Pomegranate oil-based nanocapsules enhance 3,3’-diindolylmethane action against melanoma cells
DOI:
https://doi.org/10.1590/Keywords:
Indole derivatives, Skin cancer, Nanoparticles, Metastasis, Cell invasionAbstract
Cutaneous melanoma, a highly aggressive skin cancer, is the leading cause of death among skin neoplasms. Hence, this study focused on developing a 3,3'-diindolylmethane (DIM)-loaded pomegranate oil (PO) nanocapsule suspensions and their potential effects on melanoma cells. Nanocapsule suspensions were prepared by the interfacial deposition method (Eudragit ® RS100). Medium-chain triglyceride (MCT) nanocapsules were produced for comparison. The of nanocapsule suspensions showed nanometric size (<180 nm), low polydispersity index (<0.12) (as measured by dynamic light scattering), positive zeta potential (tested by capillary microelectrophoresis), pH below 5.0 (as measured by potentiometry), DIM content, and nearly 100% encapsulation efficiency (evaluated by HPLC). The formulations were considered non-irritating (according to HET-CAM) regardless of the core constitution. Notably, PO-based nanocapsules showed a superior performance compared to the MCT-containing formulation in delaying DIM light degradation (tested by UVC radiation), lowering genotoxicity (determined by Allium cepa ), and increasing in vitro antioxidant action (measured by ABTS and FRAP). Additionally, the PO-based formulation demonstrated higher in vitro antitumoral activity in B16F10 than MCT nanocarriers (IC 50 of 6.49 and >24 µg/mL, respectively), and antimetastatic capacity by reducing B16F10 cell adhesion, colonization, and migration. Based on these results, this study suggests that the nanoencapsulation of DIM into PO nanocapsules may be a promising approach in melanoma treatment.
Downloads
References
Aly FAE, Asmaa SS, Zeinab MH. Evaluation of the antimutagenic effect of pomegranate seed oil against genotoxicity induced by nitrobenzene in mice. Glob J Pharmacol. 2014;8(2):189-195.
Amare DE. Anti-Cancer and Other Biological Effects of a Dietary Compound 3,3ʹ-Diindolylmethane Supplementation: A Systematic Review of Human Clinical Trials. Nutr Diet Suppl. 2020;12:123-137.
Amri Z, Lazreg-Aref H, Mekni M, El-Gharbi S, Dabbaghi O, Mechri B, et al. Oil characterization and lipids class composition of pomegranate seeds. BioMed Res Int. 2017:1-8.
Baccarin T, Mitjans M, Ramos D, Lemos-Senna E, Vinardell MP. Photoprotection by Punica granatum seed oil nanoemulsion entrapping polyphenol-rich ethyl acetate fraction against UVB-induced DNA damage in human keratinocyte (HaCaT) cell line. J Photochem Photobiol B Biol. 2015;153:127-136.
Benzie IFF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal Biochem. 1996;239(1):70–76.
Bernal-Chávez S, Del Prado-Audelo ML, Caballero-Florán IH, Giraldo-Gomez DM, Figueroa-Gonzalez G, Reyes-Hernandez OD, et al. Insights into terminal sterilization processes of nanoparticles for biomedical applications. Molecules. 2021;26(7):2068.
Bürk RR. A factor from a transformed cell line that affects cell migration. Proc Natl Acad Sci USA. 1973;70(2):369–372.
Cairone F, Salviti C, Lazzetti A, Fabrizi G, Troiani A, Pepi F, et al. In-Depth Chemical Characterization of Punica granatum L. Seed Oil. Foods. 2023;12(8): 1592.
Carletto B, Berton J, Ferreira TN, Dalmolin LF, Paludo KS, Mainardes RM, et al. Resveratrol-loaded nanocapsules inhibit murine melanoma tumor growth. Colloids Surf B Biointerfaces. 2016;144:65-72.
Chang KF, Lai HC, Lee SC, Huang XF, Huang YC, Chou TE, et al. The effects of patchouli alcohol and combination with cisplatin on proliferation, apoptosis and migration in B16F10 melanoma cells. J Cell Mol Med. 2023(April):1-13.
Contri RV, Ribeiro KL, Fiel LA, Pohlmann AR, Guterres SS. Vegetable oils as core of cationic polymeric nanocapsules: influence on the physicochemical properties. J Exp Nanosci. 2013;8(7-8):913-924.
