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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

Self-Assemble Amphiphilic PEO-PPO-PEO Tri-Block Co-Polymeric Methotrexate Nanomicelles to Combat MCF7 Cancer Cells

Author(s): Manoj Kumar Mishra*, Jitendra Gupta and Reena Gupta

Volume 18, Issue 6, 2021

Published on: 09 August, 2020

Page: [794 - 804] Pages: 11

DOI: 10.2174/1567201817666200810110914

Price: $65

Abstract

Background: Methotrexate (MTX) is a water-insoluble, anti-tumor agent that causes adverse effects like bone marrow suppression, chronic interstitial obstructive pulmonary disease, hepatotoxicity, leukopenia, interstitial pneumonitis and nephrotoxicity with slow drug release rate.

Objective: The present study aimed to successfully incorporate MTX into novel-targeted Pluronic (PEOPPO- PEO tri-block co-polymer) F127 polymeric micelles intended for intravenous administration with improved drug loading and sustained release behavior necessary to achieve better efficacy of MTX.

Methods: MTX-loaded Pluronic F127 micelles were characterized for critical micelle concentration, particle size and zeta potential, 1H NMR, drug loading, encapsulation efficiency characterization, cell uptake, in vitro release study along with partition coefficient and solubilization thermodynamics.

Results: The micellar formulation resulted in nano size 27.32±1.43nm of PF127/SDS, as compared to Pluronic F127 micelles or PF127/Phosphatidyl choline which were 30.52±1.18nm and 154.35±5.5nm in size, respectively. The uptake of PF127/SDS micellar formulation incorporating Rhodamine 123 in MCF7 cancer cells was found to be higher (84.25%) than PF127/PC, PF127 and MTX i.e. 66.26%, 73.59% and 53% respectively. The in vitro MTX release from PF127, PF127/SDS and PF127/PC polymeric micelles formulations was observed to be 69%, 69.5% and 66% at 12 h whereas 80.89%, 77.67% and 78.54% after 24 h, respectively and revealed a sustained release. MTX-loaded PF127/SDS micelles showed high partition coefficient and negative free energy of solubilization compared to PF127 and PF127/PC which signify self-assembly behavior and thermodynamic stability towards higher dissociation.

Conclusion: It was finally concluded that MTX-loaded PF127/SDS micelles act as a potential anticancer delivery system in comparison to PF127/PC and PF127 to combat tumor cells by enhancing their cellular uptake targeting with sustained release pattern and reducing the thermodynamic instability. Thus, PF127/SDS micellar formulation can provide a useful alternative dosage form for intravenous administration of MTX.

Keywords: Cancer cell, methotrexate, micelle, pluronic, drug delivery, anti cancer.

