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http://dx.doi.org/10.5487/TR.2018.34.3.221

Investigating Organ Toxicity Profile of Tenofovir and Tenofovir Nanoparticle on the Liver and Kidney: Experimental Animal Study  

Peter, Aniekan Imo (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Naidu, Edwin CS (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Akang, Edidiong (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Ogedengbe, Oluwatosin O (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Offor, Ugochukwu (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Rambharose, Sanjeev (Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal)
Kalhapure, Rahul (Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal)
Chuturgoon, Anil (Discipline of Medical Biochemistry, University of KwaZulu-Natal)
Govender, Thirumala (Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal)
Azu, Onyemaechi O (Discipline of Clinical Anatomy, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal)
Publication Information
Toxicological Research / v.34, no.3, 2018 , pp. 221-229 More about this Journal
Abstract
Tenofovir nanoparticles are novel therapeutic intervention in human immunodeficiency virus (HIV) infection reaching the virus in their sanctuary sites. However, there has been no systemic toxicity testing of this formulation despite global concerns on the safety of nano drugs. Therefore, this study was designed to investigate the toxicity of Tenofovir nanoparticle (NTDF) on the liver and kidney using an animal model. Fifteen adult male Sprague-Dawley (SD) rats maintained at the animal house of the biomedical resources unit of the University of KwaZulu-Natal were weighed and divided into three groups. Control animals (A) were administered with normal saline (NS). The therapeutic doses of Tenofovir (TDF) and nanoparticles of Tenofovir (NTDF) were administered to group B and C and observed for signs of stress for four weeks after which animals were weighed and sacrificed. Liver and kidney were removed and fixed in formal saline, processed and stained using H/E, PAS and MT stains for light microscopy. Serum was obtained for renal function test (RFT) and liver function test (LFT). Cellular measurements and capturing were done using ImageJ and Leica software 2.0. Data were analysed using graph pad 6, p values < 0.05 were significant. We observed no signs of behavioural toxicity and no mortality during this study, however, in the kidneys, we reported mild morphological perturbations widening of Bowman's space, and vacuolations in glomerulus and tubules of TDF and NTDF animals. Also, there was a significant elevation of glycogen deposition in NTDF and TDF animals when compared with control. In the liver, there were mild histological changes with widening of sinusoidal spaces, vacuolations in hepatocytes and elevation of glycogen deposition in TDF and NTDF administered animals. In addition to this, there were no significant differences in stereological measurements and cell count, LFT, RFT, weight changes and organo-somatic index between treatment groups and control. In conclusion, NTDF and TDF in therapeutic doses can lead to mild hepatic and renal histological damage. Further studies are needed to understand the precise genetic mechanism.
Keywords
Tenofovir nanoparticles; Liver; Kidney; Histology;
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1 Sonawane, S.J., Kalhapure, R.S., Jadhav, M., Rambharose, S., Mocktar, C. and Govender, T. (2015) Transforming linoleic acid into a nanoemulsion for enhanced activity against methicillin susceptible and resistant Staphylococcus aureus. RSC Adv., 5, 90482-90492.   DOI
2 Ogedengbe, O.O., Jegede, A.I., Onanuga, I.O., Offor, U., Naidu, E.C., Peter, A.I. and Azu, O.O. (2016) Coconut oil extract mitigates testicular injury following adjuvant treatment with antiretroviral drugs. Toxicol. Res., 32, 317-325.   DOI
3 Statistics SAoo (2016) Statistics South Africa. P0302. Midyear population estimates, 2016.
4 GBD 2015 HIV Collaborators (2016) Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the global burden of disease study 2015. Lancet HIV, 3, e361-e387.   DOI
5 UNAIDS (2017) Fact sheet - Latest statistics on the status of the AIDS epidemic.
6 Yildirimer, L., Thanh, N.T., Loizidou, M. and Seifalian, A.M. (2011) Toxicology and clinical potential of nanoparticles. Nano Today, 6, 585-607.   DOI
7 Parasuraman, S. (2011) Toxicological screening. J. Pharmacol. Pharmacother., 2, 74-79.   DOI
8 Council, N.R. (2010) Guide for the Care and Use of Laboratory Animals. National Academies Press.
9 Valdovinos, M.G., Schroeder, S.R. and Kim, G. (2003) Prevalence and correlates of psychotropic medication use among adults with developmental disabilities: 1970-2000. Int. Rev. Res. Ment. Retard., 26, 175-220.
