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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Targeted Nanoparticles for Co-delivery of 5-FU and Nitroxoline, a Cathepsin B Inhibitor, in HepG2 Cells of Hepatocellular Carcinoma

Author(s): Jaleh Varshosaz*, Monireh M. Fard, Mina Mirian and Farshid Hassanzadeh

Volume 20, Issue 3, 2020

Page: [346 - 358] Pages: 13

DOI: 10.2174/1871520619666190930124746

Price: $65

Abstract

Background: The first choice of treatment in Hepatocellular Carcinoma (HCC) is 5-fluorouracil (5-FU). Nitroxoline (NIT), a potent inhibitor of Cathepsin B, impairs tumor progression by decreased extracellular matrix degradation. The objective of the current project was designed to target nanoparticles for co-delivery of 5-FU and NIT in order to enhance the 5-FU cytotoxic effects and reduce the metastatic properties of HepG2 cells.

Methods: 5-FU and NIT were loaded in chitosan-chondroitin nanoparticles. To target the CD44 receptors of HepG2 cells, Hyaluronic Acid (HA) was conjugated to the chondroitin by adipic acid dihydrazide and the conjugation was confirmed by FTIR and 1HNMR. After physicochemical characterization and optimization of the processing variables, MTT assay was done on HepG2 and NIH3T3 cell lines to determine the cytotoxic properties of HA targeted nanoparticles. Migration of the cells was studied to compare the co-delivery of the drugs with each drug alone.

Results: The optimized nanoparticles showed the particle size of 244.7±16.3nm, PDI of 0.30±0.03, drug entrapment efficiency of 46.3±5.0% for 5-FU and 75.1±0.9% for NIT. The drug release efficiency up to 8 hours was about 37.6±0.9% for 5-FU and 62.9±0.7% for NIT. The co-delivery of 5-FU and NIT in targeted nanoparticles showed significantly more cytotoxicity than the mixture of the two free drugs, non-targeted nanoparticles or each drug alone and reduced the IC50 value of 5-FU from 3.31±0.65μg/ml to 0.17±0.03μg/ml and the migration of HepG2 cells was also reduced to five-fold.

Conclusion: Co-delivery of 5-FU and NIT by HA targeted chitosan-chondroitin nanoparticles may be promising in HCC.

Keywords: Co-delivery, 5-FU, nitroxoline, hyaluronic acid targeted chitosan-chondroitin, nanoparticles, hepatocellular carcinoma.

