Anticancer activity of liposomal formulation co-encapsulated with coumarin and phenyl butyric acid

Ali Allateef; Naeem Shalan; Zainab Lafi

doi:10.7324/JAPS.2024.181335

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Abstract

Anticancer treatments have poor pharmacokinetics, high toxicity to normal cells, and low bioavailability. As nanotechnology has advanced to a new level, many researchers have been motivated to develop a safer and more effective medication delivery method for the treatment of cancer. Nowadays, about 80% of the anticancer medications that have been approved recently are made from natural substances. This study aims to formulate liposomes loaded with coumarin (COM) and 4-phenylbutyric acid (PBA) and evaluate their antitumor effect in vitro. The liposomes were characterized using the dynamic light scattering instrument to determine their size, polydispersity, and charge. The formulated liposomes exhibited a particle size within the desired range of 100– 200 nm, with low polydispersity and suitable charge. Stability tests showed excellent stability of the liposomal formulations over 10 days in terms of size, charge, and polydispersity. High performance liquid chromatography analysis confirmed the successful encapsulation of COM and PBA within the liposomes, with high encapsulation efficiencies observed of 53%–25% for Lipo-PBA and Lipo-COM, respectively. Loading efficiency (LO%) was found to be 9%–5% for Lipo-PBA and Lipo-COM, respectively, which means the drugs were efficiently loaded within the liposome. In vitro cell viability studies demonstrated that the liposomes loaded with both COM and PBA exhibited the most effective inhibition on MDA-MB-231 breast cancer cells (30%) and A549 lung cancer cells (45%), while Lipo-COM showed potent inhibition on HT29 colorectal cancer cells (40%). Encapsulation of the drugs inside liposomes enhanced their cytotoxicity, potentially due to improved penetration into tumor cells. The findings suggest that the formulated liposomes have the potential for future clinical applications with high selectivity toward cancer cells.

Keyword: Liposomes analytical methods anticancer activity HPLC method

Citation:

Allateef A, Shalan N, Lafi Z. Anticancer activity of liposomal formulation co-encapsulated with coumarin and phenyl butyric acid. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.181335

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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10. Medina-Alarcón KP, Voltan AR, Fonseca-Santos B, Moro IJ, de Oliveira Souza F, Chorilli M, et al. Highlights in nanocarriers for the treatment against cervical cancer. Mater Sci Eng C Mater Biol Appl. 2017;80:748-59. https://doi.org/10.1016/j.msec.2017.07.021
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18. Kusaczuk M, Kr?towski R, Bartoszewicz M, Cechowska-Pasko M. Phenylbutyrate-a pan-HDAC inhibitor-suppresses proliferation of glioblastoma LN-229 cell line. Tumour Biol. 2016;37(1):931-42. https://doi.org/10.1007/s13277-015-3781-8
19. Lumpkin CJ, Harris AW, Connell AJ, Kirk RW, Whiting JA, Saieva L, et al. Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy. Sci Rep. 2023;13(1):10374. https://doi.org/10.1038/s41598-023-37496-0
20. Alshaer W, Zraikat M, Amer A, Nsairat H, Lafi Z, Alqudah DA, et al. Encapsulation of echinomycin in cyclodextrin inclusion complexes into liposomes: in vitro anti-proliferative and anti-invasive activity in glioblastoma. RSC Advances. 2019;9(53):30976-88. https://doi.org/10.1039/C9RA05636J
21. Marahatta A, Bhandary B, Lee M-R, Kim D-S, Lee YC, Kim S-R, et al. Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution. J Chromatogr B. 2012;903:118-25. https://doi.org/10.1016/j.jchromb.2012.07.004
22. Tefas LR, Sylvester B, Tomuta I, Sesarman A, Licarete E, Banciu M, et al. Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach. Drug Des Devel Ther. 2017;11:1605-21. https://doi.org/10.2147/DDDT.S129008
23. Miao ZL, Deng YJ, Du HY, Suo XB, Wang XY, Wang X, et al. Preparation of a liposomal delivery system and its in vitro release of rapamycin. Exp Ther Med. 2015;9(3):941-6. https://doi.org/10.3892/etm.2015.2201
24. Zhao Y, Ren W, Zhong T, Zhang S, Huang D, Guo Y, et al. Tumor-specific pH-responsive peptide-modified pH-sensitive liposomes containing doxorubicin for enhancing glioma targeting and anti-tumor activity. J Control Release. 2016;222:56-66. https://doi.org/10.1016/j.jconrel.2015.12.006
25. Tao A, Song Z, Feng X, Hu B, Lei X. Magnolol-Coumarin- Phenylbutyric acid conjugates: an anticancer prodrug via multiple targets. IOP Conf Ser Earth Environ Sci. 2019;330(4):042054. https://doi.org/10.1088/1755-1315/330/4/042054
26. Zhang L, Xu Z. Coumarin-containing hybrids and their anticancer activities. Eur J Med Chem. 2019;181:111587. https://doi.org/10.1016/j.ejmech.2019.111587
27. Li J, Gu Y, Zhang W, Bao CY, Li CR, Zhang JY, et al. Molecular mechanism for selective cytotoxicity towards cancer cells of diselenide-containing paclitaxel nanoparticles. Int J Biol Sci. 2019;15(8):1755-70. https://doi.org/10.7150/ijbs.34878
28. Wu J. The enhanced permeability and retention (EPR) effect: the significance of the concept and methods to enhance its application. J Pers Med. 2021;11(8):771. https://doi.org/10.3390/jpm11080771
29. Kapa?czy?ska M, Kolenda T, Przyby?a W, Zaj?czkowska M, Teresiak A, Filas V, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. 2018;14(4):910-9.