10 Bailey, S.A., Zidell, R.H. and Perry, R.W. (2004) Relationships between organ weight and body/brain weight in the rat: what is the best analytical endpoint? Toxicol. Pathol., 32, 448-466.   DOI
11 Alomar, M.J. (2014) Factors affecting the development of adverse drug reactions. Saudi Pharm. J., 22, 83-94.   DOI
12 Piao, Y., Liu, Y. and Xie, X. (2013) Change trends of organ weight background data in sprague dawley rats at different ages. J. Toxicol. Pathol., 26, 29-34.   DOI
13 Street, J.M., Souza, A.C., Alvarez Prats, A., Horino, T., Hu, X., Yuen, P.S. and Star, R.A. (2014) Automated quantification of renal fibrosis with Sirius Red and polarization contrast microscopy. Physiol. Rep., 2, e12088.   DOI
14 Onyije, F., Ngokere, A., Ligha, A., Mgbere, O. and Avwioro, O. (2017) Computer-assisted image analysis in the diagnosis of gynaecological lesions: a quantitative and comparative investigation of haematoxylin-eosin with special dyes on tissue. J. Cancer Res. Pract., 4, 5-13.   DOI
15 Gowda, S., Desai, P.B., Kulkarni, S.S., Hull, V.V., Math, A.A. and Vernekar, S.N. (2010) Markers of renal function tests. N. Am. J. Med. Sci., 2, 170-173.
16 Iavicoli, I., Fontana, L. and Nordberg, G. (2016) The effectsof nanoparticles on the renal system. Crit. Rev. Toxicol., 46,490-560.   DOI
17 Anders, M. (1980) Metabolism of drugs by the kidney. Kidney Int., 18, 636-647.   DOI
18 Kuntzman, R., Mark, L., Brand, L., Jacobson, M., Levin, W. and Conney, A. (1966) Metabolism of drugs and carcingens by human liver enzymes. J. Pharmacol. Exp. Ther., 152, 151-156.
19 Liu, L., Ye, Q., Lu, M., Chen, S.-T., Tseng, H.-W., Lo, Y.-C. and Ho, C. (2017) A new approach to deliver anti-cancer nanodrugs with reduced off-target toxicities and improved efficiency by temporarily blunting the reticuloendothelial system with intralipid. Sci. Rep., 7, 16106.   DOI
20 Ghasempour, S., Shokrgozar, M.A., Ghasempour, R. and Alipour, M. (2015) Investigating the cytotoxicity of iron oxide nanoparticles in in vivo and in vitro studies. Exp. Toxicol. Pathol., 67, 509-515.   DOI
21 Otieno, M. (2015) Why novel nanoparticle-based delivery platforms hold key for HIV/AIDS treatment and prevention? HIV/AIDS Res. Treat. Open J., 2, 81-85.   DOI
22 Ahmed, S.N. and Siddiqi, Z.A. (2006) Antiepileptic drugsand liver disease. Seizure, 15, 156-164.   DOI
23 Desai, M., Iyer, G. and Dikshit, R. (2012) Antiretroviral drugs: critical issues and recent advances. Indian J. Pharmacol., 44, 288-298.   DOI
24 Johnson, L.F., Mossong, J., Dorrington, R.E., Schomaker, M., Hoffmann, C.J., Keiser, O., Fox, M.P., Wood, R., Prozesky, H., Giddy, J., Garone, D.B., Cornell, M., Egger, M. and Boulle, A. (2013) Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Med., 10, e1001418.   DOI
25 Sohail, M.F., Sarwar, H.S., Javed, I., Nadhman, A., Hussain, S.Z., Saeed, H., Raza, A., Bukhari, N.I., Hussain, I. and Shahnaz, G. (2017) Cell to rodent: toxicological profiling of folate grafted thiomer enveloped nanoliposomes. Toxicol. Res., 6, 814-821.   DOI
26 Richman, D.D., Margolis, D.M., Delaney, M., Greene, W.C., Hazuda, D. and Pomerantz, R.J. (2009) The challenge of finding a cure for HIV infection. Science, 323, 1304-1307.   DOI