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[1]
Zhu, R.X.; Seto, W.K.; Lai, C.L.; Yuen, M.F. Epidemiology of hepatocellular carcinoma in the Asia-Pacific region. Gut Liver, 2016, 10(3), 332-339.
[http://dx.doi.org/10.5009/gnl15257] [PMID: 27114433]
[2]
Uchibori, K.; Kasamatsu, A.; Sunaga, M.; Yokota, S.; Sakurada, T.; Kobayashi, E.; Yoshikawa, M.; Uzawa, K.; Ueda, S.; Tanzawa, H.; Sato, N. Establishment and characterization of two 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Int. J. Oncol., 2012, 40(4), 1005-1010.
[http://dx.doi.org/10.3892/ijo.2011.1300] [PMID: 22179686]
[3]
Lampe, C.M.; Gondi, C.S. Cathepsin B inhibitors for targeted cancer therapy. J. Cancer Sci. Ther., 2014, 6, 417-421.
[4]
Koblinski, J.E.; Ahram, M.; Sloane, B.F. Unraveling the role of proteases in cancer. Clin. Chim. Acta, 2000, 291(2), 113-135.
[http://dx.doi.org/10.1016/S0009-8981(99)00224-7] [PMID: 10675719]
[5]
Buck, M.R.; Karustis, D.G.; Day, N.A.; Honn, K.V.; Sloane, B.F. Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem. J., 1992, 282(Pt 1), 273-278.
[http://dx.doi.org/10.1042/bj2820273] [PMID: 1540143]
[6]
Ruan, J.; Zheng, H.; Rong, X.; Rong, X.; Zhang, J.; Fang, W.; Zhao, P.; Luo, R. Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients. Mol. Cancer, 2016, 15(1), 17.
[http://dx.doi.org/10.1186/s12943-016-0503-9] [PMID: 26896959]
[7]
Zhang, Q.I.; Wang, S.; Yang, D.; Pan, K.; Li, L.; Yuan, S. Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing. Oncol. Lett., 2016, 11(5), 3265-3272.
[http://dx.doi.org/10.3892/ol.2016.4380] [PMID: 27123101]
[8]
Shim, J.S.; Matsui, Y.; Bhat, S.; Nacev, B.A.; Xu, J.; Bhang, H.E.; Dhara, S.; Han, K.C.; Chong, C.R.; Pomper, M.G.; So, A.; Liu, J.O. Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J. Natl. Cancer Inst., 2010, 102(24), 1855-1873.
[http://dx.doi.org/10.1093/jnci/djq457] [PMID: 21088277]
[9]
Lazovic, J.; Guo, L.; Nakashima, J.; Mirsadraei, L.; Yong, W.; Kim, H.J.; Ellingson, B.; Wu, H.; Pope, W.B. Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro-oncol., 2015, 17(1), 53-62.
[http://dx.doi.org/10.1093/neuonc/nou139] [PMID: 25074541]
[10]
Mirković, B.; Markelc, B.; Butinar, M.; Mitrović, A.; Sosič, I.; Gobec, S.; Vasiljeva, O.; Turk, B.; Čemažar, M.; Serša, G.; Kos, J. Nitroxoline impairs tumor progression in vitro and in vivo by regulating cathepsin B activity. Oncotarget, 2015, 6(22), 19027-19042.
[http://dx.doi.org/10.18632/oncotarget.3699] [PMID: 25848918]
[11]
Oommen, O.P.; Garousi, J.; Sloff, M.; Varghese, O.P. Tailored doxorubicin-hyaluronan conjugate as a potent anticancer glyco-drug: an alternative to prodrug approach. Macromol. Biosci., 2014, 14(3), 327-333.
[http://dx.doi.org/10.1002/mabi.201300383] [PMID: 24130147]
[12]
Gao, Y.; Ruan, B.; Liu, W.; Wang, J.; Yang, X.; Zhang, Z.; Li, X.; Duan, J.; Zhang, F.; Ding, R.; Tao, K.; Dou, K. Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. Oncotarget, 2015, 6(10), 7828-7837.
[http://dx.doi.org/10.18632/oncotarget.3488] [PMID: 25797261]
[13]
Dong, C.; Ye, D.X.; Zhang, W.B.; Pan, H.Y.; Zhang, Z.Y.; Zhang, L. Overexpression of c-fos promotes cell invasion and migration via CD44 pathway in oral squamous cell carcinoma. J. Oral Pathol. Med., 2015, 44(5), 353-360.
[http://dx.doi.org/10.1111/jop.12296] [PMID: 25482572]
[14]
Mattheolabakis, G.; Milane, L.; Singh, A.; Amiji, M.M. Hyaluronic acid targeting of CD44 for cancer therapy: From receptor biology to nanomedicine. J. Drug Target., 2015, 23(7-8), 605-618.
[http://dx.doi.org/10.3109/1061186X.2015.1052072] [PMID: 26453158]
[15]
Kim, J.H.; Moon, M.J.; Kim, D.Y.; Heo, S.H.; Jeong, Y.Y. Hyaluronic acid-based nanomaterials for cancer therapy. Polymers (Basel), 2018, 10(10), 1133.
[http://dx.doi.org/10.3390/polym10101133] [PMID: 30961058]
[16]
Liu, Z.; Jiao, Y.; Wang, Y.; Zhou, C.; Zhang, Z. Polysaccharides-based nanoparticles as drug delivery systems. Adv. Drug Deliv. Rev., 2008, 60(15), 1650-1662.
