Nanopreparations for skin cancer therapy

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Nanopreparations for skin cancer therapy

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Patrı´cia Mazureki Campos1, Maria Vito´ria Lopes Badra Bentley1 and Vladimir P. Torchilin2,3 1

School of Pharmaceutical Sciences of Ribeira˜o Preto, University of Sa˜o Paulo, Ribeira˜o Preto, Sa˜o Paulo, Brazil 2Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA 3Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

1.1 INTRODUCTION Skin cancer is divided into melanoma and non-melanoma cancers, with non-melanoma skin cancer (NMSC) subdivided into basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (Eisemann et al., 2014). Despite NMSC not being reported in cancer registries, its incidence is estimated at 2 3 million cases per year, according to the World Health Organization (2011). Most of the NMSC cases can be treated, however, melanoma cancer represents less than 2% of all skin cancer cases, but accounts for the highest number of skin cancer deaths, with increasing incidence rates over the last year (American Cancer Society, 2014). The prevalence of skin cancer is higher in people of European descent and those who live in equatorial latitudes, compared to people of Asian, African, and Hispanic descent (Agbai et al., 2014). In addition, NMSC is the most diagnosed cancer for white people worldwide, with BCC being four times more common than SCC (Chummun and McLean, 2014). However, there are reports of increasing morbidity and mortality in minority populations (Hu et al., 2009; Agbai et al., 2014). This increase in skin cancer leads to issues related to awareness of and the main causes correlated with this type of cancer. The risk factors for skin cancer, in general, are as follows: exacerbated exposure to ultraviolet (UV) radiation; photoaging; sun sensitivity; Fitzpatrick skin type, defined as people with difficulty tanning, natural blond or red hair color; and conditions that suppress the immunologic system. However, the main risk factors for melanoma are family or personal histories and presence of atypical nevi (Lomas et al., 2012; Federman et al., 2013; American Cancer Society, 2014).

Nanobiomaterials in Cancer Therapy. DOI: http://dx.doi.org/10.1016/B978-0-323-42863-7.00001-3 © 2016 Elsevier Inc. All rights reserved.

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Skin cancer is a public health problem because it is the most common worldwide malignancy and encompasses the entire population, including all socioeconomic and demographic cohorts, covering the entire lifespan (Lomas et al., 2012; Gordon, 2013). Therefore, the primary preventative care recommendation is photoprotection by wearing clothes that cover the skin against solar exposure and using sunscreens in adequate amounts on skin to decrease incidence (Federman et al., 2013).

1.2 SKIN MORPHOLOGY The skin is the largest and outermost organ of the body and exerts a vital role in maintaining homeostasis. This task is performed by a network of cells that interact among themselves. The skin protects the body from microorganisms, chemical and toxic products, as well as from the surrounding environment (Lai-Cheong and McGrath, 2009; Mathes et al., 2014). The barrier function of the skin is, in particular, played by the stratum corneum, the uppermost layer of the epidermis, which is composed of dead, cornified (protein-rich) cells within a matrix of intercellular lipids (Karadzovska et al., 2013). This layer is formed during epidermis turnover from cells that begin at the basal layer, differentiate, and end at the stratum corneum in a flattened appearance (Mathes et al., 2014). Moreover, by its constitution, the stratum corneum reduces water loss from the body (Lai-Cheong and McGrath, 2009). In general, the skin is divided into three layers: epidermis, dermis, and hypodermis. The epidermis is a stratified squamous epithelium formed by keratinocytes that originate at the basal layer by mitosis of epidermal stem cells, where there are also melanocytes. These cells migrate to the spinous layer forming polyhedral cells connected by desmosomes. Langerhans cells (responsible for immune response) are found in this same layer. Keratinocytes appear with intracellular granules of keratohyalin (future keratin), constituting the granular layer. Finally, the cells, now called corneocytes, pass through nuclei and cytoplasm loss, wherein keratin filaments align between intercellular lipids as ceramides and fatty acids, forming the stratum corneum (Lai-Cheong and McGrath, 2009; Venus et al., 2010). Melanocytes are dendritic cells derived from the neural crest that migrate during embryogenesis to the basal layer of the epidermis. These cells synthesize melanin inside melanosomes and transfer to neighboring keratinocytes (Park et al., 2008). Melanin is a pigment that protects the skin against ultraviolet radiation and its effects, it is scattered on the perinuclear area forming caps, which prevent DNA damage (Slominski et al., 2004). Langerhans cells are resident immune cells inside the skin; they constitute the first barrier for invading pathogens and act as sentinels. When activated in

1.3 Types of Cancer

response to inflammatory cytokines produced by keratinocytes, they traffic toward the draining lymph nodes, where T-cell activation occurs, where T cells become memory T cells with expression of surface markers allowing skin accumulation. In addition, Langerhans cells can participate in allergic processes (Callard and Harper, 2007; Hieronymus et al., 2014). The dermis is under the epidermis, provides elasticity and resilience to the skin, and interfaces through the dermal epidermal junction, a region with an intricate network of proteins and glycoproteins that provides adhesion. The dermis is subdivided into papillary and reticular layers, composed of: collagen and elastic fibers, ground substance (proteoglycan macromolecules), and cells, including fibroblasts, mast cells, plasma cells, dermal dendritic cells, and histiocytes. Inside the dermis there are blood vessels, lymphatic channels, and sensory nerves, as well as sweat glands (eccrine and apocrine), which are responsible for thermoregulatory sweating and excretion of other fluids. The hair follicle is an invagination of the epidermis toward the dermis with dermal papilla on its base, richly vascularized and enervated, associated with a sebaceous gland (Lai-Cheong and McGrath, 2009). The hypodermis, composed of fatty tissue surrounded by dermis tissue, stores fat, makes the body thermoregulate, and absorbs physical shock (Mathes et al., 2014).

