The objective of this work was to characterize the toxicological profile of a newly developed sunscreen formulation based on polymeric nanocapsules (NCs) loading benzophenone-3 (BZP3). NCs composed of poly(ε-caprolactone) carrot oil and Pluronic® F68 were produced by emulsification-diffusion method. Their mean particle size (Z-Ave) ranged from 280 to 420 nm, polydispersity index (PDI) was below 0.37, while zeta potential (ZP) reached about |+11 mV|. No cytotoxic effects were observed in L929 fibroblast cell line for the blank (i.e., non-loaded) NCs and BZP3-loaded NCs (BZP3-NCs). The semi-solid sunscreen formulation was stable over time (centrifugation testing) and exhibited non-Newtonian pseudoplastic behavior, which is typical of products for topical application onto the skin. The sun protection factor (SPF) value reached 8.84, when incorporating BZP3-NCs (SPF of 8.64) into the semi-solid formulation. A synergistic effect was also observed when combining the formulation ingredients of nanocapsules, i.e., SPF of carrot oil was 6.82, blank NCs was 6.84, and BZP3-loaded NCs was 8.64. From the hen's egg-chorioallantoic membrane test (HET-CAM) test, the non-irritation profile of the developed formulations could also be confirmed. The obtained results show a promising use of poly(ε-caprolactone) nanocapsules to be loaded with lipophilic sunscreens as benzophenone-3.

CEB Centre of Biological Engineering University of Minho Campus de Gualtar 4710 057 Braga Portugal

Department of Morphology Federal University of Sergipe Avenida Marechal Rondon São Cristovão 49100 000 Brazil

Department of Pharmaceutical Technology Faculty of Pharmacy University of Coimbra Pólo das Ciências da Saúde Azinhaga de Santa Comba 3000 548 Coimbra Portugal

Department of Pharmacy Pharmaceutical Technology and Physical Chemistry and Institute of Nanoscience and Nanotechnology Faculty of Pharmacy University of Barcelona 08028 Barcelona Spain

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic v v i Heyrovsky Sq 2 162 06 Prague Czech Republic

Institute of Technology and Research Av Murilo Dantas 300 Aracaju 49010 390 Brazil

Tiradentes Institute 150 Mt Vernon St Dorchester MA 02125 USA

University of Tiradentes Biotechnological Postgraduate Program Av MuriloDantas 300 Aracaju 49010 390 Brazil

See more in PubMed

Tampucci S., Burgalassi S., Chetoni P., Monti D. Cutaneous permeation and penetration of sunscreens: Formulation strategies and in vitro methods. Cosmetics. 2018;5:1. doi: 10.3390/cosmetics5010001. DOI

Serpone N., Dondi D., Albini A. Inorganic and organic UV filters: Their role and efficacy in sunscreens and suncare products. Inorg. Chim. Acta. 2007;360:794–802. doi: 10.1016/j.ica.2005.12.057. DOI

Gabros S., Zito P.M. StatPearls [Internet] StatPearls Publishing; Treasure Island, FL, USA: 2019. Sunscreens and Photoprotection. PubMed

Suh H.W., Lewis J., Fong L., Ramseier J.Y., Carlson K., Peng Z.H., Yin E.S., Saltzman W.M., Girardi M. Biodegradable bioadhesive nanoparticle incorporation of broad-spectrum organic sunscreen agents. Bioeng. Transl. Med. 2019;4:129–140. doi: 10.1002/btm2.10092. PubMed DOI PMC

Severino P., Moraes L.F., Zanchetta B., Souto E.B., Santana M.H. Elastic liposomes containing benzophenone-3 for sun protection factor enhancement. Pharm. Dev. Technol. 2012;17:661–665. doi: 10.3109/10837450.2011.580762. PubMed DOI

Cefali L.C., Ataide J.A., Eberlin S., da Silva Goncalves F.C., Fernandes A.R., Marto J., Ribeiro H.M., Foglio M.A., Mazzola P.G., Souto E.B. In vitro SPF and Photostability Assays of Emulsion Containing Nanoparticles with Vegetable Extracts Rich in Flavonoids. AAPS PharmSciTech. 2018;20:9. doi: 10.1208/s12249-018-1217-7. PubMed DOI

Souto E.B., Anselmi C., Centini M., Muller R.H. Preparation and characterization of n-dodecyl-ferulate-loaded solid lipid nanoparticles (SLN) Int. J. Pharm. 2005;295:261–268. doi: 10.1016/j.ijpharm.2005.02.005. PubMed DOI

Xia Q., Saupe A., Muller R.H., Souto E.B. Nanostructured lipid carriers as novel carrier for sunscreen formulations. Int. J. Cosmet. Sci. 2007;29:473–482. doi: 10.1111/j.1468-2494.2007.00410.x. PubMed DOI

Wawrzynczak A., Feliczak-Guzik A., Nowak I. Nanobiomaterials in Galenic Formulations and Cosmetics. Elsevier; Amsterdam, The Netherlands: 2016. Nanosunscreens: From nanoencapsulated to nanosized cosmetic active forms; pp. 25–46.

