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Current Drug Delivery

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ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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Research Article

Application of Computational Screening Tools and Nanotechnology for Enhanced Drug Synergism in Cancer Therapy

Author(s): Thu Thi Kim Ninh, Tuan Hiep Tran, Chi-Ying F. Huang* and Chien Ngoc Nguyen*

Volume 20, Issue 7, 2023

Published on: 26 August, 2022

Page: [1015 - 1029] Pages: 15

DOI: 10.2174/1567201819666220426092538

Price: $65

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Abstract

Background: Chemoresistance continues to limit the recovery of patients with cancer. New strategies, such as combination therapy or nanotechnology, can be further improved.

Objective: In this study, we applied the computational strategy by exploiting two databases (CellMiner and Prism) to sort out the cell lines sensitive to both anti-cancer drugs, paclitaxel (PTX) and dihydroartemisinin (DHA); both of which are potentially synergistic in several cell lines.

Methods: The combination of PTX and DHA was screened at different ratios to select the optimal ratio that could inhibit lung adenocarcinoma NCI-H23 the most. To further enhance therapeutic efficacy, these combinations of drugs were incorporated into a nanosystem.

Results: At a PTX:DHA ratio of 1:2 (w/w), the combined drugs obtained the best combination index (0.84), indicating a synergistic effect. The drug-loaded nanoparticles sized at 135 nm with the drug loading capacity of 15.5 ± 1.34 and 13.8 ± 0.56 corresponding to DHA and PTX, respectively, were used. The nano-sized particles improved drug internalization into the cells, resulting in the significant inhibition of cell growth at all tested concentrations (p < 0.001). Additionally, α-tubulin aggregation, DNA damage suggested the molecular mechanism behind cell death upon PTX-DHA-loaded nanoparticle treatment. Moreover, the rate of apoptosis increased from approximately 5% to more than 20%, and the expression of apoptotic proteins changed 4 and 3 folds corresponding to p-53 and Bcl-2, respectively.

Conclusion: This study was designed thoroughly by screening cell lines for the optimization of formulations. This novel approach could pave the way for the selection of combined drugs for precise cancer treatment.

Keywords: Combination therapy, synergistic effect, bio-computational tool, nanoparticles, cancer, chemoresistance.

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[1]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
[http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]
[2]
Hu, C.M.J.; Zhang, L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem. Pharmacol., 2012, 83(8), 1104-1111.
[http://dx.doi.org/10.1016/j.bcp.2012.01.008] [PMID: 22285912]
[3]
Xin, Y.; Yin, M.; Zhao, L.; Meng, F.; Luo, L. Recent progress on nanoparticle-based drug delivery systems for cancer therapy. Cancer Biol. Med., 2017, 14(3), 228-241.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2017.0052] [PMID: 28884040]
[4]
Hasanpoor, Z.; Mostafaie, A.; Nikokar, I.; Hassan, Z.M. Curcumin-human serum albumin nanoparticles decorated with PDL1 binding peptide for targeting PDL1-expressing breast cancer cells. Int. J. Biol. Macromol., 2020, 159, 137-153.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.04.130] [PMID: 32335119]
[5]
Zinatloo-Ajabshir, Z.; Zinatloo-Ajabshir, S. Preparation and characterization of curcumin niosomal nanoparticles via a simple and eco-friendly route. J. Nanostructures., 2019, 9, 784-790.
[http://dx.doi.org/10.22052/JNS.2019.04.020]
[6]
Taheri Qazvini, N.; Zinatloo, S. Synthesis and characterization of gelatin nanoparticles using CDI/NHS as a non-toxic cross-linking system. J. Mater. Sci. Mater. Med., 2011, 22(1), 63-69.
[http://dx.doi.org/10.1007/s10856-010-4178-2] [PMID: 21052793]
[7]
Zinatloo-Ajabshir, S.N. TaheriQazvini, Inverse Miniemulsion Method for Synthesis of Gelatin Nanoparticles in Presence of CDI/NHS as a Non-toxic Cross-linking System. J. Nanostructures., 2014, 4, 267-275.
[http://dx.doi.org/10.7508/jns.2014.03.003]
[8]
Nguyen, H.T.; Tran, T.H.; Kim, J.O.; Yong, C.S.; Nguyen, C.N. Enhancing the in vitro anti-cancer efficacy of artesunate by loading into poly-d,l-lactide-co-glycolide (PLGA) nanoparticles. Arch. Pharm. Res., 2015, 38(5), 716-724.
[http://dx.doi.org/10.1007/s12272-014-04243] [PMID: 24968925]
[9]
Ho, H.N.; Tran, T.H.; Tran, T.B.; Yong, C.S.; Nguyen, C.N. Nguyen, Optimization and characterization of artesunate-loaded chitosan-decorated poly(D,L-lactide-co-glycolide) acid nanoparticles. J. Nanomater., 2016, 16, 383.
[http://dx.doi.org/10.1155/2015/674175]
[10]
Poudel, K.; Banstola, A.; Tran, T.H.; Thapa, R.K.; Gautam, M.; Ou, W.; Pham, L.M.; Maharjan, S.; Jeong, J.H.; Ku, S.K.; Choi, H.G.; Yong, C.S.; Kim, J.O. Hyaluronic acid wreathed, trio-stimuli receptive and on-demand triggerable nanoconstruct for anchored combinatorial cancer therapy. Carbohydr. Polym., 2020.249116815
[http://dx.doi.org/10.1016/j.carbpol.2020.116815] [PMID: 32933663]
[11]
Preuer, K.; Lewis, R.P.I.; Hochreiter, S.; Bender, A.; Bulusu, K.C.; Klambauer, G. DeepSynergy: predicting anti-cancer drug synergy with Deep Learning. Bioinformatics, 2018, 34(9), 1538-1546.
[http://dx.doi.org/10.1093/bioinformatics/btx806] [PMID: 29253077]
[12]
Wooller, S.K.; Benstead-Hume, G.; Chen, X.; Ali, Y.; Pearl, F.M.G. Bioinformatics in translational drug discovery. Biosci. Rep., 2017, 37(4)BSR20160180
[http://dx.doi.org/10.1042/BSR20160180] [PMID: 28487472]
[13]
Yusuf, R.; Duan, Z.; Lamendola, D.; Penson, R.; Seiden, M. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr. Cancer Drug Targets, 2003, 3(1), 1-19.
[http://dx.doi.org/10.2174/1568009033333754] [PMID: 12570657]
[14]
Phung, C.D.; Le, T.G.; Nguyen, V.H.; Vu, T.T.; Nguyen, H.Q.; Kim, J.O.; Yong, C.S.; Nguyen, C.N. PEGylated-Paclitaxel and Dihydroartemisinin Nanoparticles for Simultaneously Delivering Paclitaxel and Dihydroartemisinin to Colorectal Cancer. Pharm. Res., 2020, 37(7), 129.
[http://dx.doi.org/10.1007/s11095-020-02819-7] [PMID: 32548664]
[15]
