Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Effect and Mechanism of the Lenvatinib@H-MnO2-FA Drug Delivery System in Targeting Intrahepatic Cholangiocarcinoma

Author(s): Zhouyu Ning, Lina Yang, Xia Yan, Dan Wang, Yongqiang Hua, Weidong Shi, Junhua Lin and Zhiqiang Meng*

Volume 28, Issue 9, 2022

Published on: 14 March, 2022

Page: [743 - 750] Pages: 8

DOI: 10.2174/1381612828666220113161712

Price: $65

Abstract

Background: To investigate the effects of the Lenvatinib@H-MnO2-FA administration system on the proliferation and apoptosis of Intrahepatic cholangiocarcinoma (ICC) and the underlying molecular mechanism.

Materials and Methods: In this research, hollow MnO2 (H-MnO2) was synthesized via the modified Stöber method, and H-MnO2 was modified with polyethylene glycol-bis (Amine) (NH2-PEG-NH2) and folic acid (FA) to obtain H-MnO2-PEG-FA (H-MnO2-FA). Lenvatinib was coated in the hollow cavity of H-MnO2-PEG-FA to further form a nanometre drug-carrying system (Lenvatinib@H-MnO2-PEG-FA). Lenvatinib@H-MnO2-FA was characterized through transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to verify that Lenvatinib was loaded on nanoparticles. Functionally, confocal laser scanning microscopy (CLSM), 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed to determine the effect of Lenvatinib@H-MnO2-FA on the proliferation and apoptosis of ICC cells (9810 cells). Finally, the protein levels of Raf-1MEK1/2-ERK1/2 signalling pathway components were detected through Western blotting analysis.

Results: We successfully synthesised a Lenvatinib@H-MnO2-PEG-FA administration system. The resulting nanomaterials had excellent biological stability and improved targeting effects. Functionally, Lenvatinib@ H-MnO2-FA inhibited the proliferation of 9810 cells. The Bcl-2 protein level was significantly downregulated, and the caspase-3 protein level was significantly upregulated, indicating that Lenvatinib@H-MnO2- PEG- FA promoted the apoptosis of 9810 cells. Mechanistically, Lenvatinib@H-MnO2-FA increased the phosphorylation levels of Raf, MEK1/2, and ERK1/2.

Conclusion: H-MnO2-FA can more effectively deliver Lenvatinib to inhibit proliferation and promote apoptosis in ICC, which could be the promising drug delivery nano-vehicles for delivery drugs.

Keywords: Intrahepatic cholangiocarcinoma, H-MnO2-FA, Lenvatinib, proliferation, apoptosis, Raf-1MEK1/2-ERK1/2.