Krause M., Frederiksen H., Sundberg K., Jørgensen F., Jensen L., Nørgaard P., Jørgensen C., Ertberg P., Juul A., Drzewiecki K. Presence of benzophenones commonly used as UV filters and absorbers in paired maternal and fetal samples. Environ. Int. 2018;110:51–60. doi: 10.1016/j.envint.2017.10.005. PubMed DOI

Niakousari M., Damueh M., Gahruie H.H., Bekhit A., Greiner R., Roohiejad S. Emulsion-Based Systems for Delivery of Food Active Compounds: Formation, Application, Health and Safety. 1st ed. Wiley; Croydon, UK: 2018. Conventional emulsions; pp. 1–27.

Gilbert E., Roussel L., Serre C., Sandouk R., Salmon D., Kirilov P., Haftek M., Falson F., Pirot F. Percutaneous absorption of benzophenone-3 loaded lipid nanoparticles and polymeric nanocapsules: A comparative study. Int. J. Pharm. 2016;504:48–58. doi: 10.1016/j.ijpharm.2016.03.018. PubMed DOI

Marcato P.D., Caverzan J., Rossi-Bergmann B., Pinto E.F., Machado D., Silva R.A., Justo G.Z., Ferreira C.V., Duran N. Nanostructured polymer and lipid carriers for sunscreen. Biological effects and skin permeation. J. Nanosci. Nanotechnol. 2011;11:1880–1886. doi: 10.1166/jnn.2011.3135. PubMed DOI

Paese K., Jager A., Poletto F.S., Pinto E.F., Rossi-Bergmann B., Pohlmann A.R., Guterres S.S. Semisolid formulation containing a nanoencapsulated sunscreen: Effectiveness, in vitro photostability and immune response. J. Biomed. Nanotechnol. 2009;5:240–246. doi: 10.1166/jbn.2009.1028. PubMed DOI

Siqueira N.M., Contri R.V., Paese K., Beck R.C., Pohlmann A.R., Guterres S.S. Innovative sunscreen formulation based on benzophenone-3-loaded chitosan-coated polymeric nanocapsules. Skin Pharmacol. Physiol. 2011;24:166–174. doi: 10.1159/000323273. PubMed DOI

Teixeira Z., Dreiss C.A., Lawrence M.J., Heenan R.K., Machado D., Justo G.Z., Guterres S.S., Duran N. Retinyl palmitate polymeric nanocapsules as carriers of bioactives. J. Colloid Interface Sci. 2012;382:36–47. doi: 10.1016/j.jcis.2012.05.042. PubMed DOI

Batista-Duharte A., Jorge Murillo G., Pérez U.M., Tur E.N., Portuondo D.F., Martínez B.T., Téllez-Martínez D., Betancourt J.E., Pérez O. The Hen’s Egg Test on Chorioallantoic Membrane: An Alternative Assay for the Assessment of the Irritating Effect of Vaccine Adjuvants. Int. J. Toxicol. 2016;35:627–633. doi: 10.1177/1091581816672187. PubMed DOI

Piñón-Segundo E., Llera-Rojas V.G., Leyva-Gómez G., Urbán-Morlán Z., Mendoza-Muñoz N., Quintanar-Guerrero D. Nanoscale Fabrication, Optimization, Scale-up and Biological Aspects of Pharmaceutical Nanotechnology. Elsevier; Amsterdam, The Netherlands: 2018. The emulsification-diffusion method to obtain polymeric nanoparticles: Two decades of research; pp. 51–83.

