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Published in final edited form as: Photodermatol Photoimmunol Photomed. 2018 Jan;34(1):60–68. doi: 10.1111/phpp.12368

Drug delivery strategies for chemoprevention of UVB-induced skin cancer: A review

Arvind Bagde 1, Arindam Mondal 1, Mandip Singh 1
PMCID: PMC8691077  NIHMSID: NIHMS1762590  PMID: 29150967

Abstract

Annually, more skin cancer cases are diagnosed than the collective incidence of the colon, lung, breast, and prostate cancer. Persistent contact with sunlight is a primary cause for all the skin malignancies. UVB radiation induces reactive oxygen species (ROS) production in the skin which eventually leads to DNA damage and mutation. Various delivery approaches for the skin cancer treatment/prevention have been evolving and are directed toward improvements in terms of delivery modes, therapeutic agents, and site-specificity of therapeutics delivery. The effective chemoprevention activity achieved is based on the efficiency of the delivery system used and the amount of the therapeutic molecule deposited in the skin. In this article, we have discussed different studies performed specifically for the chemoprevention of UVB-induced skin cancer. Ultra-flexible nanocarriers, transethosomes nanocarriers, silica nanoparticles, silver nanoparticles, nanocapsule suspensions, microemulsion, nanoemulsion, and polymeric nanoparticles which have been used so far to deliver the desired drug molecule for preventing the UVB-induced skin cancer.

Keywords: chemoprevention, drug delivery strategy, skin cancer, UVB radiation

1 ∣. INTRODUCTION

Currently, skin cancers are the most diagnosed cancer among all other organ malignancies.1,2 Skin cancers mainly are of two types, non-melanocytic skin cancer (NMSC) and melanoma skin cancer (MSC), depending on the cell from which they derived and their clinical behavior.3 Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the subtypes of non-melanocytic skin cancer (NMSC).2-5 Every hour, one death is reported because of melanoma skin cancer (MSC). In 2017, about 87,110 new cases of invasive MSC will be detected in the United States and 9,730 deaths will occur. According to the 2017 report of American Cancer society, the exact number of cases of basal cell carcinoma (BCCs) and squamous cell carcinoma (SCCs) is very difficult to estimate since the disease is very common; therefore, these cases are not reported to the cancer registries. However, in 2012, about 5.4 million people were detected with NMSC (many cases are detected with multiple NMSC). The yearly cost of skin cancers treatment in the United States is estimated at $8.1 billion: $3.3 billion for melanoma and about $4.8 billion for non-melanoma skin cancers.1 Ultraviolet (UV) radiation exposure is the main cause for 90 percent cases of NMSC.1 UV radiation causes ROS production in the skin layers which lead to inflammation and eventually skin cancer. Various drug delivery approaches, for example, ultra-flexible nanocarriers, transethosomes nanocarriers, silica nanoparticles, silver nanoparticles, nanocapsule suspensions, microemulsion, nanoemulsion, and polymeric nanoparticles have been used for the chemoprevention of UV-induced skin cancer.

2 ∣. SKIN

The skin constitutes 16% of the total body mass which is primarily comprised of 2 layers, epidermis and dermis. Subcutaneous tissue is located below the dermis layer6,46 (Figure 1). The epidermis has three types of cell (squamous cells, basal cells, and melanocytes). Programmed differentiation of epidermal basal cells (basal keratinocytes) leads to their migration outward through the surface of the skin to eventually form tightly linked dead but undamaged cells, corneocytes, which are the primary barriers of the epidermal layer of the skin.3 Dermis which originates from the mesoderm, underlies the epidermal layer of the skin and anchorages sweat gland, hair follicles, nerves and sebaceous glands. Dermal layer also consists of fibroblasts and immune cells which play a important role in many physiological responses in the skin.3

FIGURE 1.