« Previous Next »
[1]
Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int 2019; 39(Suppl. 1): 19-31.
[http://dx.doi.org/10.1111/liv.14095] [PMID: 30851228]
[2]
Kudo M, Izumi N, Ichida T, et al. Report of the 19th follow-up survey of primary liver cancer in Japan. Hepatol Res 2016; 46(5): 372-90.
[http://dx.doi.org/10.1111/hepr.12697] [PMID: 26970231]
[3]
Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology 2005; 128(6): 1655-67.
[http://dx.doi.org/10.1053/j.gastro.2005.03.040] [PMID: 15887157]
[4]
Vauthey JN, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Semin Liver Dis 1994; 14(2): 109-14.
[http://dx.doi.org/10.1055/s-2007-1007302] [PMID: 8047893]
[5]
Si A, Li J, Xiang H, et al. Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma. Oncotarget 2017; 8(27): 44521-32.
[http://dx.doi.org/10.18632/oncotarget.17815] [PMID: 28562348]
[6]
Berkan Ö, Arslan S, Lalem T, et al. Regulation of microRNAs in coronary atherosclerotic plaque. Epigenomics 2019; 11(12): 1387-97.
[http://dx.doi.org/10.2217/epi-2019-0036] [PMID: 31596136]
[7]
Benson AB, D’Angelica MI, Abbott DE, et al. Guidelines insights: hepatobiliary cancers, version 2.2019. J Natl Compr Canc Netw 2019; 17(4): 302-10.
[http://dx.doi.org/10.6004/jnccn.2019.0019] [PMID: 30959462]
[8]
Shen F, Xie ZH, Xia Y, Wu MC. Progress on surgical treatment of intrahepatic cholangiocarcinoma. Zhonghua Wai Ke Za Zhi 2019; 57(4): 241-6.
[PMID: 30929367]
[9]
Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell 2014; 6: 18.
[http://dx.doi.org/10.1186/2045-824X-6-18] [PMID: 25197551]
[10]
Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372(7): 621-30.
[http://dx.doi.org/10.1056/NEJMoa1406470] [PMID: 25671254]
[11]
Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 2012; 106(10): 1598-604.
[http://dx.doi.org/10.1038/bjc.2012.154] [PMID: 22516948]
[12]
Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014; 2014: 638747.
[http://dx.doi.org/10.1155/2014/638747] [PMID: 25295214]
[13]
Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008; 14(17): 5459-65.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-5270] [PMID: 18765537]
[14]
Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006; 66(24): 11851-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1377] [PMID: 17178882]
[15]
He J, Li C, Ding L, et al. Tumor targeting strategies of smart fluorescent nanoparticles and their applications in cancer diagnosis and treatment. Adv Mater 2019; 31(40): e1902409.
[http://dx.doi.org/10.1002/adma.201902409] [PMID: 31369176]
[16]
Cé R, Couto GK, Pacheco BZ, et al. Folic acid-doxorubicin polymeric nanocapsules: A promising formulation for the treatment of triple-negative breast cancer. Eur J Pharm Sci 2021; 165: 105943.
[http://dx.doi.org/10.1016/j.ejps.2021.105943] [PMID: 34260893]
[17]
Decha P, Kanokwan K, Jiraporn T, Pichaya J, Pisittawoot A. Phonopheresis associated with nanoparticle gel from phyllanthus amarus relieves pain by reducing oxidative stress and proinflammatory markers in adults with knee osteoarthritis. Chin J Integr Med 2019; 25(9): 691-5.
[http://dx.doi.org/10.1007/s11655-019-3202-8] [PMID: 31650487]
[18]
Wenwen Zhu ZD, Fu Tingting, Liu Jingjing, et al. Modulation of hypoxia in solid tumor microenvironment with MnO2 nanoparticles to enhance photodynamic therapy. Adv Func Mater 2016; 26(30): 5490-8.
[19]
Chen Q, Feng L, Liu J, et al. Intelligent albumin-MnO2 nanoparticles as pH-/H2 O2 -responsive dissociable nanocarriers to modulate tumor hypoxia for effective combination therapy. Adv Mater 2016; 28(33): 7129-36.
[http://dx.doi.org/10.1002/adma.201601902] [PMID: 27283434]
[20]
Tripaldi L, Callone E, D’Arienzo M, et al. Silica hairy nanoparticles: a promising material for self-assembling processes. Soft Matter 2021; 17(41): 9434-46.
[http://dx.doi.org/10.1039/D1SM01085A] [PMID: 34611686]
[21]
Ao J, Chiba T, Shibata S, et al. Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells. Biochem Biophys Res Commun 2021; 549: 171-8.
[http://dx.doi.org/10.1016/j.bbrc.2021.02.097] [PMID: 33676186]
[22]
Zhang Y, Li Y, Zhang J, et al. Cadmium induced inflammation and apoptosis of porcine epididymis via activating RAF1/MEK/ ERK and NF-κB pathways. Toxicol Appl Pharmacol 2021; 415: 115449.
