers and enter the systemic circulation (Jacobi et al., 2007; Lademann et al., 2006). Importantly, structure and integrity of skin will be compromised by damage or disease. Chemical or physical skin insults may cause change in skin’s barrier function, resulting in the increased permeability of numerous compounds (Ngo et al., 2010). However, a recent study on the penetration of N-(6aminohexyl)-aminopropyltrimetoxysilane nanoparticles (55 ± 6 nm diameter) on intact, tape stripped or on inflamed skin of SKH1 mice with induced allergic contact dermatitis showed no penetration of the rigid particles through the skin regardless of the kind of barrier disruption. After subcutaneous injection, however, the nanoparticles were incorporated by macrophages and transported to the regional lymph node, adverse effects were not detected (Ostrowski et al., in press). Additional factors of skin penetration and permeation The extent of dermal absorption varies from one body region to another and partially attributed to skin thickness and the number of cell layers in the SC (Ngo et al., 2010). Besides regional variation, population variability may be of relevance. Variability in skin properties reported for different groups in human population provide a potential basis for differences in the rate and extent of drug absorption between the various skin types (Mangelsdorf et al., 2006). Loss from skin surface, exfoliation, and wash effect Persistence of a chemical on skin will depend on its resistance to removal or inactivation which depends on the mechanisms of removal of nanoparticles from the skin surface including;


7

volatilization, sweating, washing, friction with or transfer to other surfaces, and exfoliation (Ngo et al., 2010). Washing influences the absorption of nanoparticles into skin. Washing and rubbing an area of substances treated skin can remove part of the dose. Washing the application site between doses, a common step in experimental protocols of dermal absorption studies may enhance percutaneous absorption (Ngo et al., 2010). Elimination and photochemical transformation Skin is capable of a wide range of metabolic functions and is recognized as a significant site of biotransformation and photochemical transformation. Cutaneous metabolism and photochemical transformation play essential role in the absorption of compounds by transforming them into metabolites (Ba¨tz et al., 2013; Go¨tz et al., 2012; Ja¨ckh et al., 2011; Ngo et al., 2010). Depending on the compound, elimination may or may not be in proportion to the dose absorbed (Marzulli & Maibach, 1975; Nigg & Stamper, 1989). Method of determining absorption and toxicity When evaluating dermal data, differences in experimental parameters such as animal species, anatomical site, skin sample preparation, skin disease presence, role of penetration enhancers, and exposure conditions affect the interpretation and comparisons between studies. It is important to control experimental condition in a systematic way (Ngo et al., 2012). Only recently, a predictive mathematical approach has been described which allows to take formulation effects into consideration, too (Guth et al., 2014). Yet applicability for nanoparticlebased formulations requires evaluation. For SNPs, present experimental data focus on physiochemical properties; vehicle effects; surface area, dose, duration, frequency of exposure; distribution and sub-anatomical pathways. Information regarding physicochemical properties of SNPs are not sufficient to draw a robust conclusion for their skin penetration, vehicle effects need more study, the experiments on dose relationships, exposure duration, surface area, frequency and sub-anatomical pathways are minimal and no information exists on the other parameters. More experimental data are needed to understand factors which affect the percutaneous penetration of SNPs. Research gaps in percutaneous penetration of SNPs are given in Tables 2 and 3.

Skin absorption and toxicity of silica nanoparticles Penetration of a material through skin barrier can trigger numerous toxic effects, both local and systemic. Compounds that reach the stratum granulosum, for example, can interact with the viable keratinocytes, and trigger an inflammatory reaction. Compounds that reach the stratum spinosum can interact with Langerhans cells (from the immune system) and initiate an allergic reaction responsible for phenomenon such as contact dermatitis. Skin cancer may also be induced following dermal exposure depending on the chemical and its ability to penetrate skin and reach the viable layers, where it can potentially transform normal cells or enhance proliferation of transformed cells. All these effects can be grouped as dermal toxicity. However, when a compound manages to cross the epidermis, it becomes accessible to dermis and potentially accessible to the systemic circulatory and lymphatic systems. As a result such compounds can damage in distal organs, by translocation through the circulatory system or by triggering systemic reactions. These can lead to a wide range of toxic effects and disease such as systemic inflammation, organ toxicity, and cancer (Crosera et al., 2009; IARC, 1997; Napierska et al., 2010; Poland et al., 2013). Toxicity of NPs can depend on

Physico-chemical properties of penetrant

Park et al. (2013)

Nabeshi et al. (2011a)

Rancan et al. (2012)

