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Current Organic Chemistry

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ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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Research Article

Nicotinamide Loaded Chitosan Nanocomplex Shows Improved Anticancer Potential: Molecular Docking, Synthesis, Characterization and In vitro Evaluations

Author(s): Ahmed M. Metwaly*, Mohamed A. Abu-Saied, Ibraheem M.M. Gobaara, Asmaa M. Lotfy, Bshra A. Alsfouk, Eslam B. Elkaeed and Ibrahim H. Eissa*

Volume 28, Issue 1, 2024

Published on: 22 January, 2024

Page: [46 - 55] Pages: 10

DOI: 10.2174/0113852728283226231227061211

Price: $65

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Abstract

This study aimed to prepare and characterize chitosan nanoparticles encapsulating a nicotinamide derivative (Ni-CS-NP). Additionally, the therapeutic effectiveness, cytotoxicity, selectivity, and immunomodulatory properties of Ni-CS-NP were evaluated in human breast and colon cancer cell lines. Chitosan nanoparticles have shown potential as drug delivery carriers due to their biocompatibility and controlled release properties. Encapsulating a nicotinamide derivative further enhances the therapeutic potential of these nanoparticles. Computational studies were employed to validate the binding interactions, providing crucial insights into the formulation's stability and effectiveness. The primary objective was to assess the cytotoxicity and safety profiles of Ni-CS-NP in human cancer cell lines. Moreover, this study aimed to investigate the specific mechanisms underlying its cytotoxic effects, including its impact on cell cycle progression, apoptosis induction, and immunomodulation. Ni-CS-NP were synthesized using the ionic gelation method and characterized using Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermo gravimetric analysis. The cytotoxicity was evaluated in breast and colon cancer cell lines through the MTT assay. Selectivity indices were calculated to determine the safety profiles. The inhibition of VEGFR-2, induction of apoptosis, cell cycle disruption, and immunomodulatory effects were assessed through molecular assays. Computational analysis demonstrated favorable binding interactions through the Ni-CS-NP complex. The characterization studies confirmed the successful synthesis of Ni-CS-NP with well-defined structural and thermal properties. Ni-CS-NP exhibited remarkable cytotoxicity with a superior safety profile against MCF7 and HCT 116 cell lines showing IC50 values of 2.32 and 2.70 μM, respectively, surpassing sorafenib's efficacy (IC50 = 4.12 and 7.55 μM, respectively). Additionally, Ni-CS-NP effectively inhibited VEGFR-2, induced both early and late apoptosis, and disrupted the cell cycle progression in MCF7 cells. Notably, Ni-CS-NP demonstrated significant immunomodulatory effects by reducing TNF-α and IL-2 levels compared to dexamethasone. The encapsulation of a nicotinamide derivative within chitosan nanoparticles (Ni-CS-NP) through the ionic gelation method proved successful. Ni-CS-NP displayed potent cytotoxicity, superior safety profiles, and promising immunomodulatory effects in human breast cancer cells. These findings highlight the potential of Ni-CS-NP as a novel therapeutic agent for breast cancer treatment, warranting further investigation for clinical applications.