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[1]
Huynh, L.; Neale, C.; Pomès, R.; Allen, C. Computational approaches to the rational design of nanoemulsions, polymeric micelles, and dendrimers for drug delivery. Nanomedicine (Lond.), 2012, 8(1), 20-36.
[http://dx.doi.org/10.1016/j.nano.2011.05.006] [PMID: 21669300]
[2]
Jones, M. Leroux, J. Polymeric micelles - a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm., 1999, 48(2), 101-111.
[http://dx.doi.org/10.1016/S0939-6411(99)00039-9] [PMID: 10469928]
[3]
Seymour, L.W.; Ulbrich, K.; Wedge, S.R.; Hume, I.C.; Strohalm, J.; Duncan, R.N. -(2-hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice. Br. J. Cancer, 1991, 63(6), 859-866.
[http://dx.doi.org/10.1038/bjc.1991.190] [PMID: 1648946]
[4]
Taymouri, S.; Varshosaz, J.; Hassanzadeh, F.; Javanmard, S.H.; Mahzouni, P. Pharmacokinetics, organ toxicity and antitumor activity of docetaxel loaded in folate targeted cholesterol based micelles. Curr. Drug Deliv., 2016, 13(4), 545-556.
[http://dx.doi.org/10.2174/1567201812666150416154552] [PMID: 25879868]
[5]
Vakilzadeh, H.; Varshosaz, J.; Minaiyan, M. Pulmonary delivery of triptorelin loaded in pluronic based nanomicelles in rat model. Curr. Drug Deliv., 2018, 15(5), 630-640.
[http://dx.doi.org/10.2174/1567201815666180209113735] [PMID: 29424314]
[6]
Kataoka, K.; Harada, A.; Nagasaki, Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv. Rev., 2001, 47(1), 113-131.
[http://dx.doi.org/10.1016/S0169-409X(00)00124-1] [PMID: 11251249]
[7]
Nishiyama, N.; Bae, Y.; Miyata, K.; Fukushima, S.; Kataoka, K. Smart polymeric micelles for gene and drug delivery. Drug Discov. Today. Technol., 2005, 2(1), 21-26.
[http://dx.doi.org/10.1016/j.ddtec.2005.05.007] [PMID: 24981751]
[8]
Nishiyama, N.; Kataoka, K. Nanostructured devices based on block copolymer assemblies for drug delivery: Designing structures for enhanced drug function. Adv. Polym. Sci., 2006, 193, 67-101.
[http://dx.doi.org/10.1007/12_025]
[9]
Chaurasia, M.; Chourasia, M.K.; Jain, N.K.; Jain, A.; Soni, V.; Gupta, Y.; Jain, S.K. Cross-linked guar gum microspheres: a viable approach for improved delivery of anticancer drugs for the treatment of colorectal cancer. AAPS PharmSciTech, 2006, 7(3), 74.
[http://dx.doi.org/10.1208/pt070374] [PMID: 17025254]
[10]
Chaurasia, M.; Chourasia, M.K.; Jain, N.K.; Jain, A.; Soni, V.; Gupta, Y.; Jain, S.K. Methotrexate bearing calcium pectinate microspheres: a platform to achieve colon-specific drug release. Curr. Drug Deliv., 2008, 5(3), 215-219.
[http://dx.doi.org/10.2174/156720108784911668] [PMID: 18673265]
[11]
Calabresi, P.B.A.C. The Pharmacological Basis of TherapeuticsL.S. Goodman, A. sqGilman (Eds.); Macmillan: New York, , 1991; p. 1202.
[12]
Khan, Z.A.; Tripathi, R.; Mishra, B. Methotrexate: a detailed review on drug delivery and clinical aspects. Expert Opin. Drug Deliv., 2012, 9(2), 151-169.
[http://dx.doi.org/10.1517/17425247.2012.642362] [PMID: 22251428]
[13]
Sharma, A.; Arora, S. Formulation and in vitro evaluation of ufasomes for dermal administration of methotrexate. ISRN Pharm., 2012, 2012873653
[http://dx.doi.org/10.5402/2012/873653] [PMID: 22745918]
[14]