-

- SNPs (70 nm); elevated level of ROS, DNA damage - Endocytosis involved in SNP70-mediated cellular effects

- Positively charged functionalization of SNP enhanced in vitro cellular uptake - Particles taken up by skin cells in a size-dependent manner - SNP (42 ± 3 nm) found in epidermal and dendritic cells - SNP (475 nm) penetration blocked by human skin

- All SNP sizes were taken up into the cell, localized into the cytoplasm - SNPs 30, 48 nm (100 mg/mL), more toxic than 118, 535 nm particles - ROS formation did not show any significant change between the controls and the exposed cells - LDH leakage was dose-, size-dependent with exposure to 30, 48 nm SNPs - No LDH leakage for either 118 or 535 nm SNPs

In vitro: - Human keratinocyte line HaCaT - Intercellular ROS - EpiDerm skin irritation on human skin equivalent model - 3T3 NRU phototoxicity test in murine 3T3 fibroblast cell In vivo: mouse; local lymph node (LLNA) In vitro: - LDH release assay - Human keratinocyte line HaCaT

In vitro: human keratinocyte line HaCaT, dendritic cells In vivo: cyanoacrylate skin surface stripping (CSSS)

In vitro: mouse keratinocytes HEL-30 - LDH release assay

In vitro: normal human dermal fibroblasts

SNPs (20, 100 nm); negatively charged (NC), weakly negatively charged (WNC) - Cytotoxicity - ROS generation - Skin irritation - Skin phototoxicity - Skin sensitization

SNPs (70, 300, 1000 nm) Zeta potentials: SNP-70, 21.6 ± 4.5 mV SNP-300, 31.3 ± 6.5 mV SNP-1000, 37.7 ± 4.6 mV - ROS generation; DNA damage

SNPs (42 ± 3 to 291 ± 9 nm); positive and negative surface charges Zeta potentials: SNP-42, 22 ± 3 mV SNP-75, 45 ± 4 mV SNP-200, 56 ± 5 mV SNP-300, 48 ± 2 mV - Cellular uptake - Skin penetration

SNPs (30, 48, 118, 535 nm) - Cellular uptake, localization - ROS formation - Cytotoxicity

Fluorescent non-porous-SiO2 (10–200 nm); different charges Zeta potentials: SNP-40, 56 ± 5 mV SNP-200, 50 ± 4 mV SNP- +10, 42 ± 4 mV SNP- 10, 18 ± 4 mV - Cytotoxicity - Genotoxicity

(continued )

Quignard et al. (2012)

S. Nafisi et al.

- Smallest particles; high, fast cytotoxicity - Genotoxic effects for negatively-charged colloids (10 nm)

Yu et al. (2009)

Park et al. (2010)

SNPs (7, 10–20 nm) reduced cell viabilities of CHKs in a dose-dependent manner - No irritation (SNP; 500 mg/ml) - No acute cutaneous irritation

In vitro: - Human keratinocyte line HaCaT - Human skin equivalent model (HSEM) In vivo: rabbit; Draize test

SNPs (7, 10–20 nm) - Cytotoxic effect - Acute cutaneous toxicity - Skin irritation NC-SNP (20 nm), more toxic than NC-SNP (100 nm) NC-SNP (20 nm) more toxic than WNC-SNP (20 nm) No irritation No phototoxicity No sensitization

Author (year)

Results

Study type

Research question

Table 2. Summary of literature data on physicochemistry, toxicity, and percutaneous penetration of silica nanoparticles (SNPs).


8 Nanotoxicology, Early Online: 1–15

Vehicle effect

Lei et al. (2010)

Boonen et al. (2011)

-

- More antitumor activity of FMS-Anti-CTLA4 than that of anti-CTL4 alone - No toxicity

- SNP (3 mm) penetrated living epidermis - By formulating in 65% ethanolic medium, reached dermis - Increased skin retention and depth of penetration to upper dermis for all- trans-retinol-AONB .