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[1]
Welch, S.P.; Huffman, J.W.; Lowe, J. Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A. J. Pharmacol. Exp. Ther., 1998, 286(3), 1301-1308.
[PMID: 9732392]
[2]
Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell. Mol. Life Sci., 2020, 77(9), 1745-1770.
[http://dx.doi.org/10.1007/s00018-019-03351-7] [PMID: 31690961]
[3]
Fathi Maroufi, N.; Taefehshokr, S.; Rashidi, M.R.; Taefehshokr, N.; Khoshakhlagh, M.; Isazadeh, A.; Mokarizadeh, N.; Baradaran, B.; Nouri, M. Vascular mimicry: Changing the therapeutic paradigms in cancer. Mol. Biol. Rep., 2020, 47(6), 4749-4765.
[http://dx.doi.org/10.1007/s11033-020-05515-2] [PMID: 32424524]
[4]
Wang, X. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front. Cell Dev. Biol., 2020, 8, 599281.
[http://dx.doi.org/10.3389/fcell.2020.599281]
[5]
Yan, J.D.; Yanrong, L.; Zhi-Yong, Z.; Guang-Yin, L.; Jin-Heng, X; Li-Yun, L.; Yue-Ming, H. Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol. Res. Pract., 2015, 211(7), 539-543.
[http://dx.doi.org/10.1016/j.prp.2015.04.003]
[6]
Bai, J. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest. New Drugs, 2020, 38(2), 229-245.
[7]
Sosnik, A.; Augustine, R. Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them. Adv. Drug Deliv. Rev., 2016, 103, 105-120.
[http://dx.doi.org/10.1016/j.addr.2015.12.022] [PMID: 26772138]
[8]
Muldakhmetov, Z. Combined computational and experimental studies of anabasine encapsulation by beta-cyclodextrin. Plants, 2022, 11(17), 2283.
[9]
Iskineyeva, A. Combined in silico and experimental investigations of resveratrol encapsulation by beta-cyclodextrin. Plants, 2022, 11(13), 1678.
[10]
Kravanja, G.; Primožič, M.; Knez, Ž.; Leitgeb, M. Chitosan-based (Nano) materials for novel biomedical applications. Molecules, 2019, 24(10), 1960.
[http://dx.doi.org/10.3390/molecules24101960] [PMID: 31117310]
[11]
Kou, S.G.; Peters, L.M.; Mucalo, M.R. Chitosan: A review of sources and preparation methods. Int. J. Biol. Macromol., 2021, 169, 85-94.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.12.005]
[12]
Soltani, M. Incorporation of Boswellia sacra essential oil into chitosan/TPP nanoparticles towards improved therapeutic efficiency. Mater Technol, 2022, 37(11), 1703-1715.
[13]
Yousefian, R.E.; Masoud, H.T.; Seyed, M.R.S.; Samira, Y.; Zamani-Esmati, P.; Nastaran, H.S. Citrus lemon essential oil nanoemulsion (CLEO-NE), a safe cell-depended apoptosis inducer in human A549 lung cancer cells with anti-angiogenic activity. J. Microencapsul., 2020, 37(5), 394-402.
[14]
Divya, K.; Jisha, M.S. Chitosan nanoparticles preparation and applications. Environ. Chem. Lett., 2018, 16(1), 101-112.
[http://dx.doi.org/10.1007/s10311-017-0670-y]
[15]
Nagpal, K.; Singh, S.K.; Mishra, D.N. Chitosan nanoparticles: A promising system in novel drug delivery. Chem. Pharm. Bull., 2010, 58(11), 1423-1430.
[http://dx.doi.org/10.1248/cpb.58.1423] [PMID: 21048331]
[16]
Zarei, B.; Tabrizi, M.H.; Rahmati, A. PEGylated lecithin-chitosan nanoparticle-encapsulated alphα-terpineol for in vitro anticancer effects. AAPS PharmSciTech, 2022, 23(4), 94.
[http://dx.doi.org/10.1208/s12249-022-02245-5] [PMID: 35314914]
[17]
Ahmad, N.; Khan, M.R.; Palanisamy, S.; Mohandoss, S. Anticancer drug-loaded chitosan nanoparticles for in vitro release, promoting antibacterial and anticancer activities. Polymers, 2023, 15(19), 3925.
[http://dx.doi.org/10.3390/polym15193925] [PMID: 37835972]
[18]
Sun, R.; Fang, L.; Lv, X.; Fang, J.; Wang, Y.; Chen, D.; Wang, L.; Chen, J.; Qi, Y.; Tang, Z.; Zhang, J.; Tian, Y. In vitro and in vivo evaluation of self-assembled chitosan nanoparticles selectively overcoming hepatocellular carcinoma via asialoglycoprotein receptor. Drug Deliv., 2021, 28(1), 2071-2084.
[http://dx.doi.org/10.1080/10717544.2021.1983077] [PMID: 34595970]
[19]
Fu, S.; Xia, J.; Wu, J. Functional chitosan nanoparticles in cancer treatment. J. Biomed. Nanotechnol., 2016, 12(8), 1585-1603.
[http://dx.doi.org/10.1166/jbn.2016.2228] [PMID: 29341581]
[20]
Elkaeed, E.B. Design, synthesis, docking, DFT, MD simulation studies of a new nicotinamide-based derivative: In vitro anticancer and VEGFR-2 inhibitory effects. Molecules, 2022, 27(14), 4606.