Paradkar, M.; Amin, J. Formulation development and evaluation of colon targeted delayed release methotrexate pellets for the treatment of colonic carcinoma. Braz. J. Pharm. Sci., 2018, 54, 1-12.
[http://dx.doi.org/10.1590/s2175-97902018000417222]
[15]
Alekseeva, A.A.; Moiseeva, E.V.; Onishchenko, N.R.; Boldyrev, I.A.; Singin, A.S.; Budko, A.P.; Shprakh, Z.S.; Molotkovsky, J.G.; Vodovozova, E.L. Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma. Int. J. Nanomedicine, 2017, 12, 3735-3749.
[http://dx.doi.org/10.2147/IJN.S133034] [PMID: 28553111]
[16]
Dixit, A.S.; Kulkarni, P.K.; Reddy, S.C. Methotrexate fast disintegrating tablet as a dosage form for dysphagia patients. Int. J. Pharm. Pharm. Sci., 2014, 6, 217-225.
[17]
Theodore, E.A.; Halith, S.M. Barish, Hepzi, F.R., Formulation and evaluation of niosomes encapsulated methotrexate. Asian J. Res. Biol. Pharm. Sci., 2015, 3, 87-94.
[18]
Li, Y.; Kwon, G.S. Methotrexate esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide). Part I: Effects of the level of methotrexate conjugation on the stability of micelles and on drug release. Pharm. Res., 2000, 17(5), 607-611.
[http://dx.doi.org/10.1023/A:1007529218802] [PMID: 10888314]
[19]
Zhang, Y.; Zhuo, R.X. Synthesis and drug release behavior of poly (trimethylene carbonate)-poly (ethylene glycol)-poly (trimethylene carbonate) nanoparticles. Biomaterials, 2005, 26(14), 2089-2094.
[http://dx.doi.org/10.1016/j.biomaterials.2004.06.004] [PMID: 15576183]
[20]
Kang, H.; Kim, J.D.; Han, S.H.; Chang, I.S. Self-aggregates of poly(2-hydroxyethyl aspartamide) copolymers loaded with methotrexate by physical and chemical entrapments. J. Control. Release, 2002, 81(1-2), 135-144.
[http://dx.doi.org/10.1016/S0168-3659(02)00058-5] [PMID: 11992686]
[21]
Rigon, R.B.; Fachinetti, N.; Severino, P.; Durazzo, A.; Lucarini, M.; Atanasov, A.G.; Mamouni, S.E.; Chorilli, M.; Santini, A.; Souto, E.B. Quantification of trans-resveratrol-loaded solid lipid nanoparticles by a validated reverse-phase HPLC photodiode array transferrin-conjugated docetaxel PLGA nanoparticles for tumor targeting: influence on MCF-7 cell cycle. Appl. Sci. (Basel), 2019, 9, 4961.
[http://dx.doi.org/10.3390/app9224961]
[22]
Campos, J.R.; Severino, P.; Santini, A.; Silva, A.M.; Shegokar, R.; Souto, S.B.; Souto, E. Solid lipid nanoparticles (SLN): prediction of toxicity, metabolism, fate and physicochemical properties.Nanopharmaceuticals. Expectations and reality of multifunctional drug delivery systems; Shegokar, R., Ed.; Elsevier: Amsterdam, Netherlands, 2020, Vol. 1, pp. 1-17.
[23]
Souto, E.B.; Silva, G.F.; Dias-Ferreira, J.; Zielinska, A.; Ventura, F.; Durazzo, A.; Lucarini, M.; Novellino, E.; Santini, A. Nanopharmaceutics: Part I-Clinical trials legislation and good manufacturing practices (GMP) of nanotherapeutics in the EU. Pharmaceutics, 2020, 12(2), 146.
[http://dx.doi.org/10.3390/pharmaceutics12020146] [PMID: 32053962]
[24]
Souto, E.B.; Silva, G.F.; Dias-Ferreira, J.; Zielinska, A.; Ventura, F.; Durazzo, A.; Lucarini, M.; Novellino, E.; Santini, A. Nanopharmaceutics: Part II-Production scales and clinically compliant production methods. Nanomaterials (Basel), 2020, 10(3), 455.
[http://dx.doi.org/10.3390/nano10030455] [PMID: 32143286]
[25]
