Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

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

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

Author(s): Jaleh Varshosaz*, Saeedeh Fardshouraki, Mina Mirian, Leila Safaeian, Setareh Jandaghian and Somayeh Taymouri

Volume 20, Issue 16, 2020

Page: [1966 - 1980] Pages: 15

DOI: 10.2174/1871520620666200619174323

Price: $65

Abstract

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug.

Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues.

Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system.

Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

Keywords: Imatinib, rituximab, KIT-5, cardiotoxicity, hepatotoxicity, lymphoblastic leukemia.

« Previous Next »
Graphical Abstract

[1]
Neglia, J.P.; Robison, L.L. Epidemiology of the childhood acute leukemias. Pediatr. Clin. North Am., 1988, 35(4), 675-692,
[http://dx.doi.org/10.1016/S0031-3955(16)36505-1] [PMID: 3047649]
[2]
Jabbour, E.; Kantarjian, H.; Cortes, J. Use of second- and thirdgeneration tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm. Clin. Lymphoma Myeloma Leuk., 2015, 15(6), 323-334.
[http://dx.doi.org//10.1016/j.clml.2015.03.006] [PMID: 25971713]
[3]
Liu-Dumlao, T.; Kantarjian, H.; Thomas, D.A.; O’Brien, S.; Ravandi, F. Philadelphia-positive acute lymphoblastic leukemia: current treatment options.. Curr. Oncol. Rep., 2012, 14(5), 387-394.,
[http://dx.doi.org//10.1007/s11912-012-0247-7] [PMID: 22669492]
[4]
Pui, C.H.; Robison, L.L.; Look, A.T. Acute lymphoblastic leukaemia.Lancet, 2008, 371(9617), 1030-1043.,
[http://dx.doi.org/10.1016/S0140-6736(08)60457-2 ] [PMID: 18358930]
[5]
Zebrack, B.J.; Zeltzer, L.K.; Whitton, J.; Mertens, A.C.; Odom, L.; Berkow, R.; Robison, L.L. Psychological outcomes in long-term survivors of childhood leukemia, Hodgkin’s disease, and nonHodgkin’s lymphoma: a report from the Childhood Cancer Survivor Study. Pediatrics, 2002, 110(1 Pt 1), 42-52.
[http://dx.doi.org/10.1542/peds.110.1.42] [PMID: 12093945]
[6]
Fielding, A.K. Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology (Am. Soc. Hematol. Educ. Program), 2011, 2011, 231-237. ,
[http://dx.doi.org/10.1182/asheducation-2011.1.231 ,] [PMID: 22160039]
[7]
Lengline, E.; Beldjord, K.; Dombret, H.; Soulier, J.; Boissel, N.; Clappier, E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1- PDGFRB fusion. Haematologica, 2013, 98(11), e146-e148.
[http://dx.doi.org/10.3324/haematol.2013.095372] [PMID: 24186319]
[8]
Robak, T.; Robak, E. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Expert Opin. Investig. Drugs, 2012, 21(7), 921-947.
[http://dx.doi.org/10.1517/13543784.2012.685650] [PMID: 22612424]
[9]
Lee, S.; Kim, D-W.; Kim, Y-J.; Chung, N-G.; Kim, Y-L.; Hwang, J-Y.; Kim, C.C. Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood,, 2003, 102(8), 3068-3070..
[http://dx.doi.org/10.1182/blood-2003-04-1180] [PMID: 12842984]
[10]
Lee, S.; Kim, Y-J.; Min, C-K.; Kim, H-J.; Eom, K-S.; Kim, D-W.; Lee, J.W.; Min, W.S.; Kim, C.C. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood, 2005. 105(9), 3449-3457.
[http://dx.doi.org/10.1182/blood-2004-09-3785] [PMID: 15657178]
[11]
Cortes, J.; Giles, F.; O’Brien, S.; Thomas, D.; Garcia-Manero, G.; Rios, M.B.; Faderl, S.; Verstovsek, S.; Ferrajoli, A.; Freireich, E.J.; Talpaz, M.; Kantarjian, H. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-α.Blood, 2003.102(1), 83-86.
[http://dx.doi.org/10.1182/blood-2003-01-0025] [PMID: 12637317]
[12]
Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C.L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med.,, 2001. 344(14), 1031-1037..