[21]
Stegemann, S.; Leveiller, F.; Franchi, D.; de Jong, H; Lindén, H. When poor solubility becomes an issue: From early stage to proof of concept. Eur. J. Pharm. Sci., 2007, 31(5), 249-261.
[http://dx.doi.org/10.1016/j.ejps.2007.05.110]
[22]
Elzatahry, A.; Eldin, M.M.J.P.f.A.T. Preparation and characterization of metronidazole‐loaded chitosan nanoparticles for drug delivery application. Polym. Adv. Technol., 2008, 19(12), 1787-1791.
[http://dx.doi.org/10.1002/pat.1195]
[23]
Moustafa, M.; Abu-Saied, M.A.; Taha, T.H.; Elnouby, M.; El Desouky, E.A.; Alamri, S.; Alrumman, S.; Shati, A.; Al-Khatani, M.; Alghamdii, H.; Al-Qthanin, R.; Al-Emam, A. New blends of acrylamide/chitosan and potato peel waste as improved water absorbing polymers for diaper applications. Polym. Polymer Compos., 2022, 30, 09673911221077559.
[http://dx.doi.org/10.1177/09673911221077559]
[24]
dos Santos, A.M.; Carvalho, S.G.; Ferreira, L.M.B.; Chorilli, M.; Gremião, M.P.D. Understanding the role of electrostatic interactions on the association of 5-fluorouracil to chitosan-TPP nanoparticles. Colloids Surf. A Physicochem. Eng. Asp., 2022, 640, 128417.
[http://dx.doi.org/10.1016/j.colsurfa.2022.128417]
[25]
Moustafa, M.; Abu-Saied, M.A.; Taha, T.; Elnouby, M.; El-shafeey, M.; Alshehri, A.G.; Alamri, S.; Shati, A.; Alrumman, S.; Alghamdii, H.; Al-Khatani, M. Chitosan functionalized AgNPs for efficient removal of Imidacloprid pesticide through a pressure-free design. Int. J. Biol. Macromol., 2021, 168, 116-123.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.12.055] [PMID: 33309655]
[26]
Raja, A.G.; Selva Arasu, K.A.; Rajaram, R. Synthesis, characterization and application of chitosan-TPP-ZnO nanocomposite for efficient treatment of effluent containing sulphur dye. Mater. Today Proc., 2022, 68, 483-490.
[http://dx.doi.org/10.1016/j.matpr.2022.07.426]
[27]
Mohy Eldin, M.; Tamer, T.M.; Abu Saied, M.A.; Soliman, E.A.; Madi, N.K.; Ragab, I.; Fadel, I. Click grafting of chitosan onto PVC surfaces for biomedical applications. Adv. Polym. Technol., 2018, 37(1), 38-49.
[http://dx.doi.org/10.1002/adv.21640]
[28]
Moustafa, M.; A Abu-Saied, M.; H Taha, T.; Elnouby, M.; A El Desouky, E.; Alamri, S.; Shati, A.; Alrumman, S.; Alghamdii, H.; Al-Khatani, M.; Al-Qthanin, R.; Al-Emam, A. Preparation and characterization of super-absorbing gel formulated from κ-carrageenan-potato peel starch blended polymers. Polymers, 2021, 13(24), 4308.
[http://dx.doi.org/10.3390/polym13244308] [PMID: 34960859]
[29]
Modi, S.J.; Kulkarni, V.M. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective. Med. Drug Discov., 2019, 2, 100009.
[http://dx.doi.org/10.1016/j.medidd.2019.100009]
[30]
Sivaraj, K.K.; Takefuji, M.; Schmidt, I.; Adams, R.H.; Offermanns, S.; Wettschureck, N. G13 controls angiogenesis through regulation of VEGFR-2 expression. Dev. Cell, 2013, 25(4), 427-434.
[http://dx.doi.org/10.1016/j.devcel.2013.04.008] [PMID: 23664862]
[31]
Pietenpol, J.; Stewart, Z. Cell cycle checkpoint signaling: Cell cycle arrest versus apoptosis. Toxicology, 2002, 181, 475-481.
[32]
Alanazi, M.M.; Eissa, I.H.; Alsaif, N.A.; Obaidullah, A.J.; Alanazi, W.A.; Alasmari, A.F.; Albassam, H.; Elkady, H.; Elwan, A. Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers. J. Enzyme Inhib. Med. Chem., 2021, 36(1), 1760-1782.
[http://dx.doi.org/10.1080/14756366.2021.1956488] [PMID: 34340610]
[33]
Shacter, E.; Weitzman, S.A.J.O. Chronic inflammation and cancer. Oncology, 2002, 16(2), 217-226, 229.
[34]
Angelo, L.S.; Kurzrock, R.J.C.c.r. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin. Cancer Res., 2007, 13(10), 2825-2830.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2416]
[35]
Ou, X.-M.; Wan-Cheng, L.; Dai-Shun, L. VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice. Int. Immunopharmacol., 2009, 9(1), 70-79.
[36]
Tian, S.; Haitian, Q.; Chengying, X.; Haiyi, G.; Fangfang, L.; Yongping, X.; Jin, L.; Liguang, L. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor‐2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci., 2011, 102(7), 1374-1380.