FIGURE 1

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Anatomy of skin showing types of skin cells. Reproduced from Korotkov K et al.46

3 ∣. UV RADIATION

UV radiation though constitutes small fraction of the solar spectrum, it is considered as a primary source of skin cancer.7 Ultraviolet radiation (UV) spectrum ranges from wavelength of 100-400 nm. Wavelength of 100 nm is considered as the borderline between non-ionizing and ionizing radiations.7,8 The UV radiation is subdivided into UVA, UVB, and UVC with the wavelength range of 315-400 nm, 280-315 nm, and 100-280 nm, respectively7 (Figure 2). UVC has highest energy with shortest wavelength, whereas UVA has least energy with the longest wavelength. Epidemiological evidence has proved that UVB radiation is the main cause of skin cancer.9 UVB radiation also causes immune suppression, oxidative stress, and sunburn. It has also been reported that UVB exposure leads to damage to the skin proteins and lipids which are the main constituents of the cell membrane.1 Although UVC radiation has ability to induce mutation and immune suppression, it is absorbed by the stratospheric ozone layer and causes minimal damage to the skin. UVA, a major component of the UV spectrum and has an ability to produce ROS in the skin, causes premature aging and can suppress immune system though its effect is less pronounced than UVB radiation.10

FIGURE 2.

FIGURE 2

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Electromagnetic spectrum of visible and UV radiation and its biologic effects on human skin. UVA generates reactive oxygen species which causes DNA damage through photosensitizing reactions. UVB-radiation-induced DNA damage leads to molecular re-arrangements which eventually results in formation of 6-4 photoproducts and cyclobutane dimers. Reproduced from D’Orazio J et al2

4 ∣. GENETIC MUTATIONS CAUSED BY UVB RADIATION

UVB exposure on the skin results in a sequence of events which leads to release of vasoactive and neuroactive mediators and cytokines which are inflammatory mediators resulting in sunburn and other skin complications.11-14 This further leads to formation of photo-dimers In the genome.2 UV radiations are also responsible for generating reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, and the hydroxyl radical which eventually leads to mutations.15 Reactive oxygen species causes oxidation of guanine and generates 8-hydroxy-2’-deoxyguanine (8-OHdG) which pairs with an adenine in place of cytosine. This mispairing of the nucleotide bases has been observed in skin tumors suggesting that ROS is responsible for skin cancer.16 Moreover, UVB also has a direct effect on nucleotide base pairing in DNA.17,18 Pyrimidine bases are mainly vulnerable for the base alteration on absorbing UV radiation. UVB and UVC radiations alter double-helical structure of DNA by breaking internal 5-6 double bonds of pyrimidines which ultimately results in mutation. It is projected that a day of sun exposure results in up to 105 UV-induced damage to each cell in the skin.19 UV radiation can also result in “UV signature mutations” in which characteristic base transition occurs, for example, TT-→CC. This type of mutation has been found in skin tumor which suggests that UV radiation causes skin malignancy.20-23

5 ∣. DELIVERY STRATEGIES FOR UVB-INDUCED SKIN CANCER

5.1 ∣. Ultra-flexible nanocarriers

Ultra-flexible nanocarriers have been used for the topical delivery of an antioxidant diindolylmethane derivative (DIM-D) for chemoprevention of skin cancer caused by UV radiation exposure.1 C-DIM derivative, 1,1-bis(3-indolyl)-1-(p-chlorophenyl) methane (DIM-D), is a natural product derived from indole-3-carbinol (I3C) and acts by inducing the expression of cell cycle inhibitors such as p21 and p27 and downregulates cyclin D1(cyclin proteins), survivin, bcl-2, bax(survival and antiapoptotic proteins). It also induces poly (ADP-Ribose)polymerase (PARP) cleavage, mitochondrial cytochrome c release, and procaspase cleavage.24 Ultra-deformable vesicles have been reported to deliver desired amount of drug into the skin because of their ability to permeate deeper layers of the skin. These nanocarriers consist of fluid membranes which help them to permeate easily through the skin layers. In a study by Boakye CH et al, the ultra-flexible nano gel containing DIM-D was formulated for increasing the drug deposition in the skin and its efficacy in preventing the UVB-induced skin cancer was evaluated. DIM-D-UltraFLEX-Nano is a stable mono-dispersion (110.50 ± 0.71 nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR, and AFM phase imaging. UltraFLEX-Nano was responsible for significant (P < .01) skin retention of a drug in contrast to polyethylene glycol solution of a drug (13.83-fold). The skin deposition of drug from polyethylene glycol solution, NLC, NLC-OA, UltraFLEX-Nano was 7.18 ± 0.75, 9.49 ± 1.55, 29.01 ± 15.07, 99.28 ± 6.88 g per gram of skin, respectively (Figure 3A). The drug release studies showed same drug release rate and extent for 0.3, 1.0, and 1.5% gels suggesting that there was no significant effect of the gelling agent (HPMC) concentration on the release pattern of the drug1 (Figure 3B).