Souto, E.B. Ethical issues in research and development of nanoparticles In: Drug Delivery Aspects, Shegokar R. (ed.). Expectations and realities of multifunctional drug delivery systems; Elsevier (Amsterdam, Netherlands) , 2020; 4, pp. 157-168.
[26]
Griset, A.P.; Walpole, J.; Liu, R.; Gaffey, A.; Colson, Y.L.; Grinstaff, M.W. Expansile nanoparticles: Synthesis, characterization, and in vivo efficacy of an acid-responsive polymeric drug delivery system. J. Am. Chem. Soc., 2009, 131(7), 2469-2471.
[http://dx.doi.org/10.1021/ja807416t] [PMID: 19182897]
[27]
Dembinski, T.C.; Green, C.D. Regulation of oestrogen responsiveness of MCF-7 human breast cancer cell growth by serum concentration in the culture medium; Hormonally Defined Media, 1983.
[http://dx.doi.org/10.1007/978-3-642-69290-1_67]
[28]
Horwitz, K.B.; Costlow, M.E.; McGuire, W.L. MCF-7; a human breast cancer cell line with estrogen, androgen, progesterone, and glucocorticoid receptors. Steroids, 1975, 26(6), 785-795.
[http://dx.doi.org/10.1016/0039-128X(75)90110-5] [PMID: 175527]
[29]
Kaminskas, L.M.; Porter, C.J. Targeting the lymphatics using dendritic polymers (dendrimers). Adv. Drug Deliv. Rev., 2011, 63(10-11), 890-900.
[http://dx.doi.org/10.1016/j.addr.2011.05.016] [PMID: 21683746]
[30]
Chaudhari, K.R.; Ukawala, M.; Manjappa, A.S.; Kumar, A.; Mundada, P.K.; Mishra, A.K.; Mathur, R.; Mönkkönen, J.; Murthy, R.S.R. Opsonization, biodistribution, cellular uptake and apoptosis study of PEGylated PBCA nanoparticle as potential drug delivery carrier. Pharm. Res., 2012, 29(1), 53-68.
[http://dx.doi.org/10.1007/s11095-011-0510-x] [PMID: 21744174]
[31]
Letchford, K.; Burt, H.M. Copolymer micelles and nanospheres with different in vitro stability demonstrate similar paclitaxel pharmacokinetics. Mol. Pharm., 2012, 9(2), 248-260.
[http://dx.doi.org/10.1021/mp2002939] [PMID: 22204437]
[32]
Batrakova, E.V.; Kabanov, A.V. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J. Control. Release, 2008, 130(2), 98-106.
[http://dx.doi.org/10.1016/j.jconrel.2008.04.013] [PMID: 18534704]
[33]
Zhang, X.; Jackson, J.K.; Burt, H.M. Development of amphiphilic diblock copolymers as micellar of taxol. Int. J. Pharm., 1996, 132, 195-206.
[http://dx.doi.org/10.1016/0378-5173(95)04386-1]
[34]
Lopes, J.R.; Loh, W. Investigation of self-assembly and micelle polarity for a wide range of ethylene oxide propylene oxide ethylene oxide block copolymers in water. Langmuir, 1998, 14, 750-756.
[http://dx.doi.org/10.1021/la9709655]
[35]
Wei, Z.; Hao, J.; Yuan, S.; Li, Y.; Juan, W.; Sha, X.; Fang, X. Paclitaxel-loaded Pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization. Int. J. Pharm., 2009, 376(1-2), 176-185.
[http://dx.doi.org/10.1016/j.ijpharm.2009.04.030] [PMID: 19409463]
[36]
Mu, C.F.; Balakrishnan, P.; Cui, F.D.; Yin, Y.M.; Lee, Y.B.; Choi, H.G.; Yong, C.S.; Chung, S.J.; Shim, C.K.; Kim, D.D. The effects of mixed MPEG-PLA/Pluronic copolymer micelles on the bioavailability and multidrug resistance of docetaxel. Biomaterials, 2010, 31(8), 2371-2379.
[http://dx.doi.org/10.1016/j.biomaterials.2009.11.102] [PMID: 20031202]
[37]
Vroman, B.; Ferreira, I.; Jérôme, C.; Jérôme, R.; Préat, V. PEGylated quaternized copolymer/DNA complexes for gene delivery. Int. J. Pharm., 2007, 344(1-2), 88-95.