[http://dx.doi.org/10.1056/NEJM200104053441401] [PMID: 11287972]
[13]
Hochhaus, A.; Kreil, S.; Corbin, A.S.; La Rosée, P.; Müller, M.C.; Lahaye, T.; Hanfstein, B.; Schoch, C.; Cross, N.C.; Berger, U.; Gschaidmeier, H.; Druker, B.J.; Hehlmann, R. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 2002.16(11), 2190-2196..
[http://dx.doi.org/10.1038/sj.leu.2402741] [PMID: 12399961]
[14]
Kantarjian, H.M.; Talpaz, M.; O’Brien, S.; Giles, F.; Garcia-Manero, G.; Faderl, S.; Thomas, D.; Shan, J.; Rios, M.B.; Cortes, J. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood, 2003.101(2), 473-475..
[http://dx.doi.org/10.1182/blood-2002-05-1451] [PMID: 12393385]
[15]
Roumiantsev, S.; Shah, N.P.; Gorre, M.E.; Nicoll, J.; Brasher, B.B.; Sawyers, C.L.; Van Etten, R.A. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr- 253 in the Abl kinase domain P-loop. Proc. Natl. Acad. Sci. USA, 2002.99(16), 10700-10705..
[http://dx.doi.org/10.1073/pnas.162140299] [PMID: 12149456]
[16]
Marslin, G.; Revina, A.M.; Khandelwal, V.K.M.; Balakumar, K.; Prakash, J.; Franklin, G.; Sheeba, C.J. Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity. Int. J. Nanomedicine, 2015, 10, 3163-3170.
[PMID: 25995626]
[17]
Mindikoglu, A.L.; Regev, A.; Bejarano, P.A.; Martinez, E.J.; Jeffers, L.J.; Schiff, E.R. Imatinib mesylate (gleevec) hepatotoxicity. Dig. Dis. Sci., 2007, 52(2), 598-601.
[http://dx.doi.org/10.1007/s10620-006-9117-1] [PMID: 17219077]
[18]
Bartolovic, K.; Balabanov, S.; Hartmann, U.; Komor, M.; Boehmler, A.M.; Bühring, H-J.; Möhle, R.; Hoelzer, D.; Kanz, L.; Hofmann, W.K.; Brümmendorf, T.H. Inhibitory effect of imatinib on normal progenitor cells in vitro.Blood, 2004, 103(2), 523-529.,
[http://dx.doi.org/10.1182/blood-2003-05-1535] [PMID: 12969987]
[19]
Harata, M.; Soda, Y.; Tani, K.; Ooi, J.; Takizawa, T.; Chen, M.; Bai, Y.; Izawa, K.; Kobayashi, S.; Tomonari, A.; Nagamura, F.; Takahashi, S.; Uchimaru, K.; Iseki, T.; Tsuji, T.; Takahashi, T.A.; Sugita, K.; Nakazawa, S.; Tojo, A.; Maruyama, K.; Asano, S. CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.Blood, 2004, 104(5), 1442-1449.,
[http://dx.doi.org//10.1182/blood-2004-02-0588] [PMID: 15155467]
[20]
Mann, G.; Trebo, M.M.; Haas, O.A.; Grümayer-Panzer, E.R.; Dworzak, M.N.; Lion, T.; Gadner, H. Philadelphia chromosomepositive mature B-cell (Burkitt cell) leukaemia. Br. J. Haematol., 2002, 118(2), 559-562.
[http://dx.doi.org/10.1046/j.1365-2141.2001.03598.x] [PMID: 12139745]
[21]
Held, G.; Pöschel, V.; Pfreundschuh, M. Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev. Anticancer Ther., 2006, 6(8), 1175-1186.
[http://dx.doi.org/10.1586/14737140.6.8.1175] [PMID: 16925484]
[22]
Thomas, D.A.; O’Brien, S.; Kantarjian, H.M. Monoclonal antibody therapy with rituximab for acute lymphoblastic leukemia. Hematol. Oncol. Clin. North Am., 2009. 23(5), 949-971..
[http://dx.doi.org/10.1016/j.hoc.2009.07.005] [PMID: 19825447]
[23]
Younes, A.; Thieblemont, C.; Morschhauser, F.; Flinn, I.; Friedberg, J.W.; Amorim, S.; Hivert, B.; Westin, J.; Vermeulen, J.; Bandyopadhyay, N.; de Vries, R.; Balasubramanian, S.; Hellemans, P.; Smit, J.W.; Fourneau, N.; Oki, Y. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive Bcell non-Hodgkin lymphoma: a non-randomised, phase 1b study Lancet Oncol., 2014.15(9), 1019-1026.
[http://dx.doi.org/10.1016/S1470-2045(14)70311-0] [PMID: 25042202]
[24]
Krishnan, V.; Xu, X.; Kelly, D.; Snook, A.; Waldman, S.A.; Mason, R.W.; Jia, X.; Rajasekaran, A.K. CD19-Targeted nanodelivery of doxorubicin enhances therapeutic efficacy in B-cell acute lymphoblastic leukemia. Mol. Pharm., 2015 12(6), 2101-2111.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00071] [PMID: 25898125]