1.3 TYPES OF CANCER The origin of skin cancer is multifactorial, but the main etiological factor is ultraviolet radiation. Skin cancer incidence increases with aging, a consequence of cumulative solar exposure (Gordon, 2013). Ultraviolet exposure is related to both melanoma and NMSC, including BCC and SCC, because ultraviolet radiation causes DNA damage, gene mutations, immunosuppression, oxidative stress, and inflammatory responses, all of which are causes directly linked to skin cancer genesis (Narayanan et al., 2010; Kim and He, 2014). UVB and UVC radiation are associated with sunburn and carcinogenesis, UVA also induces sunburn and intensifies UVB effects, but is less mutagenic. However, both UVB and UVA may promote tumor genesis by selective immunosuppression (Robinson-Bostom and McDonald, 2002). The development of skin cancer originates with premalignant lesions such as actinic keratosis, also called solar keratosis, which appears mainly in skin regions exposed to sun, and are characterized by small, raised, scaly erythematous spots surrounded by telangiectasia, hyperpigmentation, and yellow areas of discoloration (Figure 1.1a). Another sign is Bowen’s disease (Figure 1.1b), known as SCC in situ, which is preponderant in women and often appears on the legs, distinguished by welldemarcated scaly and erythematous plaques. In addition, Bowen’s disease can emerge in the mucous membrane and, potentially, progress to invasive SCC (RobinsonBostom and McDonald, 2002; Gordon, 2013; Chummun and McLean, 2014).

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FIGURE 1.1 Examples of premaligant lesions: actinic keratosis (a) defined papules with adherent scale on dorsal hand; Bowen’s disease (b) well-demarcated erythematous plaque; lentigo maligna (c) lesion with superficial spreading and irregular color/borders near eyebrow. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

Likewise, another type of premalignant lesion is lentigo maligna (Figure 1.1c), which is characterized by abnormal melanocytes restricted to the epidermis. It occurs in sun-exposed areas and may advance to lentigo maligna melanoma (Gordon, 2013; Chummun and McLean, 2014). For patients with early detection of these premalignant lesions, it is possible to start topical treatment with substances such as retinoids, 5-fluorouracil, imiquimod, and ingenol mebutate, to prevent the development to carcinoma of these lesions with complete clearance and a good cosmetic effect (Amini et al., 2010; Micali et al., 2014).

1.4 NON-MELANOMA SKIN CANCER BCC is the most common skin cancer in the Caucasian population. It accounts for 80 85% of NMSC and rarely metastasizes to other organs. However, SCC accounts for 15 20% and easily invades other tissues with higher mortality (Simoes et al., 2015). BCC (Figure 1.2a) is a malignant tumor of germinative cells in the basal layer of the epidermis and/or the root sheaths of the outer hair follicle. These tumors grow aggressively causing wide damage, but do not spread to distant areas. The main risk is cumulative UVB radiation (280 320 nm), which penetrates to the epidermis and provokes direct damage to DNA and RNA, inducing covalent bonds between pyrimidines, generating photoproducts (Madan et al., 2010; Kolk et al., 2014). If this DNA damage is not repaired, it can lead to a genome mutation, contributing to skin carcinogenesis. In order to maintain genome stability, the cells have repair mechanisms, such as nucleotide excision repair, and are critically involved in recruiting photoproducts (Kim and He, 2014). BCC is often found on the nose, ears, face, shoulders, and back. The following are subtypes of BCC: nodular lesions with necrotic centers; superficial BCC as pink patches; sclerosing BCC as yellowish plaques; and pigmented BCC as

1.4 Non-Melanoma Skin Cancer

FIGURE 1.2 Examples of NMSC lesions: (a) –BCC with nodulocystic lesion showing telangiectasia and ulceration on the top cheek; (b) –SCC with lesion presenting infiltration to connective and subcutaneous tissues near lower lip. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

dark lesions (Lacy and Alwan, 2013). In fact, BCC is a typical primary efflorescence in papula form with telangiectasia that is slow-growing. Further, at advanced stages, ulceration and erosion are observed, with tumor growth potentially reaching cartilaginous and bone tissues (Kolk et al., 2014). SCC (Figure 1.2b) is the second most common skin cancer in Caucasians, appearing in sun-exposed areas, and the most common neoplasm in non-white people, appearing in sun-protected areas subjected to frequent external trauma (Robinson-Bostom and McDonald, 2002). It is a malignant proliferation of squamous cells—epidermal keratinocytes with a high potential of metastasis to lymph nodes and other organs (Ogden and Telfer, 2009). The main factor is UV radiation that produces mutations in the p53 tumor suppressor gene, which functions as a tumor suppressor by inducing apoptosis of cells that have DNA damage, the kind of alteration that is recurrent in SCC (Robinson-Bostom and McDonald, 2002). SCC lesions emerge in areas with long-term UV exposure. In general, these lesions are predisposed to actinic keratosis (irregular arrangement of epidermis from atypical cells) or immunosuppressed status, but also arise from other etiologic factors such as chronic inflammation or degenerative influences. Lesions possess a tumor width larger than 2 cm and depth greater than 6 mm and exhibit infiltration to connective and subcutaneous tissues, positive margins, high mitotic activity, and ulceration (Kolk et al., 2014; Mavropoulos et al., 2014). When a complete invasion of epidermis occurs, this constitutes an intraepithelial carcinoma or transitional epithelium, which are considered in situ carcinomas (Kolk et al., 2014). According to the World Health Organization, SCC can be classified into spindle-cell SCC (aggressive behavior), adenoid (pseudoglandular) SCC, verrucous carcinoma (favorable diagnosis), keratinizing SCC, basosquamous SCC, and lymphoepithelioma-like carcinoma (Heenan et al., 1996). The choice of SCC tumor removal depends on multiple factors including size and site of the lesion, clinical and histological type, and treatment costs (National Collaborating Centre for Cancer, 2010).