Contri RV, Fiel LA, Alnasif N, Pohlmann AR, Guterres SS, Schäfer-Korting M. Skin penetration and dermal tolerability of acrylic nanocapsules: Influence of the surface charge and a chitosan gel used as vehicle. Int J Pharm. 2016;507(1-2):12-20.
da Silva JLG, Viana AR, Passos DF, Krause LMF, Miron VV, Schetinger MRC., et al. Istradefylline modulates purinergic enzymes and reduces malignancy-associated factors in B16F10 melanoma cells. Purinerg Signal. 2022:1-18.
Dalcin AJF, Vizzotto BS, Bochi GV, Guarda NS, Nascimento K, Sagrillo MR, et al. Nanoencapsulation of the flavonoid dihydromyricetin protects against the genotoxicity and cytotoxicity induced by cationic nanocapsules. Colloids Surf B Biointerfaces. 2019;173:798-805.
Etebari M, Jafarian-Dehkordi A, Lame V. Evaluation of protective effect of amifostine on dacarbazine induced genotoxicity. Res Pharm Sci. 2015;10(1):73–79.
Ferreira LM, Cervi VF, Sari MHM, Barbieri AV, Ramos AP, Copetti PM, et al. Diphenyl diselenide loaded poly (ε-caprolactone) nanocapsules with selective antimelanoma activity: Development and cytotoxic evaluation. Mater Sci Eng C. 2018;91:1-9.
Ferreira LM, Sari MHM, Cervi VF, Gehrcke M, Barbieri AV, Zborowski VA, et al. Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug. Colloids Surf B Biointerfaces. 2016;144:214-221.
Ferreira LM, Cervi VF, Gehrcke M, da Silveira EF, Azambuja JH, Braganhol E, et al. Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: selective antiglioma formulation for intravenous administration. Colloids Surf B Biointerfaces. 2015;130:272-277.
Fessi HPFD, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55(1):1–4.
Giuliani LG, Pegoraro NS, Camponogara C, Osmari BF, Brum BT, Reolon JB, et al. Locust bean gum based hydrogel containing nanocapsules for 3,3 ′ -diindolylmethane delivery in skin inflammatory conditions. J Drug Deliv Sci. Technol. 2022;78(April):103960.
Gomes GS, Maciel TR, Piegas EM, Michels LR, Colomé LM, Freddo RJ, et al. Optimization of Curcuma Oil/Quinine-Loaded Nanocapsules for Malaria Treatment. AAPS PharmSciTech. 2018;19(2):551–564.
Guan X. Cancer metastases: Challenges and opportunities. Acta Pharm Sin B. 2015;5(5):402–418.
Gupta S, Das D, Mitra PK, Halder S, Datta AK. Assessment of Cytotoxicity Induced by Hazardous Chemotherapeutic Drugs Cyclophosphamide and 5-Fluorouracil in Allium cepa Assay for Ecological Safety. Cytologia. 2020;85(2):151–155.
Hajra S, Basu A, Singha RS, Patra AR, Bhattacharya S. Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3′-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis. Free Radic Res. 2017;51(9-10):812–827.
Heo JR, Lee GA, Kim GS, Hwang KA, Choi KC. Phytochemical-induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis and differentiation in malignant melanoma cells. Phytomed. 2018;39(December 2017):100–110.
Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). ICCVAM-Recommended Test Method Protocol: Hen’s Egg Test—Chorioallantoic Membrane (HET-CAM) Test Method. 2010;13(1):B30-B38.
Iqbal J, Abbasi BA, Ahmad R, Batool R, Mahmood T, Ali B, et al. Potential phytochemicals in the fight against skin cancer: Current landscape and future perspectives. Biomed Pharmacother. 2019;109(October 2018):1381–1393.
Kamnev AA, Shchelochkov AG, Perfiliev YD, Tarantilis PA, Polissiou MG. Spectroscopic investigation of indole-3-acetic acid interaction with iron (III). J Mol Struct. 2001;563:565-572.
Kim EK, Jang M, Song MJ, Kim D, Kim Y, Jang HH. Redox-mediated mechanism of chemoresistance in cancer cells. Antioxidants. 2019;8(10):1–18.
Leite MN, Viegas JSR, Praça FSG, Paula NA, Ramalho LNZ, Bentley MV, et al. Ex vivo model of human skin (hOSEC) for assessing the dermatokinetics of the anti-melanoma drug Dacarbazine. Eur J Pharm Sci. 2021;160(February):105769.
Li WX, Chen LP, Sun MY, Li JT, Liu HZ, Zhu W. 3’3-Diindolylmethane inhibits migration, invasion and metastasis of hepatocellular carcinoma by suppressing FAK signaling. Oncotarget. 2015;6(27):23776–23792.