[25]
Fan, Y.; Du, W.; He, B.; Fu, F.; Yuan, L.; Wu, H.; Dai, W.; Zhang, H.; Wang, X.; Wang, J.; Zhang, X.; Zhang, Q. The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin.Biomaterials, 2013, 34(9), 2277-2288.,
[http://dx.doi.org/10.1016/j.biomaterials.2012.12.012] [PMID: 23290525]
[26]
Ma, W.; Liu, J.; Xie, J.; Zhang, X.; Zhou, H.; Yao, H.; Zhang, W.; Guo, D.; Zhu, L.; Xiao, L.; Wu, D.; Xu, H.; Chen, S.; Zhao, Y. Modulating the growth and imatinib sensitivity of chronic myeloid leukemia stem/progenitor cells with Pullulan/MicroRNA nanoparticles in vitro. J. Biomed. Nanotechnol., 2015, 11(11), 1961-1974.
[http://dx.doi.org/10.1166/jbn.2015.2147 ] [PMID: 26554155]
[27]
Benny, O.; Menon, L.G.; Ariel, G.; Goren, E.; Kim, S-K.; Stewman, C.; Black, P.M.; Carroll, R.S.; Machluf, M. Local delivery of poly lactic-co-glycolic acid microspheres containing imatinib mesylate inhibits intracranial xenograft glioma growth. Clin. Cancer Res., 2009, 15(4), 1222-1231.,
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1316] [PMID: 19190128]
[28]
Labala, S.; Mandapalli, P.K.; Kurumaddali, A.; Venuganti, V.V.K. Layer-by-layer polymer coated gold nanoparticles for topical delivery of imatinib mesylate to treat melanoma. Mol. Pharm., 2015, 12(3), 878-888.,
[http://dx.doi.org//10.1021/mp5007163] [PMID: 25587849]
[29]
Palamà, I.E.; Leporatti, S. Luca, Ed.; Renzo, N.D.; Maffia, M.; Gambacorti-Passerini, C. Imatinib-loaded polyelectrolyte microcapsules for sustained targeting of BCR-ABL+ leukemia stem cells. Nanomedicine, 2010, 5, p. (3)419-431.
[30]
Akagi, S.; Nakamura, K.; Miura, D.; Saito, Y.; Matsubara, H.; Ogawa, A.; Matoba, T.; Egashira, K.; Ito, H. Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension.. Int. Heart J., 2015, 56(3), 354-359.,
[http://dx.doi.org/10.1536/ihj.14-338] [PMID: 25902888]
[31]
Negi, L.M.; Jaggi, M.; Joshi, V.; Ronodip, K.; Talegaonkar, S. Hyaluronan coated liposomes as the intravenous platform for delivery of imatinib mesylate in MDR colon cancer. Int. J. Biol. Macromol., 2015, 73, 222-235.,
[http://dx.doi.org/10.1016/j.ijbiomac.2014.11.026 ] [PMID: 25478964]
[32]
Ye, P.; Zhang, W.; Yang, T.; Lu, Y.; Lu, M.; Gai, Y.; Ma, X.; Xiang, G. Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting.Int. J. Nanomedicine, 2014, 9, 2167-2178.,
[http://dx.doi.org/10.2147/IJN.S60178] [PMID: 24855354]
[33]
Gupta, B.; Poudel, B.K.; Pathak, S.; Tak, J.W.; Lee, H.H.; Jeong, J-H.; Choi, H.G.; Yong, C.S.; Kim, J.O. Effects of formulation variables on the particle size and drug encapsulation of imatinib-loaded solid lipid nanoparticles. AAPS PharmSciTech, 2016, 17(3), 652- 662.,
[http://dx.doi.org/10.1208/s12249-015-0384-z] [PMID: 26304931]
[34]
Palamà, I.E.; Cortese, B.; D’Amone, S.; Arcadio, V.; Gigli, G. Coupled delivery of imatinib mesylate and doxorubicin with nanoscaled polymeric vectors for a sustained downregulation of BCR-ABL in chronic myeloid leukemia. Biomater. Sci., 2015, 3(2), 361-372.,
[http://dx.doi.org/10.1039/C4BM00289J] [PMID: 26218127]
[35]
Mendonça, L.S.; Moreira, J.N.; de Lima, M.C.P.; Simões, S. Co-encapsulation of anti-BCR-ABL siRNA and imatinib mesylate in transferrin receptor-targeted sterically stabilized liposomes for chronic myeloid leukemia treatment.Biotechnol. Bioeng., 2010, 107(5), 884-893.,
[http://dx.doi.org/10.1002/bit.22858] [PMID: 20632368]
[36]
Mirsafaei, R.; Heravi, M.M.; Ahmadi, S.; Moslemin, M.H.; Hosseinnejad, T. In situ prepared copper nanoparticles on modified KIT-5 as an efficient recyclable catalyst and its applications in click reactions in water. J. Mol. Catal. Chem., 2015, 402, 100-108.
