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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

Papain Mediated Synthesized Gold Nanoparticles Encore the Potency of Bioconjugated Flutamide

Author(s): Xiao Xu and Libo Man*

Volume 22, Issue 4, 2021

Published on: 27 February, 2020

Page: [557 - 568] Pages: 12

DOI: 10.2174/1389201021666200227121144

Price: $65

Abstract

Background: Prostate cancer is the second most common cause of male cancer death after lung cancer in the US. Therefore, there is an urgent need for a highly effective therapeutic drug at substantially low doses.

Objective: Anti-androgen drug flutamide was delivered to the prostate cancer cells using Papain Mediated Synthesized Gold Nanoparticles (PGNPs) as the drug delivery system. PGNPs and flutamide worked synergistically against cancer cells.

Methods: Flutamide was used to bioconjugate with PGNPs to improve its efficacy against prostate cancer. The synthesis and bioconjugation of flutamide with PGNPs (F-PGNPs) were characterized by various characterization techniques such as UV-vis spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and zeta potential to ensure the synthesis, size, shape, size distribution, and stability. The drug loading efficiency of flutamide in F-PGNPs was confirmed and validated by UV-vis spectroscopy. Eventually, in vitro studies were performed to determine the potency of F-PGNPs, changes in nuclear morphology, and generation of Reactive Oxygen Species (ROS).

Results: The efficacy of F-PGNPs (IC50 is 46.54 μg/mL) was found to be improved significantly over pure flutamide (IC50 is 64.63 μg/mL) against human prostate cancer PC-3 cell line whereas F-PGNPs did not show any significant toxicity up to a fairly high concentration toward normal mouse macrophage J774A.1 cells. The apoptotic effects and ROS generation of F-PGNPs were analyzed by increased permeability of the cell membrane and condensed chromatin with deep blue and green fluorescent nucleus, respectively.

Discussion: The results clearly showed that F-PGNPs significantly improved the potency of flutamide by delivering it directly into the nucleus of cancer cells through caveolae-dependent endocytosis. Conclusion: Thus, the greater inhibitory effect of F-PGNPs over the pure drug would be of great advantage during prostate cancer treatment.

Keywords: Flutamide, papain, gold nanoparticles, prostate cancer, mouse macrophages, Carica papaya.

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[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Wang, G.; Zhao, D.; Spring, D.J.; DePinho, R.A. Genetics and biology of prostate cancer. Genes Dev., 2018, 32(17-18), 1105-1140.
[http://dx.doi.org/10.1101/gad.315739.118] [PMID: 30181359]
[3]
Patel, A.R.; Klein, E.A. Risk factors for prostate cancer. Nat. Clin. Pract. Urol., 2009, 6(2), 87-95.
[http://dx.doi.org/10.1038/ncpuro1290] [PMID: 19198622]
[4]
Goh, C.L.; Schumacher, F.R.; Easton, D.; Muir, K.; Henderson, B.; Kote-Jarai, Z.; Eeles, R.A. Genetic variants associated with predisposition to prostate cancer and potential clinical implications. J. Intern. Med., 2012, 271(4), 353-365.
[http://dx.doi.org/10.1111/j.1365-2796.2012.02511.x ] [PMID: 22308973]
[5]
Kolonel, L.N.; Altshuler, D.; Henderson, B.E. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat. Rev. Cancer, 2004, 4(7), 519-527.
[http://dx.doi.org/10.1038/nrc1389] [PMID: 15229477]
[6]
Huggins, C. Effect of Orchiectomy and Irradiation on Cancer of the Prostate. Ann. Surg., 1942, 115(6), 1192-1200.
[http://dx.doi.org/10.1097/00000658-194206000-00030] [PMID: 17858048]
[7]
Huggins, C. The Treatment of Cancer of the Prostate: (The 1943 Address in Surgery before the Royal College of Physicians and Surgeons of Canada). Can. Med. Assoc. J., 1944, 50(4), 301-307.
[PMID: 20323054]
[8]
Datta, K.; Muders, M.; Zhang, H.; Tindall, D.J. Mechanism of lymph node metastasis in prostate cancer. Future Oncol., 2010, 6(5), 823-836.
[http://dx.doi.org/10.2217/fon.10.33] [PMID: 20465393]
[9]
Labrie, F. Mechanism of action and pure antiandrogenic properties of flutamide. Cancer, 1993, 72(12)(Suppl.), 3816-3827. 72:12+<3816: AID-CNCR2820721711>3.0.CO;2-3
[http://dx.doi.org/10.1002/1097-0142(19931215)] [PMID: 8252497]
[10]
Matsuda, T.; Junicho, A.; Yamamoto, T.; Kishi, H.; Korkmaz, K.; Saatcioglu, F.; Fuse, H.; Muraguchi, A. Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells. Biochem. Biophys. Res. Commun., 2001, 283(1), 179-187.
[http://dx.doi.org/10.1006/bbrc.2001.4758] [PMID: 11322786]
[11]
Karvonen, U.; Jänne, O.A.; Palvimo, J.J. Pure antiandrogens disrupt the recruitment of coactivator GRIP1 to colocalize with androgen receptor in nuclei. FEBS Lett., 2002, 523(1-3), 43-47.
[http://dx.doi.org/10.1016/S0014-5793(02)02929-0] [PMID: 12123801]
[12]
Hua, Y.; Shun, T.Y.; Strock, C.J.; Johnston, P.A. High-content positional biosensor screening assay for compounds to prevent or disrupt androgen receptor and transcriptional intermediary factor 2 protein-protein interactions. Assay Drug Dev. Technol., 2014, 12(7), 395-418.
[http://dx.doi.org/10.1089/adt.2014.594] [PMID: 25181412]
[13]
Ilagan, R.; Zhang, L.J.; Pottratz, J.; Le, K.; Salas, S.; Iyer, M.; Wu, L.; Gambhir, S.S.; Carey, M. Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model. Mol. Cancer Ther., 2005, 4(11), 1662-1669.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0197] [PMID: 16275987]
[14]
Lee, Y-F.; Lin, W-J.; Huang, J.; Messing, E.M.; Chan, F.L.; Wilding, G.; Chang, C. Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells. Cancer Res., 2002, 62(21), 6039-6044.
[PMID: 12414626]
[15]
Górowska-Wójtowicz, E.; Hejmej, A.; Kamińska, A.; Pardyak, L.; Kotula-Balak, M.; Dulińska-Litewka, J.; Laidler, P.; Bilińska, B. Anti-androgen 2-hydroxyflutamide modulates cadherin, catenin and androgen receptor phosphorylation in androgen-sensitive LNCaP and androgen-independent PC3 prostate cancer cell lines acting via PI3K/Akt and MAPK/ERK1/2 pathways. Toxicol. In Vitro, 2017, 40, 324-335.
[http://dx.doi.org/10.1016/j.tiv.2017.01.019] [PMID: 28163245]
[16]
Wysowski, D.K.; Fourcroy, J.L. Flutamide hepatotoxicity. J. Urol., 1996, 155(1), 209-212.
[http://dx.doi.org/10.1016/S0022-5347(01)66596-0] [PMID: 7490837]
[17]
Çetin, M.; Demirci, D.; Ünal, A.; Altinbaş, M.; Güven, M.; Unlühizarci, K. Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma. Hum. Exp. Toxicol., 1999, 18(3), 137-140.
[http://dx.doi.org/10.1177/096032719901800301] [PMID: 10215102]
[18]
Hejmej, A.; Bilinska, B. The effects of flutamide on cell-cell junctions in the testis, epididymis, and prostate. Reprod. Toxicol., 2018, 81, 1-16.
[http://dx.doi.org/10.1016/j.reprotox.2018.06.014] [PMID: 29958919]
[19]
Riehle, K.J.; Dan, Y.Y.; Campbell, J.S.; Fausto, N. New concepts in liver regeneration. J. Gastroenterol. Hepatol., 2011, 26(Suppl. 1), 203-212.
[http://dx.doi.org/10.1111/j.1440-1746.2010.06539.x] [PMID: 21199532]
[20]
Iram, S.; Zehra, M.; Wahid, I.; Baker, A.; Khan, A.R.A.; Ali, N.; Ahmad, S.; Khan, M.S. Cisplatin bioconjugated enzymatic GNPs amplify the effect of cisplatin with acquiescence. Scientific Report, 2019, 9, 13826.
[http://dx.doi.org/10.1038/s41598-019-50215-y]
[21]
Green, L.S.; Jellinek, D.; Bell, C.; Beebe, L.A.; Feistner, B.D.; Gill, S.C.; Jucker, F.M.; Janjić, N. Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. Chem. Biol., 1995, 2(10), 683-695.
[http://dx.doi.org/10.1016/1074-5521(95)90032-2] [PMID: 9383475]
[22]
Khan, S.; Rizvi, S.M.D.; Avaish, M.; Arshad, M.; Bagga, P.; Khan, M.S. A novel process for size controlled biosynthesis of gold nanoparticles using bromelain. Mater. Lett., 2015, 159, 373-376.
[http://dx.doi.org/10.1016/j.matlet.2015.06.118]
[23]
Ravindra, P. Protein-Mediated Synthesis of Gold Nanoparticles. Mater. Sci. Eng. B, 2009, 163(2), 93-98.
[http://dx.doi.org/10.1016/j.mseb.2009.05.013]
[24]
Ashraf, S.; Abbasi, A.Z.; Pfeiffer, C.; Hussain, S.Z.; Khalid, Z.M.; Gil, P.R.; Parak, W.J.; Hussain, I. Protein-mediated synthesis, pH-induced reversible agglomeration, toxicity and cellular interaction of silver nanoparticles. Colloids Surf. B Biointerfaces, 2013, 102, 511-518.
[http://dx.doi.org/10.1016/j.colsurfb.2012.09.032] [PMID: 23107938]
[25]
Raju, D.; Mendapara, R.; Mehta, U.J. Protein mediated synthesis of au-Ag bimetallic nanoparticles. Mater. Lett., 2014, 124, 271-274.
[http://dx.doi.org/10.1016/j.matlet.2014.03.087]
[26]
Treuel, L.; Brandholt, S.; Maffre, P.; Wiegele, S.; Shang, L.; Nienhaus, G.U. Impact of protein modification on the protein corona on nanoparticles and nanoparticle-cell interactions. ACS Nano, 2014, 8(1), 503-513.
[http://dx.doi.org/10.1021/nn405019v] [PMID: 24377255]
[27]
Wang, J.C.; Chen, G.; Pang, Y.J.; Zhang, W.G.; Liu, G. B.; Meng, Y.; Zhao, C. Z; Publ, T., Ed.; Engineered Technologies in Materials Science, Geotechnics, Environment and Mechanical Engineering, 2013. : pp. 752.
[28]
Silva, C. R. ; da Oliveira, M.B.N.; Motta, E.S.; Almeida, G.S.; de Varanda, L.L.; Pádula, M.; de, Leitão, A.C.; Caldeira-de-Araújo, A. Genotoxic and cytotoxic safety evaluation of papain (Carica papaya L.) using in vitro assays. Biomed Res. Int., 2010, 2010.
[29]
Mohr, T.; Desser, L. Plant proteolytic enzyme papain abrogates angiogenic activation of Human Umbilical Vein Endothelial Cells (HUVEC) in vitro. BMC Complement. Altern. Med., 2013, 13(1), 231.
[http://dx.doi.org/10.1186/1472-6882-13-231] [PMID: 24053149]
[30]
Gill, L.S. Ethnomedical Uses of Plants in Nigeria; Uniben Press, 1992.
[31]
Müller, A.; Barat, S.; Chen, X.; Bui, K.C.; Bozko, P.; Malek, N.P.; Plentz, R.R. Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines. Int. J. Oncol., 2016, 48(5), 2025-2034.
[http://dx.doi.org/10.3892/ijo.2016.3411] [PMID: 26935541]
[32]
Salem, I.I.; Lopez, J.M.R.; Galan, A.C. Analytical Profiles of Drug Substances and Excipients., Elsevier: Netherlands;; , 2001, Vol. 27, . p. 389.