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1. Zargar A, Chang S, Kothari A, Snijders AM, Mao JH, Wang J, et al. Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy. Chronic Dis Transl Med. 2019;5(4):258-66. https://doi.org/10.1016/j.cdtm.2019.11.001

2. Lafi Z, Alshaer W, Gharaibeh L, Alqudah DA, AlQuaissi B, Bashaireh B, et al. Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line. PLoS One. 2023;18(9):e0291981. https://doi.org/10.1371/journal.pone.0291981

3. Puri V, Nagpal M, Singh I, Singh M, Dhingra GA, Huanbutta K, et al. A comprehensive review on nutraceuticals: therapy support and formulation challenges. Nutrients. 2022;14(21):4637. https://doi.org/10.3390/nu14214637

4. Nsairat H, Lafi Z, Al-Sulaibi M, Gharaibeh L, Alshaer W. Impact of nanotechnology on the oral delivery of phyto-bioactive compounds. Food Chemistry. 2023;424:136438. https://doi.org/10.1016/j.foodchem.2023.136438

5. Küpeli Akkol E, Genç Y, Karpuz B, Sobarzo-Sánchez E, Capasso R. Coumarins and coumarin-related compounds in pharmacotherapy of cancer. Cancers (Basel). 2020;12(7):1959. https://doi.org/10.3390/cancers12071959

6. Lon?ar M, Jakovljevi? M, Šubari? D, Pavli? M, Buzjak Služek V, Cindri? I, et al. Coumarins in food and methods of their determination. Foods. 2020;9(5):645. https://doi.org/10.3390/foods9050645

7. Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A. Coumarin: a natural, privileged and versatile scaffold for bioactive compounds. Molecules. 2018;23(2):250. https://doi.org/10.3390/molecules23020250

8. Wu Y, Xu J, Liu Y, Zeng Y, Wu G. A review on anti-tumor mechanisms of coumarins. Front Oncology. 2020;10:592853. https://doi.org/10.3389/fonc.2020.592853

9. Rawat A, Vijaya Bhaskar Reddy A. Recent advances on anticancer activity of coumarin derivatives. Eur J Med Chem Rep. 2022;5:100038. https://doi.org/10.1016/j.ejmcr.2022.100038

10. Medina-Alarcón KP, Voltan AR, Fonseca-Santos B, Moro IJ, de Oliveira Souza F, Chorilli M, et al. Highlights in nanocarriers for the treatment against cervical cancer. Mater Sci Eng C Mater Biol Appl. 2017;80:748-59. https://doi.org/10.1016/j.msec.2017.07.021

11. Al-Azzawi H, Alshaer W, Esawi E, Lafi Z, Abuarqoub D, Zaza R, et al. Multifunctional nanoparticles recruiting hyaluronic acid ligand and polyplexes containing low molecular weight protamine and ATP-Sensitive DNA motif for doxorubicin delivery. J Drug Deliv Sci Technol. 2022;69:103169. https://doi.org/10.1016/j.jddst.2022.103169

12. Cheng R, Liu L, Xiang Y, Lu Y, Deng L, Zhang H, et al. Advanced liposome-loaded scaffolds for therapeutic and tissue engineering applications. Biomaterials. 2020;232:119706. https://doi.org/10.1016/j.biomaterials.2019.119706