[http://dx.doi.org/10.1016/j.molcata.2015.03.006]
[37]
Shereen, E.; Abdel Karima, R.A.F. Spectrophotometric determination of imatinib mesylate using charge transfer complexes in pure form and pharmaceutical formulation. Chem. Rapid Commun., 2014, 2(3), 55-58.
[38]
Tsai, P-C.; Hernandez-Ilizaliturri, F.J.; Bangia, N.; Olejniczak, S.H.; Czuczman, M.S. Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin. Cancer Res., 2012, 18(4), 1039-1050.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1429] [PMID: 22228637]
[39]
Force, T.; Krause, D.S.; Van Etten, R.A. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat. Rev. Cancer, 2007, 7(5), 332-344.,
[http://dx.doi.org/10.1038/nrc2106] [PMID: 17457301 ]
[40]
Herman, E.H.; Knapton, A.; Rosen, E.; Thompson, K.; Rosenzweig, B.; Estis, J.; Agee, S.; Lu, Q.A.; Todd, J.A.; Lipshultz, S.; Hasinoff, B.; Zhang, J. A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat.Toxicol. Pathol., 2011, 39(7), 1091-1106.,
[http://dx.doi.org/10.1177/0192623311419524] [PMID: 21937741]
[41]
Kerkelä, R.; Grazette, L.; Yacobi, R.; Iliescu, C.; Patten, R.; Beahm, C.; Walters, B.; Shevtsov, S.; Pesant, S.; Clubb, F.J.; Rosenzweig, A.; Salomon, R.N.; Van Etten, R.A.; Alroy, J.; Durand, J.B.; Force, T. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med., 2006, 12(8), 908-916.,
[http://dx.doi.org/10.1038/nm1446 ] [PMID: 16862153]
[42]
Maharsy, W.; Aries, A.; Mansour, O.; Komati, H.; Nemer, M. Ageing is a risk factor in imatinib mesylate cardiotoxicity.Eur. J. Heart Fail., 2014, 16(4), 367-376.,
[http://dx.doi.org/10.1002/ejhf.58] [PMID: 24504921]
[43]
Zhou, S.; Zheng, S.; Shan, Y.; Li, L.; Zhang, X.; Wang, C. Rituximab-conjugated and doxorubicin-loaded microbubbles combined with ultrasound irradiation inhibits proliferation and induces apoptosis in Raji cell lines. Oncol. Rep., 2016, 35(2), 801-808.,
[http://dx.doi.org/10.3892/or.2015.4468] [PMID: 267184871980]
[44]
Song, L.; Zhang, W.; Chen, H.; Zhang, X.; Wu, H.; Ma, M.; Wang, Z.; Gu, N.; Zhang, Y. Apoptosis-promoting effect of rituximab-conjugated magnetic nanoprobes on malignant lymphoma cells with CD20 overexpression. Int. J. Nanomedicine, 2019, 14, 921-936.,
[http://dx.doi.org/10.2147/IJN.S185458] [PMID: 30787607]
[45]
Zhou, S.; Wu, D.; Yin, X.; Jin, X.; Zhang, X.; Zheng, S.; Wang, C.; Liu, Y. Intracellular pH-responsive and rituximab-conjugated mesoporous silica nanoparticles for targeted drug delivery to lymphoma B cells. J. Exp. Clin. Cancer Res., 2017, 36(1), 24-34..
[http://dx.doi.org/10.1186/s13046-017-0492-6] [PMID: 28166836]
[46]
Gholipour, N.; Jalilian, A.R.; Khalaj, A.; Johari-Daha, F.; Yavari, K.; Sabzevari, O.; Khanchi, A.R.; Akhlaghi, M. Preparation and radiolabeling of a lyophilized (kit) formulation of DOTA-rituximab with ⁹⁰Y and ¹¹¹In for domestic radioimmunotherapy and radioscintigraphy of non-Hodgkin’s lymphoma. Daru, 2014, 22(1), 58.
[http://dx.doi.org/10.1186/2008-2231-22-58] [PMID: 25074720]
[47]
Tang, X.; Xie, C.; Jiang, Z.; Li, A.; Cai, S.; Hou, C.; Wang, J.; Liang, Y.; Ma, D. Rituximab (anti-CD20)-modified AZD-2014- encapsulated nanoparticles killing of B lymphoma cells. Artif. Cells Nanomed. Biotechnol., 2018, 46(sup2), 1063-1073..
[http://dx.doi.org/10.1080/21691401.2018.1478844] [PMID: 30198340]
[48]
Lim, A.Y.; Segarra, I.; Chakravarthi, S.; Akram, S.; Judson, J.P. Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. BMC Pharmacol., 2010, 10, 14-4.
[http://dx.doi.org/10.1186/1471-2210-10-14 ] [PMID: 20950441]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy