Solubility Enhancement of Methotrexate by Solid Nanodispersion Approach for the Improved Treatment of Small Cell Lung Carcinoma

Author(s): Karthikeyan Rajalingam, Venkateshwaran Krishnaswami, Shanmugarathinam Alagarsamy, Ruckmani Kandasamy*

Journal Name: Current Topics in Medicinal Chemistry

Volume 21 , Issue 2 , 2021


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Aims: The present work aimed to develop MT loaded solid Nano dispersion by improving its solubility, half-life and bioavailability in biological system thereby this formulation may be afforded economically.

Background: Small cell lung carcinoma is a type of malignant tumor characterized by uncontrolled cell growth at lung tissues. The potent anti-cancer drug methotrexate (MT) chosen for the present work is poorly soluble in water (BCS type IV class) with short half-life and hepatotoxic effect.

Objective: With the concept of polymeric surfactant to improve the solubility along with wettability of drugs, the present work has been hypothesized to improve its solubility using polyvinyl pyrollidone (PVP K30) polymer and α- tocopheryl polyethylene glycol 1000 succinate (TPGS) surfactant, thereby the bioavailability is expected to get enhanced. By varying the PVP K30 and TPGS ratios different formulations were developed using emulsification process.

Methods: The developed MT loaded solid nanodispersion was further characterized for its particle size, charge, morphology, encapsulation efficiency and in-vitro release behavior etc.

Results: The results of FT-IR spectrometric analysis indicated the compatibility nature of MTX, PVPK30 and TPGS. The developed formulations showed spherical morphology, particle size ranging from 59.28±24.2 nm to 169.33±10.85 nm with a surface charge ranging from -10.33 ± 2.81mV to -9.57 ± 1.2 mV. The in vitro release studies as performed by dialysis bag method showed a sustained release pattern as checked by UV Spectrophotometer. Residual solvent analysis for MTXNDs performed by HPLC indicates there is no residual DMSO in the formulation. Transmission electron microscopic image of MTXNDs revealed that the particles are spherical shaped with a solid core structure. Haemolytic assay indicates that the developed formulation is safe for intravenous administration. Cell culture studies in A549 cells indicates the enhanced cytotoxic effect for the developed formulation.

Conclusion: This proof of study indicates that the developed formulation may have anticancer potential for SCLC treatment.

Keywords: Methotrexate, Carcinoma, Nanodispersion, Solubility, SCLC treatment, Anticancer potential.

[1]
Cooper, W.A.; Lam, D.C.; O’Toole, S.A.; Minna, J.D. Molecular biology of lung cancer. J. Thorac. Dis., 2013, 5(Suppl. 5), S479-S490.
[PMID: 24163741]
[2]
Stupp, R.; Monnerat, C.; Turrisi, A.T., III; Perry, M.C.; Leyvraz, S. Small cell lung cancer: state of the art and future perspectives. Lung Cancer, 2004, 45(1), 105-117.
[http://dx.doi.org/10.1016/j.lungcan.2003.12.006] [PMID: 15196740]
[3]
Tendler, S.; Holmqvist, M.; Wagenius, G.; Lewensohn, R.; Lambe, M.; De Petris, L. Educational level, management and outcomes in small-cell lung cancer (SCLC): A population-based cohort study. Lung Cancer, 2020, 139, 111-117.
[http://dx.doi.org/10.1016/j.lungcan.2019.11.008] [PMID: 31760352]
[4]
Lin, M.W.; Su, K.Y.; Su, T.J.; Chang, C.C.; Lin, J.W.; Lee, Y.H.; Yu, S.L.; Chen, J.S.; Hsieh, M.S. Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer. Lung Cancer, 2018, 125, 282-290.
[http://dx.doi.org/10.1016/j.lungcan.2018.10.006] [PMID: 30429033]
[5]
Bernaczek, K.; Mielańczyk, A.; Mielańczyk, Ł.; Neugebauer, D.; Grzywna, Z.J. Self-assembling water-soluble polymethacrylate-MTX conjugates: The significance of macromolecules architecture on drug conjugation efficiency, the final shape of particles, and drug release. J. Biomed. Mater. Res. B Appl. Biomater., 2019, 107(8), 2476-2487.
[http://dx.doi.org/10.1002/jbm.b.34338] [PMID: 30773803]
[6]
Rahman, M.d.; Moshikur, Md. RaihanChowdhury, Rie.; Wakabayashi.; Yoshiro Tahara.; Muhammad Moniruzzaman.; Masahiro Goto.; Ionic liquids with methotrexate moieties as a potential anticancerprodrug: Synthesis, characterization and solubility evaluation. J. Mol. Liq., 2019, 278, 226-233.
[http://dx.doi.org/10.1016/j.molliq.2019.01.063]
[7]
Kurmi, B.D.; Gajbhiye, V.; Kayat, J.; Jain, N.K. Lactoferrin-conjugated dendritic nanoconstructs for lung targeting of methotrexate. J. Pharm. Sci., 2011, 100(6), 2311-2320.
[http://dx.doi.org/10.1002/jps.22469] [PMID: 21491447]
[8]
National Cancer Institute. MTX was approved by FDA for the treatment of small cell lung carcinoma, 2019. Available from: https://www.cancer.gov/about-cancer/treatment/drugs/lung
[9]
Black, D.J.; Livingston, R.B. Antineoplastic drugs in 1990: a review (part I). Drugs, 1990, 39(4), 489-501.
[http://dx.doi.org/10.2165/00003495-199039040-00002] [PMID: 2190792]
[10]
Alice, R. Oliveira.; Lilia, B.; Caland.; Edilene, G.; Oliveira.; Eryvaldo, S. T.; Egito.; Matheus, F. F.; Pedrosa and Arnóbio A.; Silva Júnior. HPLC-DAD and UV-Vis Spectrophotometric Methods for Methotrexate Assay in Different Biodegradable Microparticles. J. Braz. Chem. Soc., 2015, 26(4), 649-659.
[11]
Karami, F.; Ranjbar, S.; Ghasemi, Y.; Negahdaripour, M. Analytical methodologies for determination of methotrexate and its metabolites in pharmaceutical, biological and environmental samples. J. Pharm. Anal., 2019, 9(6), 373-391.
[http://dx.doi.org/10.1016/j.jpha.2019.06.001] [PMID: 31890337]
[12]
Sawant, K.K.; Dodiya, S.S. Recent advances and patents on solid lipid nanoparticles. Recent Pat. Drug Deliv. Formul., 2008, 2(2), 120-135.
[http://dx.doi.org/10.2174/187221108784534081] [PMID: 19075903]
[13]
Duarte, Í.; Corvo, M.L.; Serôdio, P.; Vicente