27 Mamo, T., Moseman, E.A., Kolishetti, N., Salvador-Morales, C., Shi, J., Kuritzkes, D.R., Langer, R., von Andrian, U. and Farokhzad, O.C. (2010) Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine (Lond.), 5, 269-285.   DOI
28 Parboosing, R., Maguire, G.E., Govender, P. and Kruger, H.G. (2012) Nanotechnology and the treatment of HIV infection. Viruses, 4, 488-520.   DOI
29 Liu, J., Huang, Y., Kumar, A., Tan, A., Jin, S., Mozhi, A. and Liang, X.J. (2014) pH-sensitive nano-systems for drug delivery in cancer therapy. Biotechnol. Adv., 32, 693-710.   DOI
30 Zhang, Q., Wang, X., Li, P.Z., Nguyen, K.T., Wang, X.J., Luo, Z., Zhang, H., Tan, N.S. and Zhao, Y. (2014) Biocompatible, uniform, and redispersible mesoporous silica nanoparticles for cancer targeted drug delivery in vivo. Adv. Funct. Mater., 24, 2450-2461.   DOI
31 Shi, J., Votruba, A.R., Farokhzad, O.C. and Langer, R. (2010) Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett., 10, 3223-3230.   DOI
32 Yoo, J.-W., Irvine, D.J., Discher, D.E. and Mitragotri, S. (2011) Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat. Rev. Drug Discov., 10, 521-535.   DOI
33 Rambharose, S., Kalhapure, R.S. and Govender, T. (2017) Nanoemulgel using a bicephalous heterolipid as a novel approach to enhance transdermal permeation of tenofovir. Colloids Surf. B Biointerfaces, 154, 221-227.   DOI
34 Daglar, B., Ozgur, E., Corman, M., Uzun, L. and Demirel, G. (2014) Polymeric nanocarriers for expected nanomedicine: current challenges and future prospects. RSC Adv., 4, 48639-48659.   DOI
35 Zoroddu, M.A., Medici, S., Ledda, A., Nurchi, V.M., Lachowicz, J.I. and Peana, M. (2014) Toxicity of nanoparticles. Curr. Med. Chem., 21, 3837-3853.   DOI
36 Suvarna, V.M. and Sangave, P.C. (2017) Development and validation of stability indicating rp-hplc method for tenofovir solid lipid nanoparticles. IJPSR, 8, 658-666.
37 Matlhola, K., Katata-Seru, L., Tshweu, L., Bahadur, I., Mak- gatho, G. and Balogun, M. (2015) Formulation and optimization of Eudragit RS PO-tenofovir nanocarriers using Box-Behnken experimental design. J. Nanomater., 2015, 630690.
38 Alukda, D., Sturgis, T. and Youan, B.C. (2011) Formulation of tenofovir-loaded functionalized solid lipid nanoparticles intended for HIV prevention. J. Pharm. Sci., 100, 3345-3356.   DOI
39 Karim, Q.A., Karim, S.S.A., Frohlich, J.A., Grobler, A.C., Baxter, C., Mansoor, L.E., Kharsany, A.B., Sibeko, S., Mlisana, K.P., Omar, Z., Gengiah, T.N., Maarschalk, S., Arulappan, N., Mlotshwa, M., Morris, L. and Taylor, D. (2010) Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science, 329, 1168-1174.   DOI
40 Mayer, K.H., Maslankowski, L.A., Gai, F., El-Sadr, W.M., Justman, J., Kwiecien, A., Masse, B., Eshleman, S.H., Hendrix, C., Morrow, K., Rooney, J.F. and Soto-Torres, L. (2006) Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS, 20, 543-551.   DOI
41 Rambharose, S., Kalhapure, R.S., Akamanchi, K.G. and Govender, T. (2015) Novel dendritic derivatives of unsaturated fatty acids as promising transdermal permeation enhancers for tenofovir. J. Mater. Chem. B, 3, 6662-6675.
42 National Research Council (1985) Guide for the Care and Use of Laboratory Animals. National academy of science, Washington, DC, USA.