13. Wu X, Wu Y, He L, Wu L, Wang X, Liu Z. Effects of the intestinal microbial metabolite butyrate on the development of colorectal cancer. J Cancer. 2018;9(14):2510-7. https://doi.org/10.7150/jca.25324

14. Chen M, Jiang W, Xiao C, Yang W, Qin Q, Mao A, et al. Sodium butyrate combined with docetaxel for the treatment of lung adenocarcinoma A549 cells by targeting Gli1. OncoTargets Ther. 2020;13:8861-75. https://doi.org/10.2147/OTT.S252323

15. Iannitti T, Palmieri B. Clinical and experimental applications of sodium phenylbutyrate. Drugs in R D. 2011;11:227-49. https://doi.org/10.2165/11591280-000000000-00000

16. Ryu SH, Kaiko GE, Stappenbeck TS. Cellular differentiation: potential insight into butyrate paradox? Mol Cell Oncol. 2018;5(3):e1212685. https://doi.org/10.1080/23723556.2016.1212685

17. Kusaczuk M, Bartoszewicz M, Cechowska-Pasko M. Phenylbutyric Acid: simple structure - multiple effects. Curr Pharm Des. 2015;21(16):2147-66. https://doi.org/10.2174/1381612821666150105160059

18. Kusaczuk M, Kr?towski R, Bartoszewicz M, Cechowska-Pasko M. Phenylbutyrate-a pan-HDAC inhibitor-suppresses proliferation of glioblastoma LN-229 cell line. Tumour Biol. 2016;37(1):931-42. https://doi.org/10.1007/s13277-015-3781-8

19. Lumpkin CJ, Harris AW, Connell AJ, Kirk RW, Whiting JA, Saieva L, et al. Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy. Sci Rep. 2023;13(1):10374. https://doi.org/10.1038/s41598-023-37496-0

20. Alshaer W, Zraikat M, Amer A, Nsairat H, Lafi Z, Alqudah DA, et al. Encapsulation of echinomycin in cyclodextrin inclusion complexes into liposomes: in vitro anti-proliferative and anti-invasive activity in glioblastoma. RSC Advances. 2019;9(53):30976-88. https://doi.org/10.1039/C9RA05636J

21. Marahatta A, Bhandary B, Lee M-R, Kim D-S, Lee YC, Kim S-R, et al. Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution. J Chromatogr B. 2012;903:118-25. https://doi.org/10.1016/j.jchromb.2012.07.004

22. Tefas LR, Sylvester B, Tomuta I, Sesarman A, Licarete E, Banciu M, et al. Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach. Drug Des Devel Ther. 2017;11:1605-21. https://doi.org/10.2147/DDDT.S129008

23. Miao ZL, Deng YJ, Du HY, Suo XB, Wang XY, Wang X, et al. Preparation of a liposomal delivery system and its in vitro release of rapamycin. Exp Ther Med. 2015;9(3):941-6. https://doi.org/10.3892/etm.2015.2201

24. Zhao Y, Ren W, Zhong T, Zhang S, Huang D, Guo Y, et al. Tumor-specific pH-responsive peptide-modified pH-sensitive liposomes containing doxorubicin for enhancing glioma targeting and anti-tumor activity. J Control Release. 2016;222:56-66. https://doi.org/10.1016/j.jconrel.2015.12.006

25. Tao A, Song Z, Feng X, Hu B, Lei X. Magnolol-Coumarin- Phenylbutyric acid conjugates: an anticancer prodrug via multiple targets. IOP Conf Ser Earth Environ Sci. 2019;330(4):042054. https://doi.org/10.1088/1755-1315/330/4/042054

26. Zhang L, Xu Z. Coumarin-containing hybrids and their anticancer activities. Eur J Med Chem. 2019;181:111587. https://doi.org/10.1016/j.ejmech.2019.111587

27. Li J, Gu Y, Zhang W, Bao CY, Li CR, Zhang JY, et al. Molecular mechanism for selective cytotoxicity towards cancer cells of diselenide-containing paclitaxel nanoparticles. Int J Biol Sci. 2019;15(8):1755-70. https://doi.org/10.7150/ijbs.34878

28. Wu J. The enhanced permeability and retention (EPR) effect: the significance of the concept and methods to enhance its application. J Pers Med. 2021;11(8):771. https://doi.org/10.3390/jpm11080771

29. Kapa?czy?ska M, Kolenda T, Przyby?a W, Zaj?czkowska M, Teresiak A, Filas V, et al. 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci. 2018;14(4):910-9.