[http://dx.doi.org/10.1111/j.1349-7006.2011.01939.x]
[37]
Zhang, Y.; Xiaowei, D.; Changhong, M. Propofol attenuated TNF-α-modulated occludin expression by inhibiting Hif-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells. BMC Anesthesiol., 2019, 19, 1-11.
[38]
Chitosan. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/71853
[39]
Sacco, P.; Pedroso-Santana, S.; Kumar, Y.; Joly, N.; Martin, P.; Bocchetta, P. Ionotropic gelation of chitosan flat structures and potential applications. Molecules, 2021, 26(3), 660.
[http://dx.doi.org/10.3390/molecules26030660] [PMID: 33513925]
[40]
Metwaly, A.M.; Abdel-Raoof, A.M.; Abdulaziz, A.A.; El-Zomrawy, A.A.; Ashmawy, A.M. Preparation and characterization of patuletin-loaded chitosan nanoparticles with improved selectivity and safety profiles for anticancer applications. J. Chem., 2023, 2023.
[http://dx.doi.org/10.1155/2023/6684015]
[41]
Abu-Saied, M.A.; El-Desouky, E.A.; Soliman, E.A.; El-Naim, G.A. Novel sulphonated poly (vinyl chloride)/poly (2-acrylamido-2-methylpropane sulphonic acid) blends-based polyelectrolyte membranes for direct methanol fuel cells. Polym. Test., 2020, 89, 106604.
[http://dx.doi.org/10.1016/j.polymertesting.2020.106604]
[42]
Abu-Saied, M.A.; Soliman, E.A.; Abualnaj, K.M.; El Desouky, E. Highly conductive polyelectrolyte membranes poly(vinyl alcohol)/Poly(2-acrylamido-2-methyl propane sulfonic acid) (PVA/PAMPS) for fuel cell application. Polymers, 2021, 13(16), 2638.
[http://dx.doi.org/10.3390/polym13162638] [PMID: 34451178]
[43]
AbdElhafez, S.E.; Taha, T.; Mansy, A.E.; El-Desouky, E.; Abu-Saied, M.A.; Eltaher, K.; Hamdy, A.; El Fawal, G.; Gamal, A.; Hashim, A.M.; Elgharbawy, A.S.; El-Latif, M.M.A.; Hamad, H.; Ali, R.M. Experimental optimization with the emphasis on techno-economic analysis of production and purification of high value-added bioethanol from sustainable corn stover. Energies, 2022, 15(17), 6131.
[http://dx.doi.org/10.3390/en15176131]
[44]
Abu-Saied, M.; Khalil, K.A.; Al-Deyab, S.S. Preparation and characterization of poly vinyl acetate nanofiber doping copper metal. Int. J. Electrochem. Sci., 2012, 7(3), 2019-2027.
[http://dx.doi.org/10.1016/S1452-3981(23)13859-4]
[45]
Mohy, E.M.; Emad, S.; Ellen, H. Immobilized metal ions cellophane-PGMA‐grafted membranes for affinity separation of β‐galactosidase enzyme. I. Preparation and characterization. J. Appl. Polym. Sci., 2009, 111(5), 2647-2656.
[46]
Hossain, M.I. Synthesis and characterization of graphene oxide-ammonium ferric sulfate composite for the removal of dyes from tannery wastewater. J. Mater. Res. Technol., 2021, 12, 1715-1727.
[http://dx.doi.org/10.1016/j.jmrt.2021.03.097]
[47]
Eissa, I.H.; Yousef, R.G.; Elkady, H.; Elkaeed, E.B.; Alsfouk, A.A.; Husein, D.Z.; Ibrahim, I.M.; Elhendawy, M.A.; Godfrey, M.; Metwaly, A.M. Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers. Comput. Biol. Chem., 2023, 107, 107953.
[http://dx.doi.org/10.1016/j.compbiolchem.2023.107953] [PMID: 37673011]
[48]
Alley, M.C. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res, 1988, 48(3), 589-601.
[49]
Van de Loosdrecht, A.; Beelen, R.H.; Ossenkoppele, G.J.; Broekhoven, M.G.; Langenhuijsen, M.M. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. 1994, 174(1-2), 311-320.
[http://dx.doi.org/10.1016/0022-1759(94)90034-5]
[50]
Mahdy, H.A.; Elkady, H.; Taghour, M.S.; Elwan, A.; Dahab, M.A.; Elkady, M.A.; Elsakka, E.G.E.; Elkaeed, E.B.; Alsfouk, B.A.; Ibrahim, I.M.; Eissa, I.H.; Metwaly, A.M. New theobromine derivatives inhibiting VEGFR-2: Design, synthesis, antiproliferative, docking and molecular dynamics simulations. Future Med. Chem., 2023, 15(14), 1233-1250.
[http://dx.doi.org/10.4155/fmc-2023-0089] [PMID: 37466069]
[51]
Yousef, R.G.; Elwan, A.; Gobaara, I.M.M.; Mehany, A.B.M.; Eldehna, W.M.; El-Metwally, S.A.; A Alsfouk, B.; Elkaeed, E.B.; Metwaly, A.M.; Eissa, I.H. Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: In vitro and in silico studies. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 2206-2222.
[http://dx.doi.org/10.1080/14756366.2022.2110868] [PMID: 35980113]

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