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Despite UV radiation being the principal risk factor associated with NMSC, there are other related factors, such as human papillomavirus, iatrogenic immunosuppression, HIV/AIDS, non-Hodgkin lymphoma, photosensitizing drugs (e.g., fluoroquinolone antibiotics), and occupational factors (Madan et al., 2010). The management of NMSC must consider surgical and non-surgical options focusing on complete tumor removal, producing a cure, being as minimally invasive as possible and maintaining an aesthetic result. Excisional surgery has been employed for the excision of NMSC in an outpatient procedure with the aim of complete tumor removal, which offers shorter healing, in addition to histologic examination of tissue. Moreover, other techniques including curettage, electrodesiccation, and Mohs micrographic surgery provide detailed microscopic visualization of tissue removed with guaranteed tumor clearance. However, when a wide area is affected, by potential disfigurement and functional impairment, non-surgical options could be used (Madan et al., 2010; Chummun and McLean, 2014; Parikh et al., 2014). If an early NMSC diagnosis is made based on patient and tumor characteristics, it is possible to regard destructive treatment options in monotherapy or conjugated therapies such as topical modalities, photodynamic therapy, cryosurgery, and radiotherapy. Among the non-surgical options, the topical therapy is convenient, offers good cosmesis with less chance of scarring and the possibility of treating large areas. One example of a topical therapy approved by the US Food and Drug Administration (FDA) for NMSC is the immunomodulating agent imiquimod 5%. However, it is necessary to have patient compliance and to consider costs for long-term treatment and be aware of producing false-negative margins, which impairs the efficacy of surgery excision (Galiczynski and Vidimos, 2011; Lazareth, 2013).

1.5 MELANOMA SKIN CANCER Among melanoma subtypes, melanoma skin cancer (MSC) is the most prevalent, accounting for approximately 90% of cases, occupying 19th position for cancer worldwide (Ali et al., 2013) and it could be considered the most dangerous form of skin cancer. The incidence of MSC has been increasing in lighter-skinned people, but pigmented people are usually diagnosed in advanced stages, which contributes to the high mortality rate associated with MSC (Stubblefield and Kelly, 2014). Notably, the total incidence is higher in elderly white women (Ingraffea, 2013). If melanoma is detected early surgical removal can provide a cure (Shackleton and Quintana, 2010). Several etiological factors are associated with MSC development, including environmental and genetic factors. Skin pigmentation is a decisive factor that influences the appearance of malignant changes, and interactions between genetic and environmental factors bring different rates of incidence (Ali et al., 2013).

1.5 Melanoma Skin Cancer

FIGURE 1.3 Examples of MSC lesions: (a) Papule occupied by accumulation of proliferative melanocytes present in the back; (b) lesion near the ear indicating asymmetry and irregular color. Courtesy of dermatologist Dr. Aguinaldo Bonalumi Filho.

The patterns of sun exposure govern the site origin of lesions in the head, neck, or extremity, which are related to chronic exposure and, at the same time, period UV exposure, with truncal lesions (Ingraffea, 2013). The transition of normal melanocytes to melanoma cells involves several steps, which modify the processes of cell proliferation, differentiation, and death, until the progressive genetic mutations result in the carcinogenic effects of UV radiation. Furthermore, high nevus counts present in sun-protected areas subject to intermittent UV radiation can develop into MSC (Mandala and Voit, 2013). The MSC morphology (Figure 1.3) appears as patches, plaques, nodules, and pigmented tumors, but scarcely as a polypoidal with a stalk (Plotnick et al., 1990; Cockerell, 2012). In general, MSC lesions have a diameter greater than 6 mm; however, smaller lesions could be diagnosed, which arise on sun-exposed skin (Cockerell, 2012). The prognosis is defined by histological characteristics such as tumor thickness; lesions smaller than 1 mm have a good prognosis, with 10-year survival, dropping to 54% survival for larger than 4 mm. Furthermore, epithelial ulcerations in the initial examination should be considered a worse prognosis (Balch et al., 2001; Green et al., 2012). Additional features such as high mitotic rate, tumor vascularity, and lymphovascular invasion contribute to the increased risk of metastasis (Ali et al., 2013). There are four types of MSC: (i) superficial spreading, which indicates that the tumor is flat, slow-growing, with irregular borders and pigmentation, enlarging in radial directions, and occurring in areas of intermittent sun exposure; (ii) nodular, which indicates that the tumor enlarges as a nodule that may ulcerate and hemorrhage and can present on any area; (iii) lentigo maligna, present on chronic sun-exposed areas of the head, neck, and forearms, with large macules with variegated pigmentation and irregular borders; and (iv) acral lentiginous, indicating areas with variegated pigmentation that are very slow-growing and usually appear on the palms and soles (Scolyer et al., 2011; Ingraffea, 2013). Molecular characteristics are, in part, related to the frequency of BRAF or NARS and KIT mutations and based on the pattern of UV exposure. BRAF mutations

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often appear in intermittent UV exposure and KIT mutations in chronic or unexposed skin (Mandala and Voit, 2013). Most MSCs have activated mutations on BRAF or NARS proto-oncogenes; these oncogenic modifications may serve as targets to improve therapy (Broekaert et al., 2010). BRAF mutations located on the kinase domain promote an increase in kinase activity and substitution of valine to glutamate in the glycine-rich loop, but reports suggest that this isolated mutation is insufficient and other genetic mutations are necessary to induce the entire transformation of melanocytes (Mandala and Voit, 2013). Regarding the impact of the BRAF mutation on MSC, data indicate that this mutation emerges in young people without cumulative UV exposure, but for people with no mutations, high doses of UV radiation are required for MSC to occur (Curtin et al., 2005; Bauer et al., 2011). Overall, the management of the BRAF mutation is a turning point for controlling the spread of disease (Mandala and Voit, 2013), and for those who do not carry a known mutation for understanding the growth and metastasis of MSC, research efforts should be made to improve disease therapy (Shackleton and Quintana, 2010). Currently, there is no topical treatment approved by the FDA for MSC, and the recommendation is excisional surgery associated with systemic immunotherapy, Yervoy® (Ipilimumab), or oral tablets of Zelboraf® (Vemurafenib) (Zhang et al., 2013).