[http://dx.doi.org/10.1016/j.ijpharm.2007.06.044] [PMID: 17689899]
[38]
Kadam, Y.; Yerramilli, U.; Bahadur, A. Solubilization of poorly water-soluble drug carbamezapine in pluronic micelles: effect of molecular characteristics, temperature and added salt on the solubilizing capacity. Colloids Surf. B Biointerfaces, 2009, 72(1), 141-147.
[http://dx.doi.org/10.1016/j.colsurfb.2009.03.027] [PMID: 19403275]
[39]
Torchilin, V.P. Structure and design of polymeric surfactant-based drug delivery systems. J. Control. Release, 2001, 73(2-3), 137-172.
[http://dx.doi.org/10.1016/S0168-3659(01)00299-1] [PMID: 11516494]
[40]
Aliabadi, H.M.; Lavasanifar, A. Polymeric micelles for drug delivery. Expert Opin. Drug Deliv., 2006, 3(1), 139-162.
[http://dx.doi.org/10.1517/17425247.3.1.139] [PMID: 16370946]
[41]
Li, Y.; Xu, R.; Couderc, S.; Bloor, D.M.; Holzwarth, J.F.; Wyn-Jones, E. Binding of tetradecyltrimethylammonium bromide to the ABA block copolymer pluronic F127 (EO 97 PO 69 EO 97): Electromotive force, microcalorimetry, and light scattering studies. Langmuir, 2001, 17, 5742-5747.
[http://dx.doi.org/10.1021/la010004x]
[42]
Kabanov, A.V.; Batrakova, E.V.; Alakhov, V.Y. An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers. J. Control. Release, 2003, 91(1-2), 75-83.
[http://dx.doi.org/10.1016/S0168-3659(03)00211-6] [PMID: 12932639]
[43]
Ye, W.; Zhu, L.; Xia, S.; Zhang, X. Dual pH-/temperature-responsive and fluorescent hydrogel for controlled drug delivery. J. Polymer Eng., 2018, 38, 371-379.
[http://dx.doi.org/10.1515/polyeng-2016-0228]
[44]
Chatterjee, S.; Hui, P.C.; Kan, C.W.; Wang, W. Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy. Sci. Rep., 2019, 9(1), 11658.
[http://dx.doi.org/10.1038/s41598-019-48254-6] [PMID: 31406233]
[45]
Krishan, A.; Fitz, C.M.; Andritsch, I. Drug retention, efflux, and resistance in tumor cells. Cytometry, 1997, 29(4), 279-285.
[http://dx.doi.org/10.1002/(SICI)1097-0320(19971201)29:4<279:AID-CYTO3>3.0.CO;2-5] [PMID: 9415409]
[46]
Kabanov, A.V.; Batrakova, E.V.; Alakhov, V.Y. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J. Control. Release, 2002, 82(2-3), 189-212.
[http://dx.doi.org/10.1016/S0168-3659(02)00009-3] [PMID: 12175737]
[47]
Alakhov, V.Yu. Moskaleva EYu; Batrakova, E.V.; Kabanov, A.V. Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer. Bioconjug. Chem., 1996, 7(2), 209-216.
[http://dx.doi.org/10.1021/bc950093n] [PMID: 8983343]
[48]
Kabanov, A.V.; Batrakova, E.V.; Alakhov, V.Y. Pluronic block copolymers for overcoming drug resistance in cancer. Adv. Drug Deliv. Rev., 2002, 54(5), 759-779.
[http://dx.doi.org/10.1016/S0169-409X(02)00047-9] [PMID: 12204601]
[49]
Ishikawa, T. ATP/Mg2+-dependent cardiac transport system for glutathione S-conjugates. A study using rat heart sarcolemma vesicles. J. Biol. Chem., 1989, 264(29), 17343-17348.
[PMID: 2793858]
[50]
Zauner, W.; Farrow, N.A.; Haines, A.M.R. In vitro uptake of polystyrene microspheres: effect of particle size, cell line and cell density. J. Control. Release, 2001, 71(1), 39-51.
[http://dx.doi.org/10.1016/S0168-3659(00)00358-8] [PMID: 11245907]

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