Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Nanoliposomal Encapsulation Enhances In Vivo Anti-Tumor Activity of Niclosamide against Melanoma

Author(s): Mahdi Hatamipour, Mahmoud R. Jaafari, Amir A. Momtazi-Borojeni, Mahin Ramezani and Amirhossein Sahebkar*

Volume 19, Issue 13, 2019

Page: [1618 - 1626] Pages: 9

DOI: 10.2174/1871520619666190705120011

Price: $65

Abstract

Background: Niclosamide is an FDA-approved and old anti-helminthic drug used to treat parasitic infections. Recent studies have shown that niclosamide has broad anti-tumor effects relevant to the treatment of cancer. However, this drug has a low aqueous solubility hindering its systemic use. Herein, we report the preparation and characterization of niclosamide nanoliposomes and their in vivo anti-tumor effects.

Methods: Nanoliposomes were prepared using thin-film method and the drug was encapsulated with a remote loading method. The nanoliposomes were investigated by the observation of morphology, analysis of particle size and zeta potential. Additionally, qualitative and quantitative analyses were performed using HPLC. We assessed the in vitro cytotoxicity of the nanoliposomal niclosamide on B16F10 melanoma cells. Inhibition of tumor growth was investigated in C57BL/6 mice bearing B16F0 melanoma cancer.

Results: Analytical results indicated that the nanoliposomal system is a homogeneous and stable colloidal dispersion of niclosamide particles. Atomic force microscopy images and particle size analysis revealed that all niclosamide particles had a spherical shape with a diameter of approximately 108nm. According to in vitro and in vivo studies, nanoliposomal niclosamide exhibited a better anti-tumor activity against B16F10 melanoma tumor compared with free niclosamide.

Conclusion: Nanoliposomal encapsulation enhanced the aqueous solubility of niclosamide and improved its anti-tumor properties.

Keywords: Liposome, niclosamide, nanomedicine, melanoma, cancer, B16F10.