1.6 PENETRATION PATHWAYS OF SKIN The skin is a selective and effective membrane of the body that protects from chemical penetration. This barrier function is fulfilled by the stratum corneum, which is considered a rate-limiting pass to permeate therapeutic agents applied on the skin. The stratum corneum can be expressed as a two-compartment model, represented by corneocytes, keratin-filled cells, embedded into a lipid matrix, composed of ceramides with nine subtypes, cholesterol, and free fatty acids. The architecture of stratum corneum provides great diffusional resistance, which is important in establishing a steady-state drug flux to promote drug entry (Michniak-Kohn et al., 2005; Barry, 2006). This compartmental model, which constitutes a tortuous way, was proposed by Elias (1983). When a substance is at the skin surface (Figure 1.4), there are four options for entry to reach the viable epidermis, which are as follows: (i) via hair follicles, which are associated with sebaceous glands; (ii) via intracellular mechanisms; (iii) via intercellular mechanisms; and (iv) through eccrine sweat ducts (not shown in Figure 1.4). The “easy” way to enter the skin would be follicular, but this pathway occupies only 0.1% of total superficial area. By the density of appendageal area, however, it works as a shunt in the short term; previously, steady-state diffusion, for ions and polar molecules, also for targeting of polymers and colloidal particles (Michniak-Kohn et al., 2005; Barry, 2006).

1.6 Penetration Pathways of Skin

FIGURE 1.4 Scheme of penetration pathways through the skin: intracellular, intercellular and follicular. The upper right inset is a close-up of the stratum corneum showing the intracellular pathway and the tortuous intercellular pathway. Reprinted from Current Opinion in Colloid & Interface Science, vol. 17/issue 3, Bolzinger, M.A., Brianc¸on, S., Pelletier, J., Chevalier, Y. Penetration of drugs through skin, a complex rate-controlling membrane, p. 10, Copyright (2012), with permission from Elsevier.

The skin offers an alternative pathway for allowing topical application of a sustained drug delivery system into the blood circulation, decreasing the side effects of conventional administrations (oral and parenteral). In addition, developing and optimizing drug entry through loading into topical products has been a good strategy because it is possible to offer more efficacy for delivery in and through the skin by this route (Lademann et al., 2009; Bolzinger et al., 2012). In designing therapeutic products for use through the skin, it should be recalled that, first, the stratum corneum displays barrier properties (lipid domain, as a gelphase membrane with complex arrangement). Second, the viable epidermis is predominantly a hydrophilic layer (70% water). Thus, hydrophilic drugs permeate into the skin through the intracellular pathway, inside the stratum corneum, infiltrating among several sheets of corneocytes (through lipid head group regions), unlike hydrophobic drugs, which may easily enter the stratum corneum (through lipid tails), forming a reservoir due to the aqueous domain of the subsequent layer. In other words, there is a relationship between the skin constitution and the

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physicochemical properties of a drug including the following: (i) molar mass (MW) related to the diffusion coefficient; (ii) number of hydrogen bonds established in the route; and (iii) octanol water partition coefficient (log Ko/w), which reveals the stratum corneum/water partition. Further, passive diffusion through the skin is accomplished by the concentration gradient of substances, after a sequence of interactions with the keratin of corneocytes and lipid partitions (Guy and Hadgraft, 1985; Naik et al., 2000; Liu et al., 2011). It is possible to calculate drug permeability by calculating the permeability coefficient (log kP) based on the Potts Guy relationship log kP (cm/h) 5 22.7 1 0.71 log Ko/w 2 0.0061 MW (Potts and Guy, 1992). In addition, another theoretical aspect, but no less important, is drug permeation across the stratum corneum driven by the equation J 5 (Dm. Cv. P)/L described by Fick’s law, where J is the flux, Dm is the diffusion coefficient of the drug in the membrane, Cv is the drug concentration in the vehicle, P is the partition coefficient, and L is the stratum corneum thickness. Therefore, through this equation, it is possible to identify ways to change the drug flux, which can be altered by using chemical penetration enhancers contained in the formulation, influencing the Dm, or by using nanocarriers with high drug concentrations that will modify Cv (Barry, 2006). Drug transport across the skin implies diffusion inside the intercellular region through interspersing the lipids surrounded by the corneocytes. The intercellular pathway is considered important for drug entry inside the skin (Prausnitz and Langer, 2008). In order to increase the skin permeability and increase the thermodynamic activity of the drug, different methods have been used, such as, drug delivery systems (nanotechnology-based systems), stratum corneum modification (chemical enhancers—fatty acids, alcohols, and surfactants), and electrically assisted methods (ultrasound, iontophoresis, electroporation) (Alvarez-Roman et al., 2004; Barry, 2006; Polat et al., 2011; Prow et al., 2011; Tomoda et al., 2011). Recent experiments have demonstrated that the follicular pathway works as an efficient long-term reservoir for topical products. In addition, the development of drug delivery systems has focused on this, by considering it as a target along with its morphologic characteristics, allowing for access to blood circulation and/or deep skin layers (Lademann et al., 2009). Other studies have shown that appendages are important for small molecules, because the flux measured was three times lower where the appendages were absent, compared to normal skin (Illel et al., 1991). After penetration through the main barrier, the stratum corneum, the molecule encounters another environment, less restrictive for passive diffusion, but which can also provide a different mechanism of transport such as binding and sequestration, active transport, and metabolism. In addition, through the epidermal dermal junction, the dermis is accessed, which is enhanced through vascularization and the lymphatic system, with significant drug transport and distribution in the skin, both facilitating drug clearance (Jepps et al., 2013).

1.7 Drug Delivery Systems Applied to Skin Cancer Treatment

Nanocarriers are interesting tools for skin drug delivery, particularly for liposomes, polymeric and lipid nanoparticles, because they can form a film on the skin and provoke occlusion effects, producing local drug delivery to the epidermis and dermis and systemic action by deep penetration (Bolzinger et al., 2011). Another issue is the interaction between the nanoparticles and stratum corneum and, consequently, lipid disruption and nanocarrier integrity, as observed with lipophilic carriers. Moreover, particle stiffness alters skin permeability, establishing that rigid particles, such as polymeric and lipid nanoparticles, do not infiltrate intact skin, but that deformable particles, such as transfersomes and ethosomes, can pass through the interspaces of the stratum corneum (Bolzinger et al., 2012). Considering that particles in the size of hundreds of nanometers can penetrate deeper into hair follicles and persist for 10 days, much longer when considering the stratum corneum and isolated substances, if massage is applied, they are a good option for topical skin therapy (Lademann et al., 2007). Overall, nanocarriers can locate the drug within the hair follicle, where the drug is released and can penetrate independently. For example, nanoparticles 40 nm in diameter were found inside Langerhans cells in an excised human skin model (Lademann et al., 2011). In the same way, nanocarriers can be used as chemical enhancers by increasing the drug solubility and partitioning into the skin (Prausnitz and Langer, 2008). Several researches have used normal skin, but little attention has been paid to absorption in damaged skin. Diseases that modify skin integrity, such as the stratum corneum in wounds and inflammation, or disturbed epidermal cell differentiation in NMSC, can lead to damaged skin. The permeation profiles of nanoparticles in damaged skin models have been created to mimic these pathological conditions as stripped human skin ex vivo, removal of stratum corneum as disruption of a physical barrier (Alnasif et al., 2014) and a three-dimensional human SCC construct model, which includes hyperkeratosis and epidermal atrophy with less functional barrier (Obrigkeit et al., 2009). Within this method, higher permeation of Nile red loaded into a flexible nanocarrier was observed for stripped skin compared to normal skin, and in 6 h, the stripped skin already presented increased nanocarriers into viable skin layers, an effect that was more pronounced after 24 h. This was not observed for normal skin, thus showing that disrupted skin exhibits less of a barrier. The same situation was encountered for normal and SCC construct models, more Nile red was delivered to diseased skin (Alnasif et al., 2014).

1.7 DRUG DELIVERY SYSTEMS APPLIED TO SKIN CANCER TREATMENT Nano-sized drug delivery systems have huge potential for the treatment of cancer cells because they are able to deliver drugs into tumors by the enhanced

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permeability and retention (EPR) effect that results from high permeability of tumor vasculature (Torchilin, 2011). In search of selective cancer treatment, using local features of tumor is a specific way of using abnormalities in favor of anticancer target therapy based on nano-sized systems (Greish, 2010). In this context, specific binding to target cancer cells or utilizing the tumor microenvironment characteristics open new opportunities to improve the efficacy of cancer treatment, decreasing the harm done to healthy cells (Allen and Cullis, 2004; Tiwari et al., 2012). Numerous factors stimulate the utilization of nanomedicine for drug delivery, such as increased drug solubility, modulating drug release, protecting drugs against degradation, avoiding premature metabolism, cooperating with biodistribution, and reduced side effects. In addition, nanoparticles applied to cancer therapy can alter limitations that are frequently common for chemotherapeutic agents, such as lack of specificity and high toxicity, which generates pronounced side effects (Dı´az and Vivas-Mejia, 2013). Nanocarriers are defined as a system that loads drugs incorporated into organic or inorganic matrixes with a size of 10 1000 nm. They can have different shapes, surface charge, functionality, and stability, as well as several in vivo applications. Recently, theranostic particles have been developed, which encapsulate drugs/imaging agents, allowing both treatment and monitoring of the cancer, as well as stimuliresponsible carriers, which are sensitive to physical and chemical stimuli releasing the drug (Lim et al., 2013b). There are several possibilities for building a specific and multifunctional nanocarrier, considering the characteristics of the pathology, action site and carrier systems, some of these options are presented in Figure 1.5.

FIGURE 1.5 Representation of multifunctional nanocarrier where drugs A and B can be loaded into a liposome or micelle showing several possibilities for improving the selectivity and efficacy of the system. PEG, poly(ethylene glycol). Reprinted from Nature Reviews Drug Discovery, vol. 13/issue 11, Torchilin, V.P., Multifunctional, stimulisensitive nanoparticulate systems for drug delivery, p. 14, Copyright (2014), with permission from Elsevier.

1.8 Liposomes

A good rational design for drug delivery focused on skin cancer therapy should involve tumor targeting because cancer cells express particular features that can be useful; for example, differences in the expression pattern of receptors between normal and cancer cells, which become a custom drug delivery system (Torchilin, 2014). One example of this would be to use receptors involved in NMSC, such as the ErbB family of receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR), HER2, HER3, HER4, which, structurally, have a conserved cytoplasmic catalytic domain, a hydrophobic transmembrane domain, and a glycosylated extracellular ligand-binding domain. These receptors participate in the tumorigenesis, contributing to their overexpression (Salomon et al., 1995; Kra¨hn et al., 2001). Therefore, the construction of a drug delivery system based on receptor overexpression is possible if a specific binder (e.g., monoclonal antibody, peptide) is present on the nanocarrier as a surface modification and attaches to target tissue or cells, thus demonstrating the concept of active targeting (Sawant and Torchilin, 2012; Torchilin, 2014). Among the nanocarriers utilized in application to skin cancer therapy are those with transdermal, topical, and systemic applications. Specifically, these carriers could be polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, nanosuspensions, liposomes, micelles, silica nanoparticles, dendrimers, gold nanoparticles, and magnetic nanoparticles (Dianzani et al., 2014; Simoes et al., 2015). A promising technology, magnetic nanoparticles, works through an external alternating magnetic field to transform their magnetic energy into heat as a dynamic response to a dipole with their magnetic moments. The hyperthermia provokes cell death, and this delivery system can also load drugs, which decreases dosage by the synergy added by the magnetic effect (Lim et al., 2013b). A well-designed formulation for skin cancer treatment through topical application is indispensable, which would be able to increase drug penetration across the stratum corneum, as well as deliver the drug into deep skin layers because tumors are located in deep sites. At the same time, it is important to consider that molecules used to treat skin cancer are hydrophilic and of high molecular weight and are thus hard to get into the skin (Taveira and Lopez, 2011).

1.8 LIPOSOMES Liposomes are a vesicular-form drug delivery system composed of phospholipids in a bilayered membrane with aqueous phase inside and between the lipid bilayers. They offer biocompatibility, biodegrability, and low toxicity. Liposomes are able to encapsulate lipophilic compounds in the lipophilic layer membrane and hydrophilic substances in the aqueous core. They do not provoke immune system activation and easily incorporate new substances added to lipid mixtures or by different preparation methods. They can be multilamellar (several concentric bilayers) with size from 500 to 5000 nm or unilamellar with sizes

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ranging from approximately 100 nm (small) to 200 800 nm (large) (Voinea and Simionescu, 2002; Torchilin, 2005). If they have an antibody attached to the external membrane, liposomes become susceptible to accumulation on specific target sites. In addition, they can deliver their loads inside the cells or to individual cell compartments (Torchilin, 2005) or, with PEG-binding on the surface, can increase specificity, accumulating near tumor vessels (Yuan et al., 1994). Related to biocompatibility with the stratum corneum, liposomes have high affinity, are biodegradable, and are able to increase drug delivery to the skin (Rahimpour and Hamishehkar, 2012). Liposomes with different compositions were developed in order to improve the stability and modify the penetration across membranes, such as the stratum corneum. These new generations are transfersomes®, niosomes, and ethosomes®, which are composed of phosphatidylcoline and sodium cholate, phosphatidylcoline and ethanol, and non-ionic surfactants, respectively. They are flexible and deformable, passing through the pores present on the skin surface, and carry the drug toward deep skin layers (Santana and Zanchetta, 2011). There are reports of drugs encapsulated in liposomes to treat skin cancer such as aloe-emodin for NMSC treatment (Chou and Liang, 2009), bleomycin in ultradeformable liposomes to treat SCC (Lau et al., 2005), cationic liposomes carrying small interfering RNA (Yano et al., 2004), and T4N5 molecules with amphiphilic phospholipids topically applied to repair DNA enzymes to prevent skin cancer. This kind of entrapment prevents the thermal degradation of the molecule (Ceccoli et al., 1989). Few reports describe topical application of liposomes with chemotherapy; instead, intravenous administration is described. Some examples are cisplatinalginate for targeted delivery to EGFR-positive ovarian cancer cells (Wang et al., 2014) and oxaliplatin into PEGylated liposomes to improve antitumor activity (Nakamura et al., 2014). The topical application was related to the use of pro-drug 5-aminolevulinic acid (5-ALA) for photodynamic therapy, it involved liposomes and ethosomes® loading 5-ALA into the skin, and both showed increased 5-ALA entry. Moreover, ethosomes® had a better penetration into the skin in in vivo studies (Fang et al., 2008). Ethosomes® carrying chemotherapy substances have been described. Studies of ethosomes® containing 5-fluorouracil for transdermal delivery in in vitro skin penetration showed that this delivery system was able to increase the amount of 5-fluorouracil in human skin and hypertrophic scar tissue, and is considered highly efficient for skin penetration (Zhang et al., 2012). Other ethosomes® containing paclitaxel were able to perform topical delivery of the drug in the stratum corneum epidermis membrane model and increase its antiproliferative activity in an SCC model compared to unbound drug, suggesting a potential treatment for SCC (Paolino et al., 2012). Niosomes, in topical delivery, were loaded with 5-fluorouracil for treatment of skin cancer. This system was able to substantially increase the drug penetration in

1.9 Nanoemulsions and Nanosuspensions

human stratum corneum and epidermis membranes, as well as improve the cytotoxic effect on SKMEL-28 (human melanoma cells) and HaCaT (non-melanoma skin cancer cells), showing its potential for topical application and enhancing the drug cytotoxic property (Paolino et al., 2008). In summary, liposomes and new generations of liposomes are very useful for carrying drugs to treat skin cancer, stimulating their uses in several drugs and becoming good pharmaceuticals in skin cancer treatment through topical application.

1.9 NANOEMULSIONS AND NANOSUSPENSIONS A nanoemulsion can be described as a group of dispersed particles with remarkably small droplet sizes in a range of 20 200 nm, depending on the preparation method. Droplet sizes from 100 to 500 nm, constitute translucent or transparent systems, and are kinetically stable. They are isotropic systems that are thermodynamically stable (low Brownian motion—small droplet size). They are composed of oil, surfactants, co-surfactants, and aqueous phases. This system requires a high-energy process to be formed (e.g., ultrasound generator and high-pressure homogenization) and can be produced on an industrial scale. This delivery system is typically employed for drugs with poor solubility and hydrophobic compounds because it can improve bioavailability. Other advantages include the small amount of surfactants in the composition compared to microemulsions and offering long-term stable systems (Aboofazeli, 2010). Nanosuspension is defined as a submicron colloidal dispersion of drugs in nanosized particles, solubilized by surfactants. This system is used to enhance the solubility of poorly water-soluble drugs and lipid media. This strategy increases the bioavailability of molecules with low solubility/low permeability and, consequently, drug safety and efficacy, and it also provides passive drug targeting. Nanosuspensions can be prepared by several techniques, such as a precipitation method and high-pressure homogenization (Patel and Agrawal, 2011). The nanosized systems enable a larger interfacial area and improve the transport properties of drugs. These systems have been used for controlled drug delivery into specific skin layers by their affinity for skin (Guglielmini, 2008; Medina et al., 2011). A nanoemulsion with magnetic properties was reported to be sensitive to hyperthermia treatment and loaded with Foscan® (photosensitizer). It was shown to adequately penetrate into the skin layers, making it a promising system for the treatment of skin cancer (Primo et al., 2007). In another report, 5-ALA carried by nanoemulsion demonstrated enhanced penetration into skin for photodynamic therapy of actinic keratosis, indicating a better treatment profile for 5-ALA in nanoemulsion and reduced lesion area (Passos et al., 2013).

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1.10 POLYMERIC NANOPARTICLES Polymeric nanoparticles include nanospheres and nanocapsules. Nanospheres are formed by a polymeric matrix, where the molecules are adsorbed on the surface or encapsulated inside the matrix. Nanocapsules constitute a vesicular system, forming an interior reservoir where the molecules are entrapped, the core is of a liquid form (oil or water) surrounded by a shell of solid material (Rao and Geckeler, 2011). Biodegradable polymeric nanoparticles are preferred because they exhibit compatibility with tissues and cells and can be composed of polymers, such as chitosan; poly(lactic-co-glycolic acid) (PLGA); poly(lactic acid) (PLA); and polyε-caprolactona (PCL). Preparation techniques for these particles are in accordance with their application and drug type. In addition, they have subcellular sizes and are non-toxic, non-inflammatory, and non-immunogenic (Kumari et al., 2010). Polymeric nanoparticles protect drugs against chemical degradation; physically stabilize the drugs; have high EPR effects, high drug loading, and the possibility of binding substances to cells and tissues through targeted delivery; and enhance cutaneous delivery of the drug through the skin by increasing the concentration gradient and decreasing side effects, such as skin irritation from topically applied drugs (Chatterjee et al., 2008; Zhang et al., 2013). A study applying this delivery system was developed using the encapsulation of 5-fluorouracil in nanoparticles formed by a hydrophobic core polymer and triblock copolymers, based on PLA/PLGA with polyethylene glycol (PEG) and propylene glycol (PPG) molecules as PEG-PPG-PEG. The authors performed cumulative release of the drug over 72 h and observed decreased cell viability for 5-fluorouracil loaded into polymeric nanoparticles (Ocal et al., 2014). Inside the photodynamic therapy area, encapsulated indocyanine green in polymeric nanoparticles with active targeting to EGFR (anti-EGFR) for treatment of SCC in mice showed that the encapsulated drug was able to decrease tumor size, apoptosis, angiogenesis, and inflammation, and was considered more effective (Gamal-Eldeen et al., 2013).