[http://dx.doi.org/10.1016/j.taap.2021.115449] [PMID: 33577919]
[23]
Ye CY, Zheng CP, Ying WW, Weng SS. Up-regulation of microRNA-497 inhibits the proliferation, migration and invasion but increases the apoptosis of multiple myeloma cells through the MAPK/ERK signaling pathway by targeting Raf-1. Cell Cycle 2018; 17(24): 2666-83.
[http://dx.doi.org/10.1080/15384101.2018.1542895] [PMID: 30382763]
[24]
Chen Q, Hang Y, Zhang T, Tan L, Li S, Jin Y. USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ ERK pathway. Am J Physiol Cell Physiol 2018; 315(6): C863-72.
[http://dx.doi.org/10.1152/ajpcell.00272.2018] [PMID: 30281322]
[25]
Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31(32): 4067-75.
[http://dx.doi.org/10.1200/JCO.2012.45.8372] [PMID: 24081937]
[26]
Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013; 31(28): 3517-24.
[http://dx.doi.org/10.1200/JCO.2012.48.4410] [PMID: 23980084]
[27]
Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015; 33(2): 172-9.
[http://dx.doi.org/10.1200/JCO.2013.54.3298] [PMID: 25488963]
[28]
Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015; 33(6): 559-66.
[http://dx.doi.org/10.1200/JCO.2013.53.7746] [PMID: 25547503]
[29]
Lee CH, Wan Y, Smith A, Xie R, Motzer RJ. Quality-adjusted time without symptoms or toxicity (Q-TWiST) for lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell carcinoma. Eur Urol Open Sci 2021; 31: 1-9.
[http://dx.doi.org/10.1016/j.euros.2021.06.008] [PMID: 34467233]
[30]
How JA, Patel S, Fellman B, et al. Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer. Gynecol Oncol 2021; 162(1): 24-31.
[http://dx.doi.org/10.1016/j.ygyno.2021.04.034] [PMID: 33958211]
[31]
Liu Z, Kiessling F, Gatjens J. Advanced nanomaterials in multimodal imaging: design, functionalization, and biomedical applications. J Nano Maters 2010; 2010: 894303.
[32]
Cabeza L, Perazzoli G, Mesas C, et al. Nanoparticles in colorectal cancer therapy: latest in vivo assays, clinical trials, and patents. AAPS PharmSciTech 2020; 21(5): 178.
[http://dx.doi.org/10.1208/s12249-020-01731-y] [PMID: 32591920]
[33]
Rostami I, Rezvani Alanagh H, Hu Z, Shahmoradian SH. Breakthroughs in medicine and bioimaging with up-conversion nanoparticles. Int J Nanomedicine 2019; 14: 7759-80.
[http://dx.doi.org/10.2147/IJN.S221433] [PMID: 31576121]
[34]
Claude-Henri C, Binot C, Sadoc JF. The involvement of liquid crystals in multichannel implanted neurostimulators, hearing and ENT infections, and cancer. Acta Otolaryngol 2019; 139(3): 316-32.
[http://dx.doi.org/10.1080/00016489.2018.1554265] [PMID: 31035839]
[35]
Balakumar V, Ryu JW, Kim H, Manivannan R, Son YA. Ultrasonic synthesis of α-MnO2 nanorods: An efficient catalytic conversion of refractory pollutant, methylene blue. Ultrason Sonochem 2020; 62: 104870.
[http://dx.doi.org/10.1016/j.ultsonch.2019.104870] [PMID: 31806556]
[36]
Wu F, Gao X, Xu X, et al. MnO2 nanosheet-assembled hollow polyhedron grown on carbon cloth for flexible aqueous zinc-ion batteries. ChemSusChem 2020; 13(6): 1537-45.
[http://dx.doi.org/10.1002/cssc.201903006] [PMID: 31797574]
[37]
Chen J, Wang Y, Wei X, et al. A composite prepared from MnO2 nanosheets and a deep eutectic solvent as an oxidase mimic for the colorimetric determination of DNA. Mikrochim Acta 2019; 187(1): 7.
[http://dx.doi.org/10.1007/s00604-019-4021-5] [PMID: 31797063]
[38]
Kolathodi MS, Palei M, Natarajan TS, Singh G. MnO2 encapsulated electrospun TiO2 nanofibers as electrodes for asymmetric supercapacitors. Nanotechnology 2020; 31(12): 125401.
[http://dx.doi.org/10.1088/1361-6528/ab5d64] [PMID: 31783388]
[39]
Li L, Xiao B, Mu J, et al. A MnO2 nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano 2019; 13(12): 14283-93.
[http://dx.doi.org/10.1021/acsnano.9b07598] [PMID: 31769966]
[40]
Liu X, Yi J, Wu K, et al. Rechargeable Zn-MnO2 batteries: advances, challenges and perspectives. Nanotechnology 2020; 31(12): 122001.
[http://dx.doi.org/10.1088/1361-6528/ab5b38] [PMID: 31766031]

Rights & Permissions Print Cite
Article Metrics
25
1
© 2024 Bentham Science Publishers | Privacy Policy