Tran, T.B.; Tran, T.H.; Vu, Y.H.; Le, T.G.; Do, T.T.; Nguyen, N.T.; Nguyen, T.T.; Pham, T.B.; Ngo, T.Q.; Luong, Q.A.; Nguyen, C.N. pH-responsive nanocarriers for combined chemotherapies: a new approach with old materials. Cellulose, 2021, 28(6), 3423-3433.
[http://dx.doi.org/10.1007/s10570-021-03769-y]
[16]
Yu, C.; Mannan, A.M.; Yvone, G.M.; Ross, K.N.; Zhang, Y.L.; Marton, M.A.; Taylor, B.R.; Crenshaw, A.; Gould, J.Z.; Tamayo, P.; Weir, B.A.; Tsherniak, A.; Wong, B.; Garraway, L.A.; Shamji, A.F.; Palmer, M.A.; Foley, M.A.; Winckler, W.; Schreiber, S.L.; Kung, A.L.; Golub, T.R. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat. Biotechnol., 2016, 34(4), 419-423.
[http://dx.doi.org/10.1038/nbt.3460] [PMID: 26928769]
[17]
Reinhold, W.C.; Sunshine, M.; Liu, H.; Varma, S.; Kohn, K.W.; Morris, J.; Doroshow, J.; Pommier, Y. CellMiner: a web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set. Cancer Res., 2012, 72(14), 3499-3511.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-1370] [PMID: 22802077]
[18]
Shankavaram, U.T.; Varma, S.; Kane, D.; Sunshine, M.; Chary, K.K.; Reinhold, W.C.; Pommier, Y.; Weinstein, J.N. CellMiner: a relational database and query tool for the NCI-60 cancer cell lines. BMC Genomics, 2009, 10(1), 277.
[http://dx.doi.org/10.1186/1471-2164-10-277] [PMID: 19549304]
[19]
Tran, T.H.; Choi, J.Y.; Ramasamy, T.; Truong, D.H.; Nguyen, C.N.; Choi, H.G.; Yong, C.S.; Kim, J.O. Hyaluronic acid-coated solid lipid nanoparticles for targeted delivery of vorinostat to CD44 overexpressing cancer cells. Carbohydr. Polym., 2014, 114, 407-415.
[http://dx.doi.org/10.1016/j.carbpol.2014.08.026] [PMID: 25263908]
[20]
Kim, J.O.; Tran, T.H.; Ramasamy, T.; Choi, J.Y.; Nguyen, H.; Pham, T.; Jeong, J-H.; Ku, S.K.; Choi, H-G.; Yong, C.S. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells. Int. J. Nanomedicine, 2015, 10, 5249-5262.
[http://dx.doi.org/10.2147/IJN.S89584] [PMID: 26346426]
[21]
Ramasamy, T.; Tran, T.H.; Choi, J.Y.; Cho, H.J.; Kim, J.H.; Yong, C.S.; Choi, H.G.; Kim, J.O. Layer-by-layer coated lipid–polymer hybrid nanoparticles designed for use in anticancer drug delivery. Carbohydr. Polym., 2014, 102, 653-661.
[http://dx.doi.org/10.1016/j.carbpol.2013.11.009] [PMID: 24507332]
[22]
Orellana, E.; Kasinski, A.; Sulforhodamine, B.; Sulforhodamine, B. SRB) Assay in Cell Culture to Investigate Cell Proliferation. Bio Protoc., 2016, 6(21)e1984
[http://dx.doi.org/10.21769/BioProtoc.1984] [PMID: 28573164]
[23]
Thapa, R.K.; Choi, J.Y.; Poudel, B.K.; Hiep, T.T.; Pathak, S.; Gupta, B.; Choi, H.G.; Yong, C.S.; Kim, J.O. Multilayer-Coated Liquid Crystalline Nanoparticles for Effective Sorafenib Delivery to Hepatocellular Carcinoma. ACS Appl. Mater. Interfaces, 2015, 7(36), 20360-20368.
[http://dx.doi.org/10.1021/acsami.5b06203] [PMID: 26315487]
[24]
Hien, T.T.; Ambite, I.; Butler, D.; Wan, M.L.Y.; Tran, T.H.; Höglund, U.; Babjuk, M.; Svanborg, C. Bladder cancer therapy without toxicity—A dose‐escalation study of alpha1‐oleate. Int. J. Cancer, 2020, 147(9), 2479-2492.
[http://dx.doi.org/10.1002/ijc.33019] [PMID: 32319672]
[25]
Kim, S.H.; Juhnn, Y.S.; Song, Y.S. Akt involvement in paclitaxel chemoresistance of human ovarian cancer cells. Ann. N. Y. Acad. Sci., 2007, 1095(1), 82-89.
[http://dx.doi.org/10.1196/annals.1397.012] [PMID: 17404021]
[26]
Li, B.; Gu, W.; Zhu, X. NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signalling pathway. J. Drug Target., 2019, 27(10), 1061-1067.
[http://dx.doi.org/10.1080/1061186X.2019.1585437] [PMID: 30782035]
[27]
Luna, A.; Elloumi, F.; Varma, S.; Wang, Y.; Rajapakse, V.N.; Aladjem, M.I.; Robert, J.; Sander, C.; Pommier, Y.; Reinhold, W.C. CellMiner Cross-Database (CellMinerCDB) version 1.2: Exploration of patient-derived cancer cell line pharmacogenomics. Nucleic Acids Res., 2021, 49(D1), D1083-D1093.