1.11 LIPID NANOPARTICLES Lipid nanoparticles were developed as alternatives to liposomes, polymeric nanoparticles, and emulsions and are constituted by a solid lipid or a blend of solid lipids that are solid at room and body temperatures. Lipid nanoparticles are typically composed of 0.1 30% (w/w) of solid lipids dispersed in an aqueous phase stabilized with 0.5 5% of surfactant, with particle sizes in the range of 40 1000 nm (Pardeike et al., 2009). Second-generation lipid nanoparticles are composed of a mixture of solid and liquid lipids with an optimal matrix in a ratio ranging from 70:30 to 99.9:0.1. Oils in this composition reduce the melting point, but are solid at body

1.11 Lipid Nanoparticles

temperature. These advanced lipid nanoparticles are called nanostructured lipid carriers (NLCs) (Uner and Yener, 2007; Pardeike et al., 2009). NLCs provide more capacity for drug loading and minimize drug expulsion during storage (Mehnert and Mader, 2001). Lipid nanoparticles can be prepared by several techniques, including high shear homogenization and ultrasound and high-pressure homogenization (hot or cold). They may be subjected to sterilization process, easy scale up for production, and also avoid organic solvents in the composition (Mehnert and Mader, 2001; Pardeike et al., 2009). Their applications can be achieved via several administration routes, such as parenteral (intravenous, intramuscular, and subcutaneous), oral, rectal, ophthalmic, and topical routes (Uner and Yener, 2007). The topical route is very attractive for this colloidal carrier because they are based on non-toxic and nonirritant lipids, which is very useful for application on damaged, inflamed, and healthy skin. They provide controlled release and their small size allows for close contact with the stratum corneum (film formation and occlusion effect), which increases the permeated amount of drug into the skin. In addition, they can protect the drug against light, oxidation, and hydrolysis (Uner and Yener, 2007; Pardeike et al., 2009). Generally, lipid nanoparticles do not enter deep into the stratum corneum in healthy skin, but can accumulate in the pilous follicles, produce an adhesive effect on the skin, and increase skin hydration, influencing drug penetration (Schafer-Korting et al., 2007). The major disadvantage frequently associated with this delivery system is the low loading capacity, which is dependent on the amount of lipid in the formulation; approximately 10% of the lipid amount is the drug loading to ensure the stability of the system (Schwarz and Mehnert, 1999; Ying et al., 2008). Depending on adhesive and occlusive effects, lipid nanoparticles can increase the residence time of antineoplasic drugs, which increases the cytotoxic effects and decreases the side effects, enhancing efficacy and pharmacokinetics (Du et al., 2010; Shrivastava et al., 2014). Several therapies have been developed with lipid nanoparticles for cancer treatment, such as a docetaxel nicotanamide complex loaded into NLC for transdermal delivery, which demonstrated better drug transportation into the skin with cumulative permeation (Fan et al., 2013). Other studies with NLC co-loaded with doxorubicin and docosahexaenoic acid showed enhanced in vitro drug activity and increased carrier penetration into MCF-7/Adr spheroid model, and would therefore be a good alternative for cancer therapy (Mussi et al., 2014). Methotrexate transported in hyaluran-coated lipid nanoparticles improved affinity for the CD44 receptor on B16F10 murine melanoma cells, increasing tumortargeting specificity, which allowed for drug accumulation into the tumor with therapeutic outcomes (Mizrahy et al., 2014). Moreover, lipid nanoparticles encapsulating resveratrol, as a chemopreventive drug, promoted an increase in antiproliferative cellular effects in keratinocytes, which is typical for cancer,

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given that this delivery system concentrates around nuclei, releasing resveratrol in a sustained manner, suggesting a promising formulation to prevent skin cancer (Teskac and Kristl, 2010).

1.12 DENDRIMERS Dendrimers are highly branched polymeric macromolecules applied to delivery systems based on nanotechnology (Lee et al., 2005; Agarwal et al., 2010). Dendrimers are non-immunogenic, globular in shape, and monodisperse in nature. They are three-dimensional nanoscale synthetic polymers and are symmetrical, with well-defined sizes and molecular weights. The properties of dendrimers have been related to several biological applications, such as bioimaging (magnetic resonance imaging), drug carrier (anticancer therapy), drug/vaccine (multivalent binding inhibitors), gene carrier, and scaffold for tissue repair (Malik et al., 2012). For drug delivery, the drug is carried through complexation, encapsulation, or conjugation. One example of dendrimers that has been extensively used and studied is polyamidoamine (PAMAM) dendrimers because they have wellestablished methods of synthesis, are stable, and possess low toxicity for PAMAM few generations (Souza et al., 2013). However, others are also commonly used as polyamines, polypeptides, polyesters, and carbohydrates and in DNA (Lee et al., 2005). Structurally, they are multibranched monomers disposed in a radial manner with a central core, which appear like tree arbors. One dendrimer is composed of several units of dendrons (Lee et al., 2005). Dendrimers are formed by a central core unit and generations (i.e., branches attached to the core), which account for the physical-chemical features of dendrimers, and terminal functional groups attached to the outermost series of branches, which account for dendrimer functionality (Malik et al., 2012). The number of branch points organized from the core toward the peripheral region defines its generation (G-1, G-2, G-3). A dendrimer of a higher generation is heavily branched and larger and has various end groups on its periphery compared to that of a lower generation (Lee et al., 2005). The end groups provide affinity and specific charge for drug binding and releasing at a certain pH or linking in a specific enzyme/microenvironment. These end groups provide wide functionality for dendrimers, allowing them to make specific deliveries by attaching to a large number of moieties, ligands, and mAbs (Agarwal et al., 2010). In addition, they modulate solubility, as hydrophilic end groups make the dendrimer soluble in aqueous solution with a hydrophobic core, and vice versa (Lee et al., 2005). The unique characteristics of dendrimers are advantageous for tumor pathophysiology because their nanometric size allows them to enter into the highly permeable vasculature of the tumor, and their high molecular weight and lymphatic dysfunction make them accumulate in the tumor region (Klajnert and

1.13 Photodynamic Therapy

Bryszewska, 2000; Gillies and Frechet, 2005). They exhibit adequate features for cancer drug delivery by enhancing drug solubility and decreasing systemic toxicity, as well as selectively accumulating in solid tumors. Furthermore, they are able to solubilize drugs such as 5-fluorouracil and paclitaxel (Ooya et al., 2003; Gupta et al., 2006). Dendrimers have been of great interest for cancer therapy because they can be designed for pathological and physiological barriers, as well as for active targeting. For example, folate receptors overexpressed in cancer cells, the site of folic acid binding, showed better therapeutic effect to tumor regression (Neerman, 2006; Agarwal et al., 2010). Improving tumor targeting can be accomplished with glycodendrimers for specific attachment to glycosylation on cancer cells through immune recognition, which was made with PAMAM functionalized with N-acetyl-glucosamine residues (with affinity for the recombinant lymphocyte receptor NKR-P1A) in mice, inoculated with B16F10 melanoma cells (Vanucci et al., 2003). Additionally, dendrimers have been used as photodynamic therapy agents due to their improved retention and selective pharmacokinetics (Abassi et al., 2014). To accomplish this, penetration through the skin is associated with size and surface charge. Recent studies reported that emulsion or pretreatment of PAMAM dendrimers enhanced the skin penetration of ketoprofen and 5-fluorouracil. Furthermore, it was observed that G-2 dendrimers permeated more deeply compared to G-4 dendrimers. Furthermore, cationic PAMAM dendrimers (primary amines) can make nano-scale holes on lipid bilayers of skin, which reduces skin resistance, improves the penetration of substances and, with the positive surface charge, generates more internalization into individual skin cells. However, G-2 dendrimers with neutral and negative surface charges are related to faster skin permeation through the extracellular route, by electrostatic repulsion with cell membranes through rapid diffusion (Yang et al., 2012). In addition, other investigations demonstrated the several ways that dendrimers and skin interact and their consequence on drug delivery into the skin (Sun et al., 2012).

1.13 PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) is a non-invasive method for the treatment of cancer. It is a light-activated modality against various types of cancer and an alternative to surgical procedures, that is becoming an ideal solution for cancers of the skin, head, and neck, such as Bowen disease, BCC, and actinic keratosis. The destruction of cancer cells is achieved by the combination of photosensitizers (PSs) and light in a PS-specific wavelength. The PS, a light-absorbing dye, is able to produce reactive oxygen species (ROS), which are highly destructive in a cell environment, with a short diffusion path length to keep them confined in the target regions (Braathen et al., 2007; Hayden et al., 2013; Lim et al., 2013a).

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The success of PDT depends on parameters, such as accumulation of PS in malignant cells and selective colocalization of light irradiation to preserve normal cells and induce apoptosis/necrosis of cancer cells with PS inside (Oleinick et al., 2001). The great advantages of PDT are very low toxicity in the absence of activating light and non-specific accumulation of PS in tissues, with minimal toxicity. The activating light is non-ionizing, thus not harmful to normal cells and those cells without accumulated PS (Master et al., 2013). PSs possess a chemical structure with an aromatic ring and hydrophobicity with low aqueous solubility, suggesting low applicability by their aggregation in biological serum. In addition, these PSs require target accumulation to be effective, usually achieved in cancer by the EPR effect. The choice of PS for cancer treatment is linked to the therapeutic window (600 1200 nm) and, consequently, the extinction coefficient in the tissue; this value is high for blue/green light, and is advantageous for epithelial-depth and post-surgical PDT, and it is low for red light, which is useful for deep tissue and solid tumor PDT (Hayden et al., 2013). In order to increase the therapeutic action, the PS loaded into a drug delivery system can achieve more solubility and selective accumulation (targeting activity driven by pathophysiolocal features of cancer microenvironment), and can be delivered inside the cells and generate ROS after light exposition (Lim et al., 2013a). Examples of delivery systems used for PDT are liposomes (Bovis et al., 2012) and polymeric nanoparticles (Yang et al., 2011). Porphyrin derivatives, chlorins, and phthalocyanine are PSs that have been studied in several nanocarriers to overcome limitations as selectivity and variable oxygen levels due to tumor hypoxia (Master et al., 2013). For topical PDT, the PS is applied on the skin, followed by laser irradiation. The most relevant PS for skin cancer is 5-ALA (precursor of endogenous protoporphyrin IX), which has a low extinction coefficient for absorption, and is excited by red light at 630 nm. For these reasons, the phthalocyanines have been of interest, given their adequate photobiological features for PDT as they are selectively retained in tumors, as well as their chemical and photochemical stability, long lifetime when excited, and low dark toxicity. Additionally, improvement of these characteristics was accomplished with a water/oil microemulsion used to promote skin delivery and equal distribution across the skin (Rossetti et al., 2011).

1.14 CONCLUSIONS The increased interest in preserving normal tissue during cancer therapy is the driving force in the search for new alternatives to non-invasively or minimally invasively destroying only the cancer cells. To improve the therapeutic efficacy and overcome limitations of drugs and pathology, topical application is a good strategy because it can deliver high drug concentrations and, through nanocarriers,

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increase drug penetration across the skin. In this context, nanocarriers in a wide diversity of materials and technologies are available for the progress of skin cancer therapy and production of selective formulations.

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