FIGURE 3.

FIGURE 3

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A, DIM-D deposition in the skin at the end of 24 h from PEG solution, NLC, NLC-OA, and UltraFLEX-Nano. B, Drug released from 0.3, 1.0, and 1.5% DIM-D-UltraFLEX-Nano HPMC gels. Data has been represented as the mean ± SD. ***P < .001. Reproduced from Boakye CH et al.1

The average cumulative number of tumors formed for UV-only treatment group was 3.3-fold more than DIM-D-UltraFLEX-Nano gel treatment group (Figure 4A). The percentage of animals that formed tumors on their dorsal skin for UV-only treatment group was 87.5% while for sunscreen SPF30 and DIM-D-UltraFLEX-Nano pretreatments was 37.5% and 62.5%, respectively (Figure 4B). The average numbers of tumors per group after 24 weeks of study were 20.00 ± 2.52, 3.00 ± 1.52, and 6.00 ± 0.58 for UV-only, sunscreen SPF 30, and DIM-D-UltraFLEX-Nano gel respectively. It was also observed that DIM-D-UltraFLEX-Nano decreased (P < .05) DNA damage (8-hydraxydeoxyguanosine), metastasis (Vimentin, MMP-9, TIMP1), skin inflammation (PCNA), immunosuppression (IL10), epidermal hyperplasia (c-myc, CyclinD1), cell survival (AKT), and increased apoptosis (p53 and p21). Also, UltraFLEX-nanocarrier containing DIM-D was able to delay tumor formation on the dorsal skin of mice in contrast to marketed sunscreen (SPF30). These studies suggest that ultra-flexible nanocarriers could be a promising drug delivery approach for the skin cancer prevention.1

FIGURE 4.

FIGURE 4

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A, Tumors formed in UV-only-irradiated group and DIM-D-UltraFLEX-Nano-gel-treated group. B, Percentage of animals showing tumors at the onset of tumorigenesis. Reproduced from Boakye CH et al.1

5.2 ∣. Lipid vesicles

Vesicles comprising dimethyl sulfoxide (DMSO) and transethosomes have been used to deliver therapeutics for inhibiting UV radiation-induced skin cancer.25 Transethosomes are lipid vesicles made up of transfersomes and ethosomes. Transfersomes are elastic nanovesides and principally consist of phospholipids and edge activators (EAs) like sodium cholate (NaCo), sodium deoxycholate, Span 60, Span 65, Span 80, Tween-20, Tween-60, Tween-80, and dipotassium glycyrrhizinate. Ethosomes are vesicles comprising essentially of phospholipids, water, and a large amount of ethanol. Transethosomes, novel ultra-deformable vesicle, were originally introduced by Song CK et al, consisting of high amount of ethanol (up to 30%) together with edge activators (surfactant).26 As transethosomes are a combination of transfersomes and ethosomes, its mechanism of skin penetration might be a combination of both (transfersomes and ethosomes) mechanisms. Transferosomes penetrate into the skin by generating osmotic gradient due to the evaporation of water while applying it on the skin surface.27 The exact mechanism of skin permeation and penetration of ethosomes is not totally understood. However, it is reported that the synergistic combination of phospholipids and ethanol leads to a deeper drug loaded distribution and penetration into the skin layers.28 Transethosomes have shown an irregular spherical shape and higher values in both vesicle elasticity and skin permeation/penetration studies. Combination of ethanol and EA in transethosomes causes a rearrangement in the lipid bilayer of these vesicles. Therefore, they are irregular spherical shaped and have higher values in both vesicle elasticity and skin permeation/penetration studies.26 DMSO has been used to develop lipid vesicles because of its antioxidant, analgesic, anti-inflammatory, and skin permeation enhancing property.

In a study by Menezes AC et al, 1-(1-naphthyl) piperazine(1-NPZ) containing transethosome(TE) and vesicles comprising dimethyl sulfoxide (NPZ-DM) were developed and characterized for its chemopreventive activity against skin diseases like severe inflammation caused by UV radiation exposure. Results of in vitro skin permeation study revealed that NPZ-DM formulation was able to significantly enhance the drug permeation through skin in contrast to NPZ-TE (P < .05; Figure 5). UVB radiation induces the leukocytes infiltration, which induces inflammation and eventually leads to tumor progression.29 MPO is frequently used as a marker of infiltrating leukocytes in UVB-exposed skin.29,30 Myeloperoxidase (MPO) activity was decreased in NPZ-DM treatment group as compared to the irradiated control group (1-C), suggesting that NPZ-DM formulation was able to inhibit UVB-induced leukocytes infiltration caused by UVB exposure. Additionally, NPZ-DM formulation has been reported to significantly decrease the activity of TN F-α (P < .05) and IL-1β (P < .05) as compared to irradiated control group (1-C). Therefore, vesicles comprising dimethyl sulfoxide (NPZ-DM) could be an superior approach of drug delivery for the skin diseases caused by UV exposure.25

FIGURE 5.

FIGURE 5

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Drug permeation through skin from NPZ-DM and NPZ-TE formulations. Values are expressed as mean ± SD (n = 3). Statistical analysis: *P < .05 vs NPZ-H2 and NPZ-TE, **P < .001 vs NPZ-H2O, NPZ-TE, and NPZ-DM. Reproduced from Menezes AC, et al.25

5.3 ∣. Silica nanoparticles

Aminopropyl functionalized mesoporous silica nanoparticles (NH2-MSN) have been used to deliver quercetin (natural flavonoid) topically for the prevention of skin cancer.31,32 Vallet-Regí M et al used ordered mesoporous materials as drug delivery system for the first time to deliver the drug.33 MCM-41-type mesoporous silica nanoparticles are excellent delivery system because of their ordered porosity, tunable pore volume, high surface area, and high drug loading.34-36 Moreover, its surface properties can be chemically modified through covalent grafting of various organic functional groups to the free silanol groups.37

In a study by Sapino S et al, siliceous MCM-41 nanopartides (MSN) were synthesized using TEOS (silica source) and CTAB as the Structure Directing Agent (SDA).31 It was observed that aminopropyl-functionalization significantly contributed in enhancing the drug loading in the complex. Photo-degradation study of quercetin showed that non-degraded flavonoid percentage of the optimized quercetin formulations, 24 hours after irradiation of UVB, was 76.5% for the complexed one and 52.6% for the non-encapsulated quercetin. Silica nanoparticulate formulations were able to deposit more quercetin in the skin (9.79 1 g/cm2 from hydro-alcoholic solution and 10.89 L g/cm2 from W/O emulsion) in contrast to formulation containing free drug (Figure 6). Skin permeation studies showed that the inclusion complexation with the inorganic nanoparticles enhanced the skin penetration after 24 hours of application of formulation without transdermal quercetin delivery. Cell proliferation study on JR8 human melanoma cells revealed that the complex with NH2-MSN was more effective at 60 μmol/L than quercetin alone, inducing about 50% cell proliferation inhibition.31

FIGURE 6.

FIGURE 6

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Skin retention after 24 h of free Quercetin (black colored) and Q/NH2-MSN_1/1 (gray colored) from different media. Each bar represents the mean ± SD obtained in three independent experiments. Reproduced from Sapino S et al.31

5.4 ∣. Silver nanoparticles

Silver nanoparticles (AgNPs) have been used against UVB-irradiation-induced DNA damage and apoptosis in human immortalized keratinocytes (HaCaT).38 Silver has been in use for centuries for the prevention and treatment of different diseases as well as in healing of skin wounds because of its exceptional free radical scavenging, antimicrobial, and anti-inflammatory properties.14,15 Silver nanoparticles were first introduced In 1990 as an ointment formulation for the healing of open wounds through their dominant anti-bacterial and anti-inflammatory properties.16,17 More than quarter of commercially available nano-based products contain silver due to its wide applicability and safety in human applications.18-20 It has been reported that pre-treated HaCaT cells with silver nanoparticles (AgNPs) when irradiated to UVB radiation resulted in significant decrease in apoptosis (~10.7%) in contrast to untreated cells (~41.6%) (Figure 7). Moreover, AgNPs pretreatment of HaCaT cells on UVB-irradiation induced G1-phase cell cycle arrest. In this study, AgNPs were efficiently internalized in UVB-irradiated cells and localized into cytoplasmic and nuclear compartments. In addition, it has been observed that expression of various genes involved in cell cycle, apoptosis, and nucleotide-excision repair was altered in HaCaT cells treated with AgNPs prior to UVB irradiation. Silver nanoparticles have also been reported in increasing the mRNA expression of NER genes that are involved in DNA repair of UVB-irradiated human keratinocytes.38

FIGURE 7.

FIGURE 7

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Decrease in apoptosis and UVB-induced cell death on pretreatment with silver nanoparticles. HaCaT cells (1 Å~ 106/plate) were grown in UVtransparent glass plates and treated with AgNPs 3 h prior to UVB exposure. After 24-h exposure of UVB radiation (A) images of the cells under phase-contrast microscope. Cells not irradiated with UVB were used as a control. Arrows indicate apoptotic cells. B, Percent cell viability in different treatment groups. Bars represent mean ± SD, n = 3; *P < .05; **P < .01. C Early apoptotic cells percent in each treatment group. Bars represent mean ± SD, n = 3; **P < .01. Reproduced from Arora S et al.38

5.5 ∣. Nanocapsule suspensions

Nanocapsule suspensions as topical formulations have been used to deliver coenzyme Q10 and vitamin E acetate for UVB-induced skin inflammation.39 In a study by Pegoraro NS et al, semisolid formulations based on nanoparticulate systems were developed for the first time by simple addition of gellan gum to nanocapsule suspensions. Results in in vivo study revealed that UVB-induced ear edema in mice was reduced by 33 ± 7%, 29 ± 3%, 66 ± 5%, 38 ± 9%, 73 ± 8%, and 70 ± 5% for non-encapsulated Q10 and VitE (FH), nanocapsules with 1%VitE without Q10 (NBP1), Q10-loaded nanocapsules with 1% VitE(NCP1), nanocapsules with 3% VitE without Q10 (NBP3), and Q10-loaded nanocapsules with 3% VitE (NCP3), silver sulfadiazine (positive control), respectively. Moreover, nanocapsule suspensions were able to reduce inflammation parameters which were evaluated through MPO activity (Figure 8). UV radiation exposure affects oxidative stress parameters by decreasing non-protein thiol levels and increasing lipidperoxidation. Nanocap suspension could increase the non-protein thiol levels (100% to NCP1 and NCP3) and decrease lipid peroxidation through lipid hydroperoxide content (100% to NCP1 and NCP3) and through TBARS assay (28 ± 4% and 100% to NCP1 and NCP3, respectively).

FIGURE 8.

FIGURE 8

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Anti-inflammatory effects of semisolid formulations on UVB-irradiation-induced skin injury in mice. Ear edema (A), myeloperoxidase (B), and NAGase (C) activities in mice submitted to UVB irradiation (0.5 J/cm2). All formulations (15 mg/ear) were immediately applied after UVB irradiation. Ear edema and cell infiltration were measured 24 h after irradiation. Each bar represents the mean + SEM (n = 6-7); ***P < .001 when compared to the naïve group. *P < .05, **P < .01, and ***P < .001 when compared to the untreated group. & P < .01 shows significant difference between semisolids containing Q10-loaded nanocapsules (NCP1 and NCP3) with semisolids containing nanocapsules without Q10 (NBP1 and NBP3). One-way ANOVA followed by post hoc Newman-Keuls test. Reproduced from Pegoraro NS et al.39