[http://dx.doi.org/10.1093/nar/gkaa968] [PMID: 33196823]
[28]
Garnett, M.J.; Edelman, E.J.; Heidorn, S.J.; Greenman, C.D.; Dastur, A.; Lau, K.W.; Greninger, P.; Thompson, I.R.; Luo, X.; Soares, J.; Liu, Q.; Iorio, F.; Surdez, D.; Chen, L.; Milano, R.J.; Bignell, G.R.; Tam, A.T.; Davies, H.; Stevenson, J.A.; Barthorpe, S.; Lutz, S.R.; Kogera, F.; Lawrence, K.; McLaren-Douglas, A.; Mitropoulos, X.; Mironenko, T.; Thi, H.; Richardson, L.; Zhou, W.; Jewitt, F.; Zhang, T.; O’Brien, P.; Boisvert, J.L.; Price, S.; Hur, W.; Yang, W.; Deng, X.; Butler, A.; Choi, H.G.; Chang, J.W.; Baselga, J.; Stamenkovic, I.; Engelman, J.A.; Sharma, S.V.; Delattre, O.; Saez-Rodriguez, J.; Gray, N.S.; Settleman, J.; Futreal, P.A.; Haber, D.A.; Stratton, M.R.; Ramaswamy, S.; McDermott, U.; Benes, C.H. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature, 2012, 483(7391), 570-575.
[http://dx.doi.org/10.1038/nature11005] [PMID: 22460902]
[29]
Barretina, J.; Caponigro, G.; Stransky, N.; Venkatesan, K.; Margolin, A.A.; Kim, S.; Wilson, C.J.; Lehár, J.; Kryukov, G.V.; Sonkin, D.; Reddy, A.; Liu, M.; Murray, L.; Berger, M.F.; Monahan, J.E.; Morais, P.; Meltzer, J.; Korejwa, A.; Jané-Valbuena, J.; Mapa, F.A.; Thibault, J.; Bric-Furlong, E.; Raman, P.; Shipway, A.; Engels, I.H.; Cheng, J.; Yu, G.K.; Yu, J.; Aspesi, P., Jr; de Silva, M.; Jagtap, K.; Jones, M.D.; Wang, L.; Hatton, C.; Palescandolo, E.; Gupta, S.; Mahan, S.; Sougnez, C.; Onofrio, R.C.; Liefeld, T.; MacConaill, L.; Winckler, W.; Reich, M.; Li, N.; Mesirov, J.P.; Gabriel, S.B.; Getz, G.; Ardlie, K.; Chan, V.; Myer, V.E.; Weber, B.L.; Porter, J.; Warmuth, M.; Finan, P.; Harris, J.L.; Meyerson, M.; Golub, T.R.; Morrissey, M.P.; Sellers, W.R.; Schlegel, R.; Garraway, L.A. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 2012, 483(7391), 603-607.
[http://dx.doi.org/10.1038/nature11003] [PMID: 22460905]
[30]
Rees, M.G.; Seashore-Ludlow, B.; Cheah, J.H.; Adams, D.J.; Price, E.V.; Gill, S.; Javaid, S.; Coletti, M.E.; Jones, V.L.; Bodycombe, N.E.; Soule, C.K.; Alexander, B.; Li, A.; Montgomery, P.; Kotz, J.D.; Hon, C.S.Y.; Munoz, B.; Liefeld, T.; Dančík, V.; Haber, D.A.; Clish, C.B.; Bittker, J.A.; Palmer, M.; Wagner, B.K.; Clemons, P.A.; Shamji, A.F.; Schreiber, S.L. Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat. Chem. Biol., 2016, 12(2), 109-116.
[http://dx.doi.org/10.1038/nchembio.1986] [PMID: 26656090]
[31]
Aghebati-Maleki, A.; Dolati, S.; Ahmadi, M.; Baghbanzhadeh, A.; Asadi, M.; Fotouhi, A.; Yousefi, M.; Aghebati-Maleki, L. Nanoparticles and cancer therapy: Perspectives for application of nanoparticles in the treatment of cancers. J. Cell. Physiol., 2020, 235(3), 1962-1972.
[http://dx.doi.org/10.1002/jcp.29126] [PMID: 31441032]
[32]
Li, Z.; Zhu, Y.; Xiang, M.; Qiu, J.; Luo, S.; Lin, F. Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate. Acta Pharmacol. Sin., 2021, 42(4), 624-632.
[http://dx.doi.org/10.1038/s41401-020-0445-z] [PMID: 32704040]
[33]
Li, N.; Guo, W.; Li, Y.; Zuo, H.; Zhang, H.; Wang, Z.; Zhao, Y.; Yang, F.; Ren, G.; Zhang, S. Construction and anti-tumor activities of disulfide-linked docetaxel-dihydroartemisinin nanoconjugates. Colloids Surf. B Biointerfaces, 2020.191111018
[http://dx.doi.org/10.1016/j.colsurfb.2020.111018] [PMID: 32304917]
[34]
Tao, J.; Tan, Z.; Diao, L.; Ji, Z.; Zhu, J.; Chen, W.; Hu, Y. Co-delivery of dihydroartemisinin and docetaxel in pH-sensitive nanoparticles for treating metastatic breast cancer via the NF-κB/MMP-2 signal pathway. RSC Advances, 2018, 8(39), 21735-21744.
[http://dx.doi.org/10.1039/C8RA02833H] [PMID: 35541720]

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