Graphical Abstract

[1]
Li, Y.; Li, P-K.; Roberts, M.J.; Arend, R.C.; Samant, R.S.; Buchsbaum, D.J. Multi-targeted therapy of cancer by niclosamide: A new application for an old drug. Cancer Lett., 2014, 349(1), 8-14.
[2]
Pan, J-X.; Ding, K.; Wang, C-Y. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells. Chin. J. Cancer, 2012, 31(4), 178-184.
[3]
Yang, W.; de Villiers, M.M. Effect of 4-sulphonato-calix[n]arenes and cyclodextrins on the solubilization of niclosamide, a poorly water soluble anthelmintic. AAPS J., 2005, 7(1), E241-E248.
[4]
Kenawy, R.; Rizk, S. Polymeric controlled release formulations of niclosamide for control of Biomphalaria alexandrina, the vector snail of schistosomiasis. Macromol. Biosci., 2004, 4(2), 119-128.
[5]
Devarakonda, B.; Hill, R.A.; Liebenberg, W.; Brits, M.; de Villiers, M.M. Comparison of the aqueous solubilization of practically insoluble niclosamide by polyamidoamine (PAMAM) dendrimers and cyclodextrins. Int. J. Pharm., 2005, 304(1-2), 193-209.
[6]
Chen, H.; Yang, Z.; Ding, C.; Chu, L.; Zhang, Y.; Terry, K.; Liu, H.; Shen, Q.; Zhou, J. Discovery of O-alkylamino-tethered niclosamide derivatives as potent and orally bioavailable anticancer agents. ACS Med. Chem. Lett., 2013, 4(2), 180-185.
[7]
Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm. Sin. B, 2015, 5(5), 442-453.
[8]
Maeda, H.; Bharate, G.Y.; Daruwalla, J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur. J. Pharm. Biopharm., 2009, 71(3), 409-419.
[9]
Maeda, H.; Nakamura, H.; Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev., 2013, 65(1), 71-79.
[10]
Jain, R.K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev., 1987, 6(4), 559-593.
[11]
Allen, T.M.; Cullis, P.R. Drug delivery systems: Entering the mainstream. Science, 2004, 303(5665), 1818-1822.
[12]
Lasic, D.D.; Papahadjopoulos, D. Liposomes revisited. Science, 1995, 267(5202), 1275-1276.
[13]
Ye, Y.; Zhang, X.; Zhang, T.; Wang, H.; Wu, B. Design and evaluation of injectable niclosamide nanocrystals prepared by wet media milling technique. Drug Dev. Ind. Pharm., 2015, 41(9), 1416-1424.
[14]
Gubernator, J. Active methods of drug loading into liposomes: Recent strategies for stable drug entrapment and increased in vivo activity. Expert Opin. Drug Deliv., 2011, 8(5), 565-580.
[15]
Barenholz, Y. Relevancy of drug loading to liposomal formulation therapeutic efficacy. J. Liposome Res., 2003, 13(1), 1-8.
[16]
Matbou Riahi, M.; Sahebkar, A.; Sadri, K.; Nikoofal-Sahlabadi, S.; Jaafari, M.R. Stable and sustained release liposomal formulations of celecoxib: In vitro and in vivo anti-tumor evaluation. Int. J. Pharm., 2018, 540(1-2), 89-97.
[17]
Alavizadeh, S.H.; Badiee, A.; Golmohammadzadeh, S.; Jaafari, M.R. The influence of phospholipid on the physicochemical properties and anti-tumor efficacy of liposomes encapsulating cisplatin in mice bearing C26 colon carcinoma. Int. J. Pharm., 2014, 473(1-2), 326-333.
[18]
Oku, N. Innovations in liposomal DDS technology and its application for the treatment of various diseases. Biol. Pharm. Bull., 2017, 40(2), 119-127.
[19]
Osada, T.; Chen, M.; Yang, X-Y.; Spasojevic, I.; Vandeusen, J.B.; Hsu, D.; Clary, B.M.; Clay, T.M.; Chen, W.; Morse, M.A. Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res., 2011, 71(12), 3978-2010.
[20]
Lu, W.; Lin, C.; Roberts, M.J.; Waud, W.R.; Piazza, G.A.; Li, Y. Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway. PLoS One, 2011, 6(12)e29290
[21]
Londoño-Joshi, A.I.; Arend, R.C.; Aristizabal, L.; Lu, W.; Samant, R.S.; Metge, B.J.; Hidalgo, B.; Grizzle, W.E.; Conner, M.B.; Forero-Torres, A. Effect of niclosamide on basal-like breast cancers. Mol. Cancer Therapeut., 2014, 13(4), 800-811.
[22]
Wieland, A.; Trageser, D.; Gogolok, S.; Reinartz, R.; Höfer, H.; Keller, M.; Leinhaas, A.; Schelle, R.; Normann, S.; Klaas, L.; Waha, A.; Koch, P.; Fimmers, R.; Pietsch, T.; Yachnis, A.T.; Pincus, D.W.; Steindler, D.A.; Brüstle, O.; Simon, M.; Glas, M.; Scheffler, B. Anticancer effects of niclosamide in human glioblastoma. Clin. Cancer Res., 2013, 19(15), 4124-4136.
[23]
Sack, U.; Walther, W.; Scudiero, D.; Selby, M.; Kobelt, D.; Lemm, M.; Fichtner, I.; Schlag, P.M.; Shoemaker, R.H.; Stein, U. Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. J. Natl. Cancer Inst., 2011, 103(13), 1018-1036.
[24]
Ren, X.; Duan, L.; He, Q.; Zhang, Z.; Zhou, Y.; Wu, D.; Pan, J.; Pei, D.; Ding, K. Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med. Chem. Lett., 2010, 1(9), 454-459.
[25]
Khanim, F.L.; Merrick, B.A.; Giles, H.V.; Jankute, M.; Jackson, J.B.; Giles, L.J.; Birtwistle, J.; Bunce, C.M.; Drayson, M.T. Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production. Blood Cancer J., 2011, 1(10), e39.
[26]
Li, R.; Hu, Z.; Sun, S-Y.; Chen, Z.G.; Owonikoko, T.K.; Sica, G.L.; Ramalingam, S.S.; Curran, W.J.; Khuri, F.R.; Deng, X. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Therapeut., 2013, 12(10), 2200-2212.
[27]
Li, R.; You, S.; Hu, Z.; Chen, Z.G.; Sica, G.L.; Khuri, F.R.; Curran, W.J.; Shin, D.M.; Deng, X. Inhibition of STAT3 by niclosamide synergizes with erlotinib against head and neck cancer. PLoS One, 2013, 8(9)e74670
[28]
You, S.; Li, R.; Park, D.; Xie, M.; Sica, G.L.; Cao, Y.; Xiao, Z-Q.; Deng, X. Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer. Mol. Cancer Ther., 2014, 13(3), 606-616.
[29]
Jin, Y.; Lu, Z.; Ding, K.; Li, J.; Du, X.; Chen, C.; Sun, X.; Wu, Y.; Zhou, J.; Pan, J. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-κB pathway and generation of reactive oxygen species. Cancer Res., 2014, 70(6), 2516-2527.
[30]
Misra, S.K.; De, A.; Pan, D. Targeted delivery of STAT-3 modulator to breast cancer stem-like cells downregulates a series of stemness genes. Mol. Cancer Ther., 2018, 17(1), 119-129.
[31]
Kim, M.O.; Choe, M.H.; Yoon, Y.N.; Ahn, J.; Yoo, M.; Jung, K-Y.; An, S.; Hwang, S-G.; Oh, J.S.; Kim, J-S. Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells. Biochem. Pharmacol., 2017, 144, 78-89.
[32]
Bhattacharyya, J.; Ren, X-R.; Mook, R.A.; Wang, J.; Spasojevic, I.; Premont, R.T.; Li, X.; Chilkoti, A.; Chen, W. Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth. Nanoscale, 2017, 9(34), 12709-12717.
[33]
Liu, C.; Armstrong, C.M.; Lou, W.; Lombard, A.P.; Cucchiara, V.; Gu, X.; Yang, J.C.; Nadiminty, N.; Pan, C.X.; Evans, C.P.; Gao, A.C. Niclosamide and bicalutamide combination treatment overcomes enzalutamide- and bicalutamide-resistant prostate cancer. Mol. Cancer Ther., 2017, 16(8), 1521-1530.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy