SYNERGISTIC EFFECT LUNG CANCER THERAPY: CO-DELIVERY OF QUERCETIN AND CISPLATIN VIA EUDRAGIT L-100 NANOPARTICLES IN VITRO

FIRAS F. AL-MAMOORI; HABIBAH A. WAHAB; WAQAS AHMAD

doi:10.22159/ijap.2024v16i6.52449

Authors

FIRAS F. AL-MAMOORI School of Pharmaceutical Science, Universiti Sains Malaysia, School of Pharmaceutical Science, University of Babylon, Iraq
HABIBAH A. WAHAB School of Pharmaceutical Science, Universiti Sains Malaysia
WAQAS AHMAD School of Pharmaceutical Science, Universiti Sains Malaysia

DOI:

https://doi.org/10.22159/ijap.2024v16i6.52449

Keywords:

Quercetin, Cisplatin nanoparticles, Lung cancer, Eudragit®L-100, Cytotoxic test, pH-sensitive polymer, Synergistic effect

Abstract

Objective: This study aims to investigate the potential of Eudragit L-100 nanoparticles for the co-delivery of quercetin and cisplatin to lung cancer cells, seeking to exploit the synergistic effects of the two drugs while overcoming their individual limitations.

Methods: We investigate the synergistic effect of co-delivering quercetin and cisplatin using Eudragit L-100 nanoparticles for lung cancer therapy. The nanoparticles were synthesized using the nanoprecipitation method, where Eudragit L-100 was dissolved in an organic solvent, followed by the incorporation of quercetin and cisplatin. The resultant nanoparticles were characterized for size, zeta potential, drug loading efficiency, and morphology using techniques such as Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM).

Results: The co-loaded Quercetin-Cisplatin Nanoparticles (Qu-Cis)-NPs formulation had a mean particle size of 475±4.77 nm. Polydispersion index of 0.266±0.093 and zeta potential was-24.03±0.89 mV. The in vitro cytotoxicity was assessed using normal cell and lung cancer cell lines in vitro studies showed that the developed nanoparticles significantly increased cancer cell mortality compared to individual drug treatments. The combination (Qu-Cis)-NPs showed more cytotoxicity on the Non-Small Lung Cancer Cell Line (NCI-H460) cancer cell line after 48 h of incubation compared to Qu loaded-NPs and Cis loaded-NPs, particularly at a concentration of 1 mg/ml. The combination showed no cytotoxicity effect on normal Human Lung fibroblast cell Lines (CCD-19 lu) cells at all concentrations after 24 h, but showed cytotoxicity effects at concentrations (0.125, 0.25, 0.5, and 1.0) mg/ml after 48 h.

Conclusion: The Eudragit L-100 nanoparticle system for co-delivering quercetin and cisplatin showed a promising synergistic effect in lung cancer treatment. It effectively addresses the solubility and toxicity issues of both drugs, offering a potentially more effective treatment option that merits further clinical investigation.

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References

Services. Available from. https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services.

The Lancet T. Globocan 2018: counting the toll of cancer. Lancet. 2018 Sep 22;392(10152):985. doi: 10.1016/S0140-6736(18)32252-9, PMID 30264708.

Siegel RL, Miller KD, Jemal A. Cancer statistics 2019. CA Cancer J Clin. 2019;69(1):7-34. doi: 10.3322/caac.21551, PMID 30620402.

World Health Organization (WHO). Cancer: 2020.

Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288-300. doi: 10.21037/tlcr.2016.06.07, PMID 27413711.

WU Q, Yang Z, Nie Y, Shi Y, Fan D. Multidrug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 2014;347(2):159-66. doi: 10.1016/j.canlet.2014.03.013, PMID 24657660.

Anwer MK, Al Mansoor MA, Jamil S, Al Shdefat R, Ansari MN, Shakeel F. Development and evaluation of PLGA polymer-based nanoparticles of quercetin. Int J Biol Macromol. 2016 Nov;92:213-9. doi: 10.1016/j.ijbiomac.2016.07.002, PMID 27381585.

Cetin M, Aktas Y, Vural I, Capan Y, Dogan LA, Duman M. Preparation and in vitro evaluation of bFGF loaded chitosan nanoparticles. Drug Deliv. 2007;14(8):525-9. doi: 10.1080/10717540701606483, PMID 18027182.

Adibkia K, Javadzadeh Y, Dastmalchi S, Mohammadi G, Niri FK, Alaei Beirami M. Naproxen eudragit RS100 nanoparticles: preparation and physicochemical characterization. Colloids Surf B Biointerfaces. 2011;83(1):155-9. doi: 10.1016/j.colsurfb.2010.11.014, PMID 21130612.

Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol. 2012;83(1):6-15. doi: 10.1016/j.bcp.2011.08.010, PMID 21856292.

Cai X, Fang Z, Dou J, YU A, Zhai G. Bioavailability of quercetin: problems and promises. Curr Med Chem. 2013;20(20):2572-82. doi: 10.2174/09298673113209990120, PMID 23514412.

Mokale VJ, Naik JB, Verma U, Yadava SK. Preparation and characterization of biodegradable glimepiride loaded PLA nanoparticles by o/w solvent evaporation method using high-pressure homogenizer: a factorial design approach. SA J Pharm Pharmacol. 2018;1(1):1.

Adibkia K, Javadzadeh Y, Dastmalchi S, Mohammadi G, Niri FK, Alaei Beirami M. Naproxen eudragit RS100 nanoparticles: preparation and physicochemical characterization. Colloids Surf B Biointerfaces. 2011;83(1):155-9. doi: 10.1016/j.colsurfb.2010.11.014, PMID 21130612.

Song X, Zhao Y, Hou S, XU F, Zhao R, He J. Dual agents loaded PLGA nanoparticles: systematic study of particle size and drug entrapment efficiency. Eur J Pharm Biopharm. 2008;69(2):445-53. doi: 10.1016/j.ejpb.2008.01.013, PMID 18374554.

XU X, FU Y, HU H, Duan Y, Zhang Z. Quantitative determination of insulin entrapment efficiency in triblock copolymeric nanoparticles by high-performance liquid chromatography. J Pharm Biomed Anal. 2006;41(1):266-73. doi: 10.1016/j.jpba.2005.10.016, PMID 16303273.

Tantishaiyakul V, Phadoongsombut N, Kamaung S, Wongwisansri S, Mathurod P. Fourier transform infrared spectrometric determination of paracetamol and ibuprofen in tablets. Pharmazie. 2010;54(2):111-4.

Panwar P, Pandey B, Lakhera PC, Singh KP. Preparation characterization and in vitro release study of albendazole encapsulated nanosize liposomes. Int J Nanomedicine. 2010 Feb 25;5:101-8. doi: 10.2147/ijn.s8030, PMID 20309396.

Vaidya A, Jain A, Khare P, Agrawal RK, Jain SK. Metronidazole-loaded pectin microspheres for colon targeting. J Pharm Sci. 2009;98(11):4229-36. doi: 10.1002/jps.21742, PMID 19492406.

Van Meerloo J, Kaspers GJ, Cloos J. Cell sensitivity assays: the MTT assay. Methods Mol Biol. 2011;731:237-45. doi: 10.1007/978-1-61779-080-5_20.

Maeda H, Sawa T, Konno T. Mechanism of tumor-targeted delivery of macromolecular drugs including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release. 2001;74(1-3):47-61. doi: 10.1016/s0168-3659(01)00309-1, PMID 11489482.

Cho K, Wang X, Nie S, Chen ZG, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008;14(5):1310-6. doi: 10.1158/1078-0432.CCR-07-1441, PMID 18316549.

Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges opportunities and clinical applications. J Control Release. 2015;200:138-57. doi: 10.1016/j.jconrel.2014.12.030, PMID 25545217.

Chourasiya A, Upadhaya A, Shukla RN. Isolation of quercetin from leaves of Azadirachta indica and antidiabetic study of the crude extracts. J Pharm Biomed Sci. 2018;25:179-81.

Abd El Rahman SN, Suhailah S. Quercetin nanoparticles: preparation and characterization. Indian J Drugs. 2016;2(3):96-103.

Mohammadi G, Mirzaeei S, Taghe S, Mohammadi P. Preparation and evaluation of eudragit® l100 nanoparticles loaded impregnated with KT tromethamine loaded PVA-HEC insertions for ophthalmic drug delivery. Adv Pharm Bull. 2019;9(4):593-600. doi: 10.15171/apb.2019.068, PMID 31857963.

Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water-soluble drug. J Control Release. 1999;57(2):171-85. doi: 10.1016/s0168-3659(98)00116-3, PMID 9971898.

Verma A, Stellacci F. Effect of surface properties on nanoparticle cell interactions. Small. 2010;6(1):12-21. doi: 10.1002/smll.200901158, PMID 19844908.

Kakran M, Sahoo NG, Bao H, Pan Y, LI L. Functionalized graphene oxide as nanocarrier for loading and delivery of ellagic acid. Curr Med Chem. 2011;18(29):4503-12. doi: 10.2174/092986711797287548, PMID 21864287.

Zhang T, MA J, LI C, Lin K, Lou F, Jiang H. Core shell lipid polymer nanoparticles for combined chemo and gene therapy of childhood head and neck cancers. Oncol Rep. 2017;37(3):1653-61. doi: 10.3892/or.2017.5365, PMID 28098869.

Trenkenschuh E, Friess W. Freeze drying of nanoparticles: how to overcome colloidal instability by formulation and process optimization. Eur J Pharm Biopharm. 2021 Aug;165:345-60. doi: 10.1016/j.ejpb.2021.05.024, PMID 34052428.

Moustafine RI, Zaharov IM, Kemenova VA. Physicochemical characterization and drug release properties of eudragit E PO/eudragit L 100-55 interpolyelectrolyte complexes. Eur J Pharm Biopharm. 2006;63(1):26-36. doi: 10.1016/j.ejpb.2005.10.005, PMID 16380241.

