Generic placeholder image

Pharmaceutical Nanotechnology

Author(s): Reza Jamali, Erfaneh Ghassami*, Masoud Sadeghi Dinani, Razieh Ghasemi and Mina Mirian

DOI: 10.2174/2211738510666220623153552

DownloadDownload PDF Flyer Cite As
Fabrication and Optimization of Electrospun Polymeric Nanofibers Loaded with 5-Fluorouracil and Rosemary Extract

Page: [232 - 246] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: Topical 5-fluorouracil (5FU) is one of the most prescribed medications for different types of skin cancer; however, it is associated with drug resistance and adverse effects. Rosemary extract has promising dose-dependent antitumor effects, as well as a synergistic effect in combination with 5-fluorouracil, besides sensitization of the 5-FU-resistant cells.

Objective: Polymeric nanofibers loaded with 5FU and rosemary extract were optimized to combine both ingredients in one controlled release drug delivery system, aiming to enhance the efficacy while retaining the adverse effects.

Methods: Polymeric nanofibers loaded with 5-FU and rosemary were fabricated via electrospinning technique. Design expert software was utilized to study the effect of independent variables, including polymer concentration, voltage, and feeding rate on the characteristics of the resulting nanofibers. Afterwards, the FTIR spectrum and release kinetic of the drug and extract from the optimized nanofibers and their cytotoxic effect against A375 cell line were investigated.

Results: The formulation composed of 6.65% PVA electrospun at 1 mL.h-1 and 17.5kV was chosen as the optimum fabrication condition. The mean diameter of the optimized nanofibers was 755 nm. The drug and rosemary extract contents were 75.38 and 93.42%, respectively. The fabrication yield was 100%, bioadhesion force was 1.28 N, and bead abundance was 10 per field. The cytotoxicity of the optimized formulation was significantly higher than the control groups.

Conclusion: According to the appropriate loading percentage, release efficiency and release kinetics, bioadhesion force, and cytotoxicity, these nanofibers could be further investigated as a topical treatment option to increase the efficacy of 5-FU.

Keywords: 5-fluorouracil, rosemary extract, electrospinning, polymeric nanofibers, transdermal drug delivery, PVA.

Graphical Abstract

[1]
Liu X, Xu H, Zhang M, Yu DG. Electrospun medicated nanofibers for wound healing: Review. Membranes (Basel) 2021; 11(10): 770.
[http://dx.doi.org/10.3390/membranes11100770] [PMID: 34677536]
[2]
Heunis TDJ, Dicks LMT. Nanofibers offer alternative ways to the treatment of skin infections. J Biomed Biotechnol 2010; 2010: 510682.
[http://dx.doi.org/10.1155/2010/510682] [PMID: 20798871]
[3]
Mehan N, Kumar M, Bhatt S, Saini V. A Current review on drug loaded nanofibers: Interesting and valuable platform for skin cancer treatment. Pharm Nanotechnol 2020; 8(3): 191-206.
[http://dx.doi.org/10.2174/2211738508666200121103110] [PMID: 31965948]
[4]
Opanasopit P, Sila-On W, Rojanarata T, Ngawhirunpat T. Fabrication and properties of capsicum extract-loaded PVA and CA nanofiber patches. Pharm Dev Technol 2013; 18(5): 1140-7.
[http://dx.doi.org/10.3109/10837450.2012.727004] [PMID: 23033938]
[5]
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: Mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3(5): 330-8.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[6]
Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther 1990; 48(3): 381-95.
[http://dx.doi.org/10.1016/0163-7258(90)90056-8] [PMID: 1707544]
[7]
Moore AY. Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders. J Dermatolog Treat 2009; 20(6): 328-35.
[http://dx.doi.org/10.3109/09546630902789326] [PMID: 19954388]
[8]
Prince GT, Cameron MC, Fathi R, Alkousakis T. Topical 5-fluorouracil in dermatologic disease. Int J Dermatol 2018; 57(10): 1259-64.
[http://dx.doi.org/10.1111/ijd.14106] [PMID: 30187924]
[9]
Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: A systematic review. Arch Dermatol 2009; 145(12): 1431-8.
[http://dx.doi.org/10.1001/archdermatol.2009.291] [PMID: 20026854]
[10]
Levy S, Furst K, Chern W. A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis. Clin Ther 2001; 23(6): 908-20.
[http://dx.doi.org/10.1016/S0149-2918(01)80078-3] [PMID: 11440290]
[11]
Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther 2002; 24(6): 990-1000.
[http://dx.doi.org/10.1016/S0149-2918(02)80012-1] [PMID: 12117087]
[12]
González-Vallinas M, Molina S, Vicente G, et al. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells. Pharmacol Res 2013; 72: 61-8.
[http://dx.doi.org/10.1016/j.phrs.2013.03.010] [PMID: 23557932]
[13]
Rotblatt M. Herbal medicine. expanded commission e monographs. Ann Intern Med 2000; 133(6): 487.
[http://dx.doi.org/10.7326/0003-4819-133-6-200009190-00031]
[14]
Naghibi F, Mosaddegh M, Mohammadi Motamed M, Ghorbani A. Labiatae family in folk medicine in Iran: From ethnobotany to pharmacology. Iran J Pharm Res 2010; 4(2): 63-79.
[15]
Andrade JM, Faustino C, Garcia C, Ladeiras D, Reis CP, Rijo P. Rosmarinus officinalis L.: An update review of its phytochemistry and biological activity. Future Sci OA 2018; 4(4): FSO283.
[http://dx.doi.org/10.4155/fsoa-2017-0124] [PMID: 29682318]
[16]
Cattaneo L, Cicconi R, Mignogna G, et al. Anti-Proliferative Effect of Rosmarinus officinalis L. Extract on Human Melanoma A375 Cells. PLoS One 2015; 10(7): e0132439.
[http://dx.doi.org/10.1371/journal.pone.0132439] [PMID: 26176704]
[17]
Visanji JM, Thompson DG, Padfield PJ. Induction of G2/M phase cell cycle arrest by carnosol and carnosic acid is associated with alteration of cyclin A and cyclin B1 levels. Cancer Lett 2006; 237(1): 130-6.
[http://dx.doi.org/10.1016/j.canlet.2005.05.045] [PMID: 16019137]
[18]
Fang Y, Yang C, Zhang L, et al. Spica prunellae extract enhances fluorouracil sensitivity of 5-fluorouracil-resistant human colon carcinoma HCT-8/5-FU Cells via TOP2α and miR-494. BioMed Res Int 2019; 2019: 5953619.
[http://dx.doi.org/10.1155/2019/5953619] [PMID: 31662984]
[19]
Anantharaju PG, Gowda PC, Vimalambike MG, Madhunapantula SV. An overview on the role of dietary phenolics for the treatment of cancers. Nutr J 2016; 15(1): 99.
[http://dx.doi.org/10.1186/s12937-016-0217-2] [PMID: 27903278]
[20]
Yáñez J, Vicente V, Alcaraz M, et al. Cytotoxicity and antiproliferative activities of several phenolic compounds against three melanocytes cell lines: Relationship between structure and activity. Nutr Cancer 2004; 49(2): 191-9.
[http://dx.doi.org/10.1207/s15327914nc4902_11] [PMID: 15489212]
[21]
Prakash V. Terpenoids as cytotoxic compounds: A perspective. Pharmacogn Rev 2018; 12(24): 166.
[http://dx.doi.org/10.4103/phrev.phrev_3_18]
[22]
Huang MT, Ho CT, Wang ZY, et al. Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res 1994; 54(3): 701-8.
[PMID: 8306331]
[23]
Ingle KP, Deshmukh AG, Padole DA, Dudhare MS, Moharil MP, Khelurkar VC. Phytochemicals: Extraction methods, identification and detection of bioactive compounds from plant extracts. J Pharmacogn Phytochem 2017; 6(1): 32-6.
[24]
Commission BP. British Pharmacopoeia 2005. London: Stationery Office 2005.
[25]
Patel G, Yadav BKN. Formulation, characterization and in vitro cytotoxicity of 5-fluorouracil loaded polymeric electrospun nanofibers for the treatment of skin cancer. Recent Pat Nanotechnol 2019; 13(2): 114-28.
[http://dx.doi.org/10.2174/1872210513666190314095643] [PMID: 30868972]
[26]
Varshosaz J, Jajanian-Najafabadi A, Soleymani A, Khajavinia A. Poly (butylene adipate-co-terephthalate) electrospun nanofibers loaded with 5-fluorouracil and curcumin in treatment of colorectal cancer cells. Polym Test 2018; 65: 217-30.
[http://dx.doi.org/10.1016/j.polymertesting.2017.11.020]
[27]
Cojocaru I, Ochiuz L. Şpac A, Popa G, Palade L, Popovici I The validation of the UV spectrophotometric method for the assay of 5 fluorouracil Farmacia 2012; 60: 379-85.
[28]
Geeta PM, Anita P. A novel effervescent bioadhesive vaginal tablet of ketoconazole: Formulation and in vitro evaluation. Int J Pharm Tech Res 2010; 2(1): 656-67.
[29]
Afonso MS. de O Silva AM, Carvalho EB, et al. Phenolic compounds from Rosemary (Rosmarinus officinalis L.) attenuate oxidative stress and reduce blood cholesterol concentrations in diet-induced hypercholesterolemic rats. Nutr Metab (Lond) 2013; 10(1): 19.
[http://dx.doi.org/10.1186/1743-7075-10-19] [PMID: 23374457]
[30]
Priyadarsini KI. The chemistry of curcumin: From extraction to therapeutic agent. Molecules 2014; 19(12): 20091-112.
[http://dx.doi.org/10.3390/molecules191220091] [PMID: 25470276]
[31]
Sfouq Aleanizy F, Yahya Alqahtani F, Alkahtani HM, et al. Colored polymeric nanofiber loaded with minoxidil sulphate as beauty coverage and restoring hair loss. Sci Rep 2020; 10(1): 4084.
[http://dx.doi.org/10.1038/s41598-020-60863-0] [PMID: 32139735]
[32]
Mwiiri FK, Daniels R. Influence of PVA molecular weight and concentration on electrospinnability of birch bark extract-loaded nanofibrous scaffolds intended for enhanced wound healing. Molecules 2020; 25(20): E4799.
[http://dx.doi.org/10.3390/molecules25204799] [PMID: 33086645]
[33]
Varshosaz J, Jahanian A, Maktoobian M. Optimization of poly(methyl vinyl ether-co-maleic acid) electrospun nanofibers as a fast-dissolving drug delivery system. Adv Biomed Res 2018; 7(1): 84.
[http://dx.doi.org/10.4103/abr.abr_83_17] [PMID: 29930924]
[34]
Baumgarten PK. Electrostatic spinning of acrylic microfibers. J Colloid Interface Sci 1971; 36(1): 71-9.
[http://dx.doi.org/10.1016/0021-9797(71)90241-4]
[35]
SÜnter EroĞlu N, CanoĞlu S, YÜksek M. Characterization, mechanical, and antibacterial properties of nanofibers derived from olive leaf, fumitory, and terebinth extracts. Turk J Chem 2020; 44(4): 1043-57.
[http://dx.doi.org/10.3906/kim-2003-45] [PMID: 33488211]
[36]
Liu Y, He JH, Yu. Jy, Zeng H. Controlling numbers and sizes of beads in electrospun nanofibers. Polymer International Polym Int 2008; 57(4): 632-6.
[http://dx.doi.org/10.1002/pi.2387]
[37]
Pillay V, Dott C, Choonara YE, et al. A review of the effect of processing variables on the fabrication of electrospun nanofibers for drug delivery applications. J Nanomater 2013; 2013: 789289.
[http://dx.doi.org/10.1155/2013/789289]
[38]
Fahmy A, Mohamed TA, Friedrich JF. XPS and IR studies of plasma polymers layer deposited from allylamine with addition of ammonia. Appl Surf Sci 2018; 458: 1006-17.
[http://dx.doi.org/10.1016/j.apsusc.2018.07.160]
[39]
Şahin OM, Sanl O, Solak E. Release of anticancer drug 5-fluorouracil from different ionically crosslinked alginate beads. J Biomater Nanobiotechnol 2012.03: 469-79
[40]
Fahmy A, Debarnot D, Friedrich J. Influence of water addition on the structure of plasma-deposited allyl alcohol polymer films. J Adhes Sci Technol 2015; 29(10): 965-80.
[http://dx.doi.org/10.1080/01694243.2015.1011367]
[41]
Fahmy A, Mohamed TA, Abu-Saied M, Helaly H, El-Dossoki F. Structure/property relationship of polyvinyl alcohol/dimethoxydimethylsilane composite membrane: Experimental and theoretical studies. Spectrochim Acta A Mol Biomol Spectrosc 2020; 228: 117810.
[http://dx.doi.org/10.1016/j.saa.2019.117810] [PMID: 31791909]
[42]
Deleanu I, Stoica AMS, Dobre L, Dobre T, Jinga S, et al. Potassium sorbate release from poly(vinyl alcohol)–bacterial cellulose films. Chem Pap 2012; 66: 138-43.
[43]
Alaqarbeh M. Green synthesis, characterization of silver sulfide nanoparticles and antibacterial activity evaluation. Chem Int 2020; 6: 42-8.
[44]
Kini S, Bahadur D, Panda D. Mechanism of anti-cancer activity of benomyl loaded nanoparticles in multidrug resistant cancer cells. J Biomed Nanotechnol 2015; 11(5): 877-89.
[http://dx.doi.org/10.1166/jbn.2015.1998] [PMID: 26349399]