Santos E.P., Freitas Z.M., Souza K.R., Garcia S., Vergnanini A. In vitro and in vivo determinations of sun protection factors of sunscreen lotions with octylmethoxycinnamate. Int. J. Cosmet. Sci. 1999;21:1–5. doi: 10.1046/j.1467-2494.1999.181658.x. PubMed DOI

Sanchez-Lopez E., Egea M.A., Cano A., Espina M., Calpena A.C., Ettcheto M., Camins A., Souto E.B., Silva A.M., Garcia M.L. PEGylated PLGA nanospheres optimized by design of experiments for ocular administration of dexibuprofen-in vitro, ex vivo and in vivo characterization. Colloids Surf. B Biointerfaces. 2016;145:241–250. doi: 10.1016/j.colsurfb.2016.04.054. PubMed DOI

Fangueiro J.F., Calpena A.C., Clares B., Andreani T., Egea M.A., Veiga F.J., Garcia M.L., Silva A.M., Souto E.B. Biopharmaceutical evaluation of epigallocatechin gallate-loaded cationic lipid nanoparticles (EGCG-LNs): In vivo, in vitro and ex vivo studies. Int. J. Pharm. 2016;502:161–169. doi: 10.1016/j.ijpharm.2016.02.039. PubMed DOI

Araujo J., Vega E., Lopes C., Egea M.A., Garcia M.L., Souto E.B. Effect of polymer viscosity on physicochemical properties and ocular tolerance of FB-loaded PLGA nanospheres. Colloids Surf. B Biointerfaces. 2009;72:48–56. doi: 10.1016/j.colsurfb.2009.03.028. PubMed DOI

De Brum T.L., Fiel L.A., Contri R.V., Guterres S.S., Pohlmann A.R. Polymeric Nanocapsules and Lipid-Core Nanocapsules Have Diverse Skin Penetration. J. Nanosci. Nanotechnol. 2015;15:773–780. doi: 10.1166/jnn.2015.9185. PubMed DOI

Davaeifar S., Modarresi M.H., Mohammadi M., Hashemi E., Shafiei M., Maleki H., Vali H., Zahiri H.S., Noghabi K.A. Synthesizing, characterizing, and toxicity evaluating of Phycocyanin-ZnO nanorod composites: A back to nature approaches. Colloids Surf. B Biointerfaces. 2019;175:221–230. doi: 10.1016/j.colsurfb.2018.12.002. PubMed DOI

Utsunomiya H., Hiraishi R., Kishimoto K., Hamada S., Abe S., Bekki Y., Kamemura N. Cytotoxicity of benzophenone-3, an organic ultraviolet filter, caused by increased intracellular Zn2+ levels in rat thymocytes. Chem. Biol. Interact. 2019;298:52–56. doi: 10.1016/j.cbi.2018.10.029. PubMed DOI

Doktorovova S., Kovacevic A.B., Garcia M.L., Souto E.B. Preclinical safety of solid lipid nanoparticles and nanostructured lipid carriers: Current evidence from in vitro and in vivo evaluation. Eur. J. Pharm. Biopharm. 2016;108:235–252. doi: 10.1016/j.ejpb.2016.08.001. PubMed DOI

Doktorovova S., Souto E.B., Silva A.M. Nanotoxicology applied to solid lipid nanoparticles and nanostructured lipid carriers—A systematic review of in vitro data. Eur. J. Pharm. Biopharm. 2014;87:1–18. doi: 10.1016/j.ejpb.2014.02.005. PubMed DOI

Rigon R.B., Goncalez M.L., Severino P., Alves D.A., Santana M.H.A., Souto E.B., Chorilli M. Solid lipid nanoparticles optimized by 22 factorial design for skin administration: Cytotoxicity in NIH3T3 fibroblasts. Colloids Surf. B Biointerfaces. 2018;171:501–505. doi: 10.1016/j.colsurfb.2018.07.065. PubMed DOI

Singh S., Lohani A., Mishra A.K., Verma A. Formulation and evaluation of carrot seed oil-based cosmetic emulsions. J. Cosmet. Laser. 2019;21:99–107. doi: 10.1080/14764172.2018.1469769. PubMed DOI

Ohman H., Vahlquist A. In vivo studies concerning a pH gradient in human stratum corneum and upper epidermis. Acta Derm. Venereol. 1994;74:375–379. doi: 10.2340/0001555574375379. PubMed DOI

McKenzie B., Kay G., Matthews K.H., Knott R.M., Cairns D. The hen’s egg chorioallantoic membrane (HET-CAM) test to predict the ophthalmic irritation potential of a cysteamine-containing gel: Quantification using Photoshop(R) and ImageJ. Int. J. Pharm. 2015;490:1–8. doi: 10.1016/j.ijpharm.2015.05.023. PubMed DOI

Nanotechnology in Cosmetics and Cosmeceuticals-A Review of Latest Advancements