[http://dx.doi.org/10.1016/j.addr.2008.09.001] [PMID: 18848591]
[17]
Reddy, K.; Krishna Mohan, G.; Satla, S.; Gaikwad, S. Natural polysaccharides: Versatile excipients for controlled drug delivery systems. Asian J. Pharm. Sci, 2011, 6(6), 275-286.
[18]
Yang, H.C.; Hon, M.H. The effect of the molecular weight of chitosan nanoparticles and its application on drug delivery. Microchem. J., 2009, 92(1), 87-91.
[http://dx.doi.org/10.1016/j.microc.2009.02.001]
[19]
Kamath, P.R.; Sunil, D. Nano-chitosan particles in anticancer drug delivery: An up-to-date review. Mini Rev. Med. Chem., 2017, 17(15), 1457-1487.
[http://dx.doi.org/10.2174/1389557517666170228105731] [PMID: 28245780]
[20]
Mattos, A.C.D.; Khalil, N.M.; Mainardes, R.M. Development and validation of an HPLC method for the determination of fluorouracil in polymeric nanoparticles. Braz. J. Pharm. Sci., 2013, 49(1), 117-126.
[http://dx.doi.org/10.1590/S1984-82502013000100013]
[21]
Badawi, M.; Kim, J.; Dauki, A.; Sutaria, D.; Motiwala, T.; Reyes, R.; Wani, N.; Kolli, S.; Jiang, J.; Coss, C.C.; Jacob, S.T.; Phelps, M.A.; Schmittgen, T.D. CD44 positive and sorafenib insensitive hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128. Oncotarget, 2018, 9(40), 26032-26045.
[http://dx.doi.org/10.18632/oncotarget.25430] [PMID: 29899840]
[22]
Figueroa, C.M.; Morales-Cruz, M.; Suárez, B.N.; Fernández, J.C.; Molina, A.M.; Quiñones, C.M.; Griebenow, K. Induction of cancer cell death by Hyaluronic acid-mediated uptake of Cytochrome c. J. Nanomed. Nanotechnol., 2015, 6(5), 316.
[PMID: 27182458]
[23]
Justus, C.R.; Leffler, N.; Ruiz-Echevarria, M.; Yang, L.V. In vitro cell migration and invasion assays. J. Vis. Exp., 2014, 88(88), 51046.
[http://dx.doi.org/10.3791/51046] [PMID: 24962652]
[24]
Li, P.; Wang, Y.; Peng, Z.; She, F.; Kong, L. Development of chitosan nanoparticles as drug delivery systems for 5-fluorouracil and leucovorin blends. Carbohydr. Polym., 2011, 85(3), 698-704.
[http://dx.doi.org/10.1016/j.carbpol.2011.03.045]
[25]
Bhumkar, D.R.; Pokharkar, V.B. Studies on effect of pH on cross-linking of chitosan with sodium tripolyphosphate: A technical note. AAPS PharmSciTech, 2006, 7(2)E50
[http://dx.doi.org/10.1208/pt070250] [PMID: 16796367]
[26]
Ragavan, B.C.V.; Tamilselvan, N.; Karthick, S.; Venkatanarayanan, R. Formulation and evaluation of 5 fluorouracil nanoparticles for the tratment of colorectal cancer. Asian J. Res. Biol. Pharm. Sci., 2015, 3(3), 109-117.
[27]
Kiaie, N.; Aghdam, R.M.; Tafti, S.H.; Emami, S.H. Statistical optimization of chitosan nanoparticles as protein vehicles, using response surface methodology. J. Appl. Biomater. Funct. Mater., 2016, 14(4), e413-e422.
[http://dx.doi.org/10.5301/jabfm.5000278] [PMID: 27647390]
[28]
Nagarwal, R.C.; Singh, P.N.; Kant, S.; Maiti, P.; Pandit, J.K. Chitosan nanoparticles of 5-fluorouracil for ophthalmic delivery: Characterization, in vitro and in vivo study. Chem. Pharm. Bull. (Tokyo), 2011, 59(2), 272-278.
[http://dx.doi.org/10.1248/cpb.59.272] [PMID: 21297311]
[29]
Deng, Q.Y.; Zhou, C.R.; Luo, B.H. Preparation and characterization of chitosan nanoparticles containing lysozyme. Pharm. Biol., 2006, 44(5), 336-342.
[http://dx.doi.org/10.1080/13880200600746246]
[30]
Raja Azalea, D.; Mohambed, M.; Joji, S.; Sankar, C. Design and evaluation of chitosan nanoparticles as novel drug carriers for the delivery of donepezil. Iran J. Pharm. Sci, 2012, 8(3), 155-164.
[31]
Hu, D.; Xu, H.; Xiao, B.; Li, D.; Zhou, Z.; Liu, X.; Tang, J.; Shen, Y. Albumin-stabilized metal–organic nanoparticles for effective delivery of metal complex anticancer drugs. ACS Appl. Mater. Interfaces, 2018, 10(41), 34974-34982.
[http://dx.doi.org/10.1021/acsami.8b12812] [PMID: 30238746]
[32]
Somasunderam, A.; Thiviyanathan, V.; Tanaka, T.; Li, X.; Neerathilingam, M.; Lokesh, G.L.R.; Mann, A.; Peng, Y.; Ferrari, M.; Klostergaard, J.; Gorenstein, D.G. Combinatorial selection of DNA thioaptamers targeted to the HA binding domain of human CD44. Biochemistry, 2010, 49(42), 9106-9112.
[http://dx.doi.org/10.1021/bi1009503] [PMID: 20843027]
[33]
Li, L.; Gu, W.; Chen, J.; Chen, W.; Xu, Z.P. Co-delivery of siRNAs and anti-cancer drugs using layered double hydroxide nanoparticles. Biomaterials, 2014, 35(10), 3331-3339.
[http://dx.doi.org/10.1016/j.biomaterials.2013.12.095] [PMID: 24456604]
[34]
Srivastava, S.; Mohammad, S.; Pant, A.B.; Mishra, P.R.; Pandey, G.; Gupta, S.; Farooqui, S. Co-delivery of 5-fluorouracil and curcumin nanohybrid formulations for improved chemotherapy against oral squamous cell carcinoma. J. Maxillofac. Oral Surg., 2018, 17(4), 597-610.
[http://dx.doi.org/10.1007/s12663-018-1126-z] [PMID: 30344406]
[35]
Anitha, A.; Sreeranganathan, M.; Chennazhi, K.P.; Lakshmanan, V.K.; Jayakumar, R. In vitro combinatorial anticancer effects of 5-fluorouracil and curcumin loaded N,O-carboxymethyl chitosan nanoparticles toward colon cancer and in vivo pharmacokinetic studies. Eur. J. Pharm. Biopharm., 2014, 88(1), 238-251.
[http://dx.doi.org/10.1016/j.ejpb.2014.04.017] [PMID: 24815764]
[36]
Balasubramanian, S.; Girija, A.R.; Nagaoka, Y.; Iwai, S.; Suzuki, M.; Kizhikkilot, V.; Yoshida, Y.; Maekawa, T.; Nair, S.D. Curcumin and 5-fluorouracil-loaded, folate- and transferrin-decorated polymeric magnetic nanoformulation: A synergistic cancer therapeutic approach, accelerated by magnetic hyperthermia. Int. J. Nanomedicine, 2014, 9, 437-459.
[PMID: 24531392]
[37]
Ni, W.; Li, Z.; Liu, Z.; Ji, Y.; Wu, L.; Sun, S.; Jian, X.; Gao, X. Dual-targeting nanoparticles: Codelivery of curcumin and 5-fluorouracil for synergistic treatment of hepatocarcinoma. J. Pharm. Sci., 2019, 108(3), 1284-1295.
[http://dx.doi.org/10.1016/j.xphs.2018.10.042] [PMID: 30395829]
[38]
Ke, M.; Wang, H.; Zhou, Y.; Li, J.; Liu, Y.; Zhang, M.; Dou, J.; Xi, T.; Shen, B.; Zhou, C. SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice. Oncotarget, 2016, 7(31), 49509-49526.
[http://dx.doi.org/10.18632/oncotarget.10375] [PMID: 27385218]
[39]
Hu, N.; Yin, J.F.; Ji, Z.; Hong, Y.; Wu, P.; Bian, B.; Song, Z.; Li, R.; Liu, Q.; Wu, F. Strengthening gastric cancer therapy by trastuzumab-conjugated nanoparticles with simultaneous encapsulation of anti-MiR-21 and 5-Fluorouridine. Cell. Physiol. Biochem., 2017, 44(6), 2158-2173.
[http://dx.doi.org/10.1159/000485955] [PMID: 29241186]
[40]
Feng, Y.; Gao, Y.; Wang, D.; Xu, Z.; Sun, W.; Ren, P. Autophagy inhibitor (LY294002) and 5-fluorouracil (5-FU) combination-based nanoliposome for enhanced efficacy against esophageal squamous cell carcinoma. Nanoscale Res. Lett., 2018, 13(1), 325.
[http://dx.doi.org/10.1186/s11671-018-2716-x] [PMID: 30328537]
[41]
Gao, Z.; Li, Z.; Yan, J.; Wang, P. Irinotecan and 5-fluorouracil-co-loaded, hyaluronic acid-modified layer-by-layer nanoparticles for targeted gastric carcinoma therapy. Drug Des. Devel. Ther., 2017, 11, 2595-2604.
[http://dx.doi.org/10.2147/DDDT.S140797] [PMID: 28919710]
[42]
Xu, N.; Huang, L.; Li, X.; Watanabe, M.; Li, C.; Xu, A.; Liu, C.; Li, Q.; Araki, M.; Wada, K.; Nasu, Y.; Huang, P. The novel combination of nitroxoline and PD-1 blockade, exerts a potent antitumor effect in a mouse model of prostate cancer. Int. J. Biol. Sci., 2019, 15(5), 919-928.
[http://dx.doi.org/10.7150/ijbs.32259] [PMID: 31182913]
[43]
Rebbaa, A. Use of cathepsin inhibitors for reversing or preventing resistance of a cancer cell to a cytotoxic agent. WO Patent 2006068742A2, 2006.
[44]
Pan, K.; Hoang, P.; Lee, C. Use of the combination in the treatment of cancer with nitroxoline and its analogues, with chemotherapeutics and immunotherapeutics. JP Patent 2019510825A 2019.

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