- Sustained release, targeted dermal delivery of alltrans-retinol from oil-in-water emulsions - Increased diffusion down to stratum corneum - Increased efficiency of quercetin encapsulated by MCM-41

In vivo: mouse, M21 melanomas xenograft mouse

In vivo: mouse established melanomas derived from s.c. injection of cells from the SW1 clone

Ex vivo: percutaneous absorption human skin

Ex vivo: percutaneous absorption porcine skin

Ex vivo: percutaneous absorption porcine skin In vivo: percutaneous absorption human skin; tape stripping In vitro: DPPH assay

SNP coated with bifunctional methoxyterminated and PEG (7 nm) - Effect on tumor

Functionalized mesoporous silica (FMS, 30 nm) bound to monoclonal antibody (mAb) to CTLA4 - Antitumor activity - Release kinetics

Dermal delivery of silica micro particles (3 mm) in water and in 65% ethanolic Spilanthes extract - Skin penetration

Dermal delivery of lipophilic fluorescent probe: all-trans-retinol-acridine orange 10-nonyl bromide (AONB) using SNP coating of negatively charged lecithin & positively charged oleylamin

Dermal delivery of all-trans-retinol by SNP-coated submicron oil-in-water emulsions

Dermal delivery of quercetin using lipid nanoparticles and colloidal silica

Dermal delivery of quercetin using MCM-41 (plain or octyl-functionalized)

(continued )

Berlier et al. (2013a)

Scalia et al. (2013)

Ghouchi-Eskandar et al. (2009b)

Ghouchi-Eskandar et al. (2009a)

Benezra et al. (2011)

Hirai et al. (2012) and Takahashi et al. (2013)

- SNP (different sizes) penetrated skin barrier, induced various immunological effects, allergic diseases; AD - By decreasing SNP size, IL-18 and TSLP production increased, led to systemic Th2 response, aggravation of AD-like skin lesions as induced by Dp antigen treatment

In vivo: mouse - Ear thickness measurements - Histopathological analysis

SNPs (30, 70, 100, 300, 1000 nm) Zeta potentials: SNP-30, 14.0 ± 0.3 mV SNP-70, 19.5 ± 1.0 mV SNP-100, 24.3 ± 0.5 mV SNP-300, 25.8 ± 0.7 mV SNP-1000, 33.2 ± 1.4 mV - Skin penetration - Skin allergic disease Specific tumor targeting High-affinity/avidity binding Favorable tumor-to-blood residence time ratios Enhanced tumor-selective Longer-term pharmacokinetic clearance

Zhang et al. (2010)

- SNP (80 nm) more strongly affect cell viability, mitochondrial membrane potential - Both particles internalized into fibroblasts within a short time - Cell adhesion, migration affected by uptake of SNPs regardless of size

In vitro: normal human dermal fibroblasts

Monodisperse SNPs (80, 500 nm) Zeta potentials: SNP-80, 5.2 ± 0.2 mV SNP-500, 9.8 ± 1.2 mV in culture medium with 10% FBS - Cytotoxicity, cellular uptake

Author (year)

Results

Study type

Research question


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Percutaneous penetration of silica nanoparticles 9

Gastaldi et al. (2012)

Michel et al. (2013)

Nabeshi et al. (2011b)

- Slower release of Trolox by inclusion in MCM-41 - Increased photostability for complex particularly in O/ W emulsion - Maintained radical scavenging activity of Trolox - Increased release rate in emulgel - Broader photoprotection range, improvement of sunscreen photostability

- Enhanced tumor volume reduction with SNP-Hyal compared to nonimmobilized Hyal - Reduced, delayed permeation

- Skin penetration was unlikely - Low toxicity - No systemic exposure - Mutagenic activity in vitro - SNPS (70 nm) penetrated stratum corneum, entered skin, lymph nodes, liver, cerebral cortex, and hippocampus

- SNPS (70 nm) observed in keratinocyte layer, Langerhans cells, and dermis of mouse - After 3 d, SNP detected in cervical lymph node cells - Best follicle penetration of SNP 646 nm in size - Optimal particle size corresponded to structure of hair and follicles

In vitro: - Release - DPPH assay In vitro: release

In vivo: mouse bearing A375 human melanoma Ex vivo: percutaneous absorption pig skin

- Modeling of consumer exposure - Modeling of environmental exposure

In vitro: - Human keratinocyte line HaCaT - DNA damage (Comet assay) - Mutagenicity assay (Ames test) In vivo: mice BALB/c

In vivo: mouse

In vitro: human terminal and vellus hairs from Caucasian males, Porcine hair follicle

Dermal delivery of Trolox using MCM-41 - Photodegradation - Antiradical activity

Dermal delivery of octyl methoxycinnamate (OMC) using MCM-41 formulated in emulgel - Release - Photostability

Hyaluronidase (Hyal) immobilized on SNP as adjuvants of carboplatin (CP) - Antitumor

Dermal delivery of caffeine using silica nanocomposites - Skin permeation studies

Skin penetration of consumers exposed to spray atmosphere of SAS nanoparticles

SNPs (70, 300, 1000 nm) Zeta potentials: SNP-70, 21.6 ± 4.5 mV SNP-300, 31.3 ± 6.5 mV SNP-1000, 37.7 ± 4.6 mV - Cellular localization - Cytotoxicity - Skin penetration - Systemic effects

SNP (70 nm) - Skin penetration - Systemic effect

Silica oxide (300–1000 nm) - Influence of hair cuticula thickness on penetration into hair follicles

Surface area, dose, duration, and frequency of exposure

Distribution

(continued )

Lademann et al. (2009)

Tsunoda (2011)

Pilloni et al. (2013)

Scodeller et al. (2013)

S. Nafisi et al.

Sub-anatomical pathways (skin appendages)

Berlier et al. (2013b)

- Greater accumulation in porcine skin - Maintained antioxidant properties - Better activity and photostability

In vitro: DPPH assay Ex vivo: percutaneous absorption porcine skin

Dermal delivery of rutin using NH2MCM-41 - Diffusion - Antiradical activity - UV irradiation - Skin permeation

Ambrogi et al. (2013)

Author (year)

Results

Study type

Research question

Table 2. Continued


10 Nanotoxicology, Early Online: 1–15


No research

No research

No research

Additional factors of skin penetration and permeation Loss from skin surface, exfoliation and wash effect Elimination and photochemical transformation Method of determining absorption and toxicity

No research

- Penetration of AHAPS-SiO2 through skin was not observed - After subcutaneous injection, AHAPS-SiO2 were incorporated by macrophages, SNP transported to regional lymph node - No adverse effects on cells, tissues In vivo: SKH1 mouse AHAPS-SiO2 (55 ± 6 nm) - Skin penetration on intact skin, tape stripped, inflamed skin - Subcutaneous injection

Ostrowski et al. (in press)

Results Study type Research question

Skin surface conditions


Author (year)

DOI: 10.3109/17435390.2014.958115

11

not only the material itself but also on the administration route to the living body. In particular, intraperitoneal and intravenous injection may lead to fatal outcomes (Hudson et al., 2008). It is important to evaluate safety of nanoparticles using specific toxicological studies prior to a wider implementation. General toxicological principles of compounds are discussed by Hayes (Hayes & Kruger, 2014). Regulatory aspects of exposure to toxic substances are specified by Wilhelm (Wilhelm et al., 2012). There remains need to increase the predictability of current nanoparticles toxicity testing by transitioning from qualitative, descriptive animal testing to quantitative, mechanistic, and pathway-based toxicity testing in human cells or cell lines using high-throughput approaches. Standard methods and platform should be used to investigate the numerous biophysicochemical interactions at the nano/bio interface (Nel et al., 2013). Classical investigation protocols must be adapted and re-standardized to the new nanosized compounds. Cell cultures (Bernstein & Vaughan, 1999), Franz diffusion cells (Franz, 1975), tape stripping (Escobar-Cha´vez et al., 2008), human skin implantations on animals, are powerful tools to study particle interaction with human dermal tissue. However, new methods and new technique applications have to be developed (Monteiro-Riviere & Inman, 2006; SCCP, 2007). In particular, microscopy techniques like Coherent anti-Stokes Raman Scattering (CARS), Transmission Electron Microscopy (TEM), Confocal Laser Scanning Microscope (CLSM), Fluorescence Lifetime Imaging Microscopy (FLIM), Near-Infrared II Fluorescence, and other ion beam techniques are necessary to visualize nanoparticles into biologic structures (Alnasif et al., 2014; Moger et al., 2008; Welsher et al., 2011). Because SNPs are widely used nanomaterials, chances of being exposed to SNPs in daily life are high. There are major concerns about the biocompatibility, toxicity, in vivo biodistribution, and efficacy of SNPs of various particle sizes. While some data reports that silica particles are biocompatible, nontoxic, and stable (Butz, 2009; ECETOC, 2006; Fruijtier-Po¨lloth, 2012; Gamer et al., 2006; Low et al., 2009; Mavon et al., 2007; Michel et al., 2013; OECD, 2004; Pfluecker et al., 2001; Rosenholm et al., 2011), others show that the uptake of nanoparticles by cells may eventually lead to perturbation of cellular pathways and induce toxicity (Hirai et al., 2012; Nabeshi et al., 2011a,b; Park et al., 2010, 2013; Quignard et al., 2012; Takahashi et al., 2013; Yu et al., 2009). Toxicity of silica NPs depends strongly on their physicochemical properties such as particle size, shape, porosity, chemical purity, and solubility (Waters et al., 2009; Yu et al., 2011, 2012). Particle surface area plays a crucial role in the toxicity of silica (Elias et al., 2000; Zhang et al., 2010) which can be related to their surface interfacing with the biological milieu rather than to particle size or shape (Fenoglio et al., 2000). In vivo toxicology data associated with the nanoparticles have led to persistent and valid safety concerns prompting particle-design modifications including size, composition, and surface chemistry (Schipper et al., 2009) and need for rapid clearance from the body within a reasonable timescale (Choi et al., 2010).