Luo Y, Wang TT, Teng Z, Chen P, Sun J, Wang Q. Encapsulation of indole-3-carbinol and 3,3′-diindolylmethane in zein/carboxymethyl chitosan nanoparticles with controlled release property and improved stability. Food Chem. 2013;139(1-4):224–230.
Lydia DE, Khusro A, Immanuel P, Esmail GA, Al-Dhabi NA, Arasu MV. Photo-activated synthesis and characterization of gold nanoparticles from Punica granatum L. seed oil: An assessment on antioxidant and anticancer properties for functional yoghurt nutraceuticals. J Photochem Photobiol B Biol. 2020;206(January):111868.
Marchiori MCL, Rigon C, Copetti PM, Sagrillo MR, Cruz L. Nanoencapsulation Improves Scavenging Capacity and Decreases Cytotoxicity of Silibinin and Pomegranate Oil Association. AAPS PharmSciTech. 2017a;18(8):3236–3246.
Marchiori MCL, Rigon C, Camponogara C, Oliveira SM, Cruz L. Hydrogel containing silibinin-loaded pomegranate oil based nanocapsules exhibits anti-inflammatory effects on skin damage UVB radiation-induced in mice. J Photochem Photobiol B Biol. 2017b;170:25-32.
Mattiazzi J, Sari MHM, Lautenchleger R, Dal Prá M, Braganhol E, Cruz L. Incorporation of 3,3′-Diindolylmethane into Nanocapsules Improves Its Photostability, Radical Scavenging Capacity, and Cytotoxicity Against Glioma Cells. AAPS PharmSciTech. 2019;20(2):1–11.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55–63.
Mukherjee C, Bhattacharyya S, Ghosh S, Bhattacharyya DK. Dietary effects of punicic acid on the composition and peroxidation of rat plasma lipid. J Oleo Sci. 2002;51(8):513-522.
Osmari BF, Medeiros GA, Reolon JB, Prado VC, Brucker N, Cruz L. Cationic nanocapsule suspension as an alternative to the sublingual delivery of nifedipine nifedipine. Pharm Dev Technol. 2023;28(5):1–11.
Patel AR, Spencer SD, Chougule MB, Safe S, Singh M. Pharmacokinetic evaluation and In Vitro-In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM). Eur J Pharm Sci. 2012;46(1-2):8–16.
Patel D, Zode SS, Vansal AK. Formulation aspects of intravenous nanosuspensions. Int J Pharm. 2020;586:119555.
Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med. 1999;26(9-10):1231-1237.
Rigon RB, Oyafuso MH, Fujimura AT, Gonçalvez ML, Prado AHD, Gremião MP, et al. Nanotechnology-based drug delivery systems for melanoma antitumoral therapy: A review. Biomed Res Int. 2015;2015:16–20.
Sharma K, Kesharwani P, Prajapati SK, Jain A, Jain D, Moby N, et al. An insight into anticancer bioactives from Punica granatum (Pomegranate). Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2022;22(4):694-702.
Thomson CA, Chow HS, Wertheim BC, Roe DJ, Stopeck A, Maskarinec G, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017;165(1):97-107.
Wang X, Zhao Y, Yu M, Xu Y. PTEN/Akt signaling-mediated activation of the mitochondrial pathway contributes to the 3, 3′-diindolylmethane-mediated antitumor effect in malignant melanoma cells. J Med Food. 2020;23(12):1248-1258.
Widiandani T, Tandian T, Zufar BD, Suryadi A, Purwanto BT, Hardjono S, et al. In vitro study of pinostrobin propionate and pinostrobin butyrate: Cytotoxic activity against breast cancer cell T47D and its selectivity index. J Public Health Afr. 2023;14(1):2516.
Ye F, Li X, Sun K, Xu W, Shi H, Bian J, et al. Inhibition of endogenous hydrogen sulfide biosynthesis enhances the anti-cancer effect of 3, 3′-diindolylmethane in human gastric cancer cells. Life Sci. 2020;(261):118348.
Yuan G, Sinclair AJ, Xu C, Li D. Incorporation and metabolism of punicic acid in healthy young humans. Mole Nutr Food Res. 2009;53(10):1336-1342.
Zare M, Shaverdi H, Kalaee SEV. Anti-cancer effects of pomegranate seed oil on esophageal cancer cell line (KYSE-30). Gen Cell Tissue. 2021;8(1):17-21.
Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, et al. Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology. Molecules. 2020;25(16):3731.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.