[33]
Rahim, M.; Iram, S.; Khan, M.S.; Khan, M.S.; Shukla, A.R.; Srivastava, A.K.; Ahmad, S. Glycation-assisted synthesized gold nanoparticles inhibit growth of bone cancer cells. Colloids Surf. B Biointerfaces, 2014, 117, 473-479.
[http://dx.doi.org/10.1016/j.colsurfb.2013.12.008] [PMID: 24368207]
[34]
Chou, T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res., 2010, 70(2), 440-446.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[35]
Jalil, S.U.; Zahera, M.; Khan, M.S.; Ansari, M.I. Biochemical synthesis of gold nanoparticles from leaf protein of Nicotiana tabacum L. cv. xanthi and their physiological, developmental, and ROS scavenging responses on tobacco plant under stress conditions. IET Nanobiotechnol., 2019, 13(1), 23-29.
[http://dx.doi.org/10.1049/iet-nbt.2018.5148] [PMID: 30964033]
[36]
Wang, L.; Li, J.; Pan, J.; Jiang, X.; Ji, Y.; Li, Y.; Qu, Y.; Zhao, Y.; Wu, X.; Chen, C. Revealing the binding structure of the protein corona on gold nanorods using synchrotron radiation-based techniques: understanding the reduced damage in cell membranes. J. Am. Chem. Soc., 2013, 135(46), 17359-17368.
[http://dx.doi.org/10.1021/ja406924v] [PMID: 24215358]
[37]
Joshi, P.; Chakraborty, S.; Dey, S.; Shanker, V.; Ansari, Z.A.; Singh, S.P.; Chakrabarti, P. Binding of chloroquine-conjugated gold nanoparticles with bovine serum albumin. J. Colloid Interface Sci., 2011, 355(2), 402-409.
[http://dx.doi.org/10.1016/j.jcis.2010.12.032] [PMID: 21216410]
[38]
Leite, F.L.; Bueno, C.C.; Da Róz, A.L.; Ziemath, E.C.; Oliveira, O.N. Theoretical models for surface forces and adhesion and their measurement using atomic force microscopy. Int. J. Mol. Sci., 2012, 13(10), 12773-12856.
[http://dx.doi.org/10.3390/ijms131012773] [PMID: 23202925]
[39]
Manke, A.; Wang, L.; Rojanasakul, Y. Mechanisms of nanoparticle-Induced oxidative stress and toxicity., Biomed. Res. Int., 2013, 2013, Article ID 942916..
[http://dx.doi.org/10.1155/2013/942916]
[40]
Goldstein, A.; Soroka, Y.; Frušić-Zlotkin, M.; Lewis, A.; Kohen, R. The bright side of plasmonic gold nanoparticles; activation of Nrf2, the cellular protective pathway. Nanoscale, 2016, 8(22), 11748-11759.
[http://dx.doi.org/10.1039/C6NR02113A] [PMID: 27224746]
[41]
Pissuwan, D.; Niidome, T.; Cortie, M.B. The forthcoming applications of gold nanoparticles in drug and gene delivery systems. J. Control. Release, 2011, 149(1), 65-71.
[http://dx.doi.org/10.1016/j.jconrel.2009.12.006] [PMID: 20004222]
[42]
Jin, S.-E.; Jin, H.-E.; Hong, S.-S. Targeted delivery system of nanobiomaterials in anticancer therapy: From cells to clinics. Biomed. Res. Int., 2014, 2014, 814208..
[43]
Duncan, B.; Kim, C.; Rotello, V.M. Gold nanoparticle platforms as drug and biomacromolecule delivery systems. J. Control. Release, 2010, 148(1), 122-127.
[http://dx.doi.org/10.1016/j.jconrel.2010.06.004] [PMID: 20547192]
[44]
Khan, S.; Haseeb, M.; Baig, M.H.; Bagga, P.S.; Siddiqui, H.H.; Kamal, M.A.; Khan, M.S. Improved efficiency and stability of secnidazole - An ideal delivery system. Saudi J. Biol. Sci., 2015, 22(1), 42-49.
[http://dx.doi.org/10.1016/j.sjbs.2014.05.009] [PMID: 25561882]
[45]
Martin-Cordero, C.; Leon-Gonzalez, A.J.; Calderon-Montano, J.M.; Burgos-Moron, E.; Lopez-Lazaro, M. Pro-oxidant natural products as anticancer agents. Curr. Drug Targets, 2012, 13(8), 1006-1028.
[http://dx.doi.org/10.2174/138945012802009044] [PMID: 22594470]
[46]
Fruehauf, J.P.; Meyskens, F.L. Jr Reactive oxygen species: a breath of life or death? Clin. Cancer Res., 2007, 13(3), 789-794.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2082] [PMID: 17289868]
[47]
Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov., 2009, 8(7), 579-591.
[http://dx.doi.org/10.1038/nrd2803] [PMID: 19478820]
[48]
Teiten, M-H.; Gaascht, F.; Dicato, M.; Diederich, M. Anticancer bioactivity of compounds from medicinal plants used in European medieval traditions. Biochem. Pharmacol., 2013, 86(9), 1239-1247.
[http://dx.doi.org/10.1016/j.bcp.2013.08.007] [PMID: 23973807]
[49]
Kroemer, G.; Galluzzi, L.; Vandenabeele, P.; Abrams, J.; Alnemri, E.S.; Baehrecke, E.H.; Blagosklonny, M.V.; El-Deiry, W.S.; Golstein, P.; Green, D.R.; Hengartner, M.; Knight, R.A.; Kumar, S.; Lipton, S.A.; Malorni, W.; Nuñez, G.; Peter, M.E.; Tschopp, J.; Yuan, J.; Piacentini, M.; Zhivotovsky, B.; Melino, G. Nomenclature Committee on Cell Death 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ., 2009, 16(1), 3-11.
[http://dx.doi.org/10.1038/cdd.2008.150] [PMID: 18846107]
[50]
Wong, R.S.Y. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30(1), 87.
[http://dx.doi.org/10.1186/1756-9966-30-87] [PMID: 21943236]
[51]
Mamboya, E.A.F. Papain, a Plant Enzyme of Biological Importance: A Review. Am. J. Biochem. Biotechnol., 2012, 8(2), 99-104.
[http://dx.doi.org/10.3844/ajbbsp.2012.99.104]
[52]
Mukherjee, P.; Bhattacharya, R.; Bone, N.; Lee, Y.K.; Patra, C.R.; Wang, S.; Lu, L.; Secreto, C.; Banerjee, P.C.; Yaszemski, M.J.; Kay, N.E.; Mukhopadhyay, D. Potential therapeutic application of gold nanoparticles in B-Chronic Lymphocytic Leukemia (BCLL): Enhancing apoptosis. J. Nanobiotechnology, 2007, 5(1), 4.
[http://dx.doi.org/10.1186/1477-3155-5-4] [PMID: 17488514]
[53]
Coulter, J.A.; Jain, S.; Butterworth, K.T.; Taggart, L.E.; Dickson, G.R.; McMahon, S.J.; Hyland, W.B.; Muir, M.F.; Trainor, C.; Hounsell, A.R.; O’Sullivan, J.M.; Schettino, G.; Currell, F.J.; Hirst, D.G.; Prise, K.M. Cell type-dependent uptake, localization, and cytotoxicity of 1.9 nm gold nanoparticles. Int. J. Nanomedicine, 2012, 7, 2673-2685.
[http://dx.doi.org/10.2147/IJN.S31751] [PMID: 22701316]
[54]
Wang, Z.; Tiruppathi, C.; Minshall, R.D.; Malik, A.B. Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano, 2009, 3(12), 4110-4116.
[http://dx.doi.org/10.1021/nn9012274] [PMID: 19919048]
[55]
Mukherjee, P.; Bhattacharya, R.; Wang, P.; Wang, L.; Basu, S.; Nagy, J.A.; Atala, A.; Mukhopadhyay, D.; Soker, S. Antiangiogenic properties of gold nanoparticles. Clin. Cancer Res., 2005, 11(9), 3530-3534.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2482] [PMID: 15867256]
[56]
Adjei, I.M.; Sharma, B.; Labhasetwar, V. Nanoparticles: Cellular uptake and cytotoxicity. In: Nanomaterial; Springer: Germany,, 2014, pp. 73-91.
[http://dx.doi.org/10.1007/978-94-017-8739-0_5]
[57]
Iram, S.; Zahera, M.; Khan, S.; Khan, I.; Syed, A.; Ansary, A.A.; Ameen, F.; Shair, O.H.M.; Khan, M.S. Gold nanoconjugates reinforce the potency of conjugated cisplatin and doxorubicin. Colloids Surf. B Biointerfaces, 2017, 160, 254-264.
[http://dx.doi.org/10.1016/j.colsurfb.2017.09.017] [PMID: 28942160]
[58]
Khalil, I.A.; Kogure, K.; Akita, H.; Harashima, H. Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol. Rev., 2006, 58(1), 32-45.
[http://dx.doi.org/10.1124/pr.58.1.8] [PMID: 16507881]
[59]
Kasamatsu, H.; Nakanishi, A. How do animal DNA viruses get to the nucleus? Annu. Rev. Microbiol., 1998, 52(1), 627-686.
[http://dx.doi.org/10.1146/annurev.micro.52.1.627] [PMID: 9891810]
[60]
Kolishetti, N.; Dhar, S.; Valencia, P.M.; Lin, L.Q.; Karnik, R.; Lippard, S.J.; Langer, R.; Farokhzad, O.C. Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. Proc. Natl. Acad. Sci. USA, 2010, 107(42), 17939-17944.
[http://dx.doi.org/10.1073/pnas.1011368107] [PMID: 20921363]

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