Pecorini G, Ferraro E, Puppi D. Polymeric systems for the controlled release of flavonoids. Pharmaceutics. 2023;15(2):628. doi: 10.3390/pharmaceutics15020628, PMID 36839955.

Derakhshandeh K, Soheili M, Dadashzadeh S, Saghiri R. Preparation and in vitro characterization of 9-nitro camptothecin loaded long circulating nanoparticles for delivery in cancer patients. Int J Nanomedicine. 2010 Aug 9;5:463-71. doi: 10.2147/ijn.s11586, PMID 20957168.

Aldemir M, Okulu E, Kosemehmetoglu K, Ener K, Topal F, Evirgen O. Evaluation of the protective effect of quercetin against cisplatin-induced renal and testis tissue damage and sperm parameters in rats. Andrologia. 2014;46(10):1089-97. doi: 10.1111/and.12197, PMID 24266675.

Mokale VJ, Naik JB, Verma U, Yadava SK. Preparation and characterization of biodegradable glimepiride loaded PLA nanoparticles by o/w solvent evaporation method using high-pressure homogenizer: a factorial design approach. SAJ Pharm Pharmacol. 2019;1(1):1.

Chitkara D, Nikalaje SK, Mittal A, Chand M, Kumar N. Development of quercetin nanoformulation and in vivo evaluation using streptozotocin-induced diabetic rat model. Drug Deliv Transl Res. 2012 Apr;2(2):112-23. doi: 10.1007/s13346-012-0063-5.

Danhier F, Ansorena E, Silva JM, Coco R, LE Breton A, Preat V. PLGA based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161(2):505-22. doi: 10.1016/j.jconrel.2012.01.043, PMID 22353619.

Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: challenges opportunities and clinical applications. J Control Release. 2015 Feb 28;200:138-57. doi: 10.1016/j.jconrel.2014.12.030, PMID 25545217.

Jain A, Jain SK. Engineered PLGA nanoparticles: an emerging therapeutic tool to treat lung cancer. Mol Pharm. 2013;10(3):838-45.

WU TH, Yen FL, Lin LT, Tsai TR, Lin CC, Cham TM. Preparation physicochemical characterization and antioxidant effects of quercetin nanoparticles. Int J Pharm. 2008;346(1-2):160-8. doi: 10.1016/j.ijpharm.2007.06.036, PMID 17689897.

Verma N, Tiwari A, Bajpai J, Bajpai AK. Swelling triggered release of cisplatin from gelatin-coated gold nanoparticles. Inorg Nano Met Chem. 2022;52(7):961-73. doi: 10.1080/24701556.2021.2025396.

Zhao H, Gagnon J, Hafeli UO. Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres. Biomagn Res Technol. 2007;5:2. doi: 10.1186/1477-044X-5-2, PMID 17407608.

Mori H, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N. Cell proliferation in cancer prevention; effects of preventive agents on estrogen related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res. 2001 Sep 1;(480-1):201-7. doi: 10.1016/s0027-5107(01)00200-7, PMID 11506814.

Zhang Y, Chan HF, Leong KW. Advanced materials and processing for drug delivery: the past and the future. Adv Drug Deliv Rev. 2013;65(1):104-20. doi: 10.1016/j.addr.2012.10.003, PMID 23088863.

Khan M, Khan M, Zhang H. Synergistic effect of quercetin and cisplatin in ovarian cancer cells: mechanistic insight into apoptosis and oxidative stress. Cancer Lett. 2019;452:270-80. doi: 10.1016/j.canlet.2019.01.038.

Danhier F, Ansorena E, Silva JM, Coco R, LE Breton A, Preat V. PLGA based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161(2):505-22. doi: 10.1016/j.jconrel.2012.01.043, PMID 22353619.

WU TH, Yen FL, Lin LT, Tsai TR, Lin CC, Cham TM. Preparation physicochemical characterization and antioxidant effects of quercetin nanoparticles. Int J Pharm. 2008;346(1-2):160-8. doi: 10.1016/j.ijpharm.2007.06.036, PMID 17689897.

Zhao H, Gagnon J, Hafeli UO. Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres. Biomagn Res Technol. 2007;5:2. doi: 10.1186/1477-044X-5-2, PMID 17407608.

Verma N, Tiwari A, Bajpai J, Bajpai AK. Swelling triggered release of cisplatin from gelatin-coated gold nanoparticles. Inorg Nano Met Chem. 2022;52(7):961-73. doi: 10.1080/24701556.2021.2025396.

Mori H, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N. Cell proliferation in cancer prevention; effects of preventive agents on estrogen related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res. 2001;480-481:201-7. doi: 10.1016/s0027-5107(01)00200-7, PMID 11506814.

Zhang Y, Chan HF, Leong KW. Advanced materials and processing for drug delivery: the past and the future. Adv Drug Deliv Rev. 2013;65(1):104-20. doi: 10.1016/j.addr.2012.10.003, PMID 23088863.