Conclusions Loading to SNPs can improve physicochemical stability of labile drugs and to adjust the release profile and skin penetration. Yet, the results of this literature survey show that the data related to toxicity of SNPs are few and is insufficient to clearly identify and characterize the health hazards SNPs may pose, and defining the appropriate conditions for safe use of these materials is currently not possible. Accurate assessment of nanoparticles penetration depends on 10 parameters of percutaneous penetration. For SNPs,

12

S. Nafisi et al.

Table 3. Research gaps nanoparticles (SNPs).


in

percutaneous

10 Factors affecting percutaneous penetration of nanoparticles (Ngo et al., 2012) 1 2 3 4 5 6 7


8 9 10

Physiochemical properties of the nanoparticle Vehicle effects Surface area, dose, duration, and frequency of exposure Distribution Sub-anatomical pathways (skin appendages) Skin surface conditions Additional factors of skin penetration and permeation Loss from skin surface, exfoliation and wash effect Elimination and photochemical transformation Method of determining absorption and toxicity

penetration

of

silica

Researches on silica nanoparticles (SNPs) + + Minimal research Minimal research Minimal research Minimal research No research No research No research No research

experimental data are focused on six parameters and there are no data on the other parameters (Tables 2 and 3). Moreover, only results from short-term in vivo studies of SNPs are available while data following chronic dermal are still to be awaited. In addition, relationships among SNPs, physicochemical properties, absorbency, localization, and biological responses, are not well understood. Besides relative lack of information on the safety or hazards of SNPs, often conflicting evidence is emerging in the literature as a result of a general lack of standard procedures, as well as insufficient characterization of silica nanomaterials in biological systems. Information is insufficient to clearly identify and characterize the health hazards SNPs may pose, and defining the appropriate conditions for safe use of these materials is currently not possible. There are gaps in understanding human and environmental risk that manufactured SNPs may pose for those occupational exposed and for consumers. There is need for assessing the health and environmental impacts, the nanoparticles life cycle, the human exposure routes, the behavior of nanoparticles in the body, and the risk for workers. In particular, dermal absorption and skin penetration of nanoparticles need an evaluation by most advanced analytical techniques. Understanding the behavior of NPs when they contact the skin surface and their interaction with the different skin layers would ultimately lead to the design of the ‘‘ideal’’ carrier or diagnostic agent in terms of the physicochemical parameters of the NPs, in addition to other factors (e.g. formulation and environmental factors) influencing skin penetration of NPs.

Declaration of interest The authors report that they have no conflicts of interest. Financial support of the German Research Foundation (SFB 1112, Project C02) is gratefully acknowledged.

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Shaving effects on percutaneous penetration: clinical implications.

Percutaneous penetration--methodological considerations.

Biology of percutaneous penetration.

Percutaneous penetration of indomethacin.

In vivo penetration of bare and lipid-coated silica nanoparticles across the human stratum corneum.

Continuous polymer nanocoating on silica nanoparticles.

Cooperative transmembrane penetration of nanoparticles.

The percutaneous penetration of nandrolone decanoate.

A reversible light-operated nanovalve on mesoporous silica nanoparticles.

Topography-driven bionano-interactions on colloidal silica nanoparticles.

Oxime ligation on the surface of mesoporous silica nanoparticles.

Silica Nanoparticles Effects on Blood Coagulation Proteins and Platelets.

Solid silica nanoparticles: applications in molecular imaging.

Clotting activity of polyphosphate-functionalized silica nanoparticles.

Toxicology of silica nanoparticles: an update.

Reducing ZnO nanoparticles toxicity through silica coating.

Cisplatin-functionalized silica nanoparticles for cancer chemotherapy.

Nucleation and growth of monodisperse silica nanoparticles.

Native silica nanoparticles are powerful membrane disruptors.

Polymer Nanoparticles.

Metrics and clinical relevance of percutaneous penetration and lateral spreading.

A Possible Percutaneous Penetration Pathway That Should Be Considered.

Progress and perspectives on targeting nanoparticles for brain drug delivery.

Percutaneous Endoscopic Gastrostomy in Children: Caregivers' Perspectives.