5.6 ∣. Microemulsions

Microemulsions (ME) have been used as topical nanocarriers for caffeine (CAF) to enhance CAF skin retention and subsequently improve its therapeutic effect on UVB-induced skin carcinogenesis.40 ME is a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution with significant advantages, including thermodynamic stability, high solubilization capacities for both hydrophilic and hydrophobic molecules, easy formation, and small droplet size. Moreover, ME have been extensively used in pharmaceutical applications for the topical delivery of therapeutics.14 Briefly, 374.18 μg/cm2 of caffeine was found to permeate from a microemulsion formulation in 24 hours in skin permeation study in contrast to control (conventional gel) which was 240.44 μg/cm2. ME resulted in skin deposition amount (177.28 ± 14.24 μg/g skin tissue) which was nearly threefold more than the control (68.94 ± 9.65 μg/g skin tissue) with statistically significant difference (P < .05). Pharmacodynamics studies demonstrated that CAF-loaded ME was superior in terms of increasing apoptotic sunburn cells (P < .05) as compared with control (Figure 9). All the results in this study suggested that the ME could be a promising vehicle for the topical delivery of CAF for UVB-induced skin carcinogenesis.40

FIGURE 9.

FIGURE 9

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Results of apoptotic sunburn cells quantitation in epidermis of normal skin, skin treated with UVB, skin treated with UVB+Vehicle, and skin treated with UVB+CAF. Values are mean ± SD (n = 3). *P < .05. Reproduced from Ma H et al.40

Microemulsions have also been utilized as a topical carrier systems for delivery of quercetin.41 In a study by Vicentini FT et al, quercetin-loaded microemulsion was able to inhibit UVB-exposure-induced proteinase secretion/activity and helped in the maintaining the normal GSH level which was reduced by approximately twofold on UVB exposure as compare to non-irradiated control group.41 In vitro skin permeation of quercetin from micellar, canola oil, and propylene glycol (control), formulations was less than 9.40 ± 0.57ug/cm2 of the skin, while, to w/o microemulsion formulation showed significant permeation of the drug 16.94 ± 0.84ug/cm2 in 12-hr skin permeation study.41

5.7 ∣. Hydrophilic ointment/cream

Hydrophilic ointment- or cream-based formulations have also been used for evaluating the efficacy of green tea polyphenols (GTP) in UV-induced injury in the mouse skin.42

In a study by Vayalil PK et al, it was reported that green tea polyphenols may be supplemented for the treatment/prevention of UV-induced skin diseases in topical skin care products such as sunscreens, skin care lotions, moisturizing creams, facial and depilatory creams. Topical formulation containing green tea polyphenols (GTP) showed a significant prevention of UVB-induced depletion of antioxidant enzymes such as catalase (51%-92%, P < .001), glutathione peroxidase (78%-100%, P < .005-.001), and glutathione level (87%-100%, P < .005). Further, this study showed that epigallocatechin-3-gallate (EGCG), a constituent of GTP, helped in reducing the UVB-induced oxidative damage and the expression of MAPK proteins, which are responsible for carcinogenesis. This was the first attempt to formulate green tea polyphenols topical cream to reduce the UV-radiation-induced skin damage.42

5.8 ∣. Polymeric NPs

Polymeric NPs have been used as drug delivery systems in the treatment of skin malignancies. A study by Sahu S et al, reported that topical formulation of ethyl cellulose NPs containing quercetin helps in releasing the drug in a controlled manner and increasing the skin retention of the drug.43 Further, drug permeation study demonstrated that the amount of drug permeated at the end of 24 hours was 74.8 μg/cm2 with skin permeation rate constant of 0.4559 percent/cm2/hour. The results from in vitro drug release study showed that the formulation could release only 50% of drug after 24 hour suggesting its controlled release property. In ex vivo skin permeation study, about 25% of drug was retained in the skin, whereas 19.6% of drug permeated from the skin suggesting that less amount of drug is reaching the systemic circulation to avoid its adverse effects. Therefore, quercetin-loaded polymeric nanoparticles could be one of the strategy for UVB-induced skin damage.43

5.9 ∣. Nanoemulsions

Nanoemulsions have been used to deliver natural antioxidants like quercetin for the prevention of the skin cancer.44 In a study by Casagrande R et al, non-ionic emulsion with high lipid content and anionic emulsion with low lipid content were used to deliver the drug. The UVB irradiation (0.31%-3.69 J/cm2) induced a dose-dependent increase in the myeloperoxidase (MPO) activity (4%-2708%) and depletion of reduced glutathione (GSH) (22%-68%) in the skin of hairless mice after 6 hours. In this study, quercetin nanoemulsion inhibited the MPO activity increase (62% and 59%, respectively), GSH depletion (119% and 53%, respectively), and proteinases secretion/activity. This was the first study to demonstrate the effectiveness of topical formulations containing quercetin to inhibit the UVB-irradiation-induced skin damage.44

Nanoemulsions have also been used to deliver chemotherapeutic natural compounds for the UVB-induced skin cancer.45 In a study by Brownlow B et al, topical nanoemulsion of genistein (soy isoflavone) was formulated and evaluated for the chemoprevention of skin cancer. It has also been reported that genistein nanoemulsion containing tocomine as an oil phase with a mixture of Solutol R HS-15 (SHS15) and vitamin E TPGS (TPGS) in a ratio 60:40 as a surfactant and co-surfactant showed slow release of drug from both the cream and liquid formulations. Further, the optimized nanoemulsion having excellent biocompatibility showed high chemopreventive property against L929 fibroblasts, suggesting its application as chemopreventive agent in a topical formulation.45

6 ∣. CONCLUSION

UVB radiation is the primary cause of all types of skin cancer. Variety of drug delivery strategies have been explored by the researchers all over the world. For the UVB-induced skin cancer, ultra-flexible nanocarriers, transethosomes, silica nanoparticles, silver nanoparticles, nanocapsule suspensions, microemulsion, nanoemulsion, polymeric nanoparticles have been utilized to deliver the desired drug. All the studies covered in this review have shown promising results in the chemoprevention of UVB-induced skin malignancies. Nanoparticulate drug delivery appears to be a promising approach for depositing and carrying the desired amount of drug in the skin layers because of its ability to entrap both lipophilic and hydrophilic drugs, high stability and delivering the drug to the target. However, for successful clinical translation of such delivery systems require consideration of several important bio-relevant factors including skin layer distribution of nanocarriers, long-term toxicity issues, skin metabolism of nanocarrier excipients.

6.1 ∣. Limitation for using nanopartides in skin cancer chemoprevention

Nanoparticles though are very good delivery systems for topical use especially for their role as sunscreens since they do not have to cross to the deeper layers of the skin. One of the challenges could be their large-scale manufacture, batch-to-batch variation, and shelf stability, but these issues have been addressed in other cosmetic-based formulations. However, in molecules which have to be delivered to the deeper skin layers, there is still lot of controversy if nanoparticles can cross the barrier stratum corneum. Further delivery of high molecular compounds, proteins, peptides may also be limited since there are challenges with these molecules. Nevertheless, in the end, the ultimate factor governing their use would be based on the cost of manufacture and production and benefits as compared to traditional preparations.

6.2 ∣. Future Direction of Nano-chemoprevention of skin cancer

It is expected that as formulation and manufacturing strategies improve, nanoparticle formulations would be more used topically in chemoprevention of skin cancer. The choice of the right molecule and its encapsulation would be the driving factor in governing the use of these delivery systems. Further, nanoparticles containing molecules beyond small molecules (peptides, proteins) with multiple mechanisms which can be more effective than the existing sunscreen formulations with a plethora of many different agents with varied levels of long-term toxicity would be the guiding principles for their commercialization.

ACKNOWLEDGEMENTS

The authors acknowledges National Institute on Minority Health and Health Disparities(NIMHD) P20 program (Grant#IP20MD006738-03 to M.S.), Cancer Institute of the National Institutes of Health under Award Number R21CA175618 and Moffitt Skin Cancer SPORE Special Cycle-Women and Minority Development Research Program(DRP) award (Grant # 4P50CA168536) and all the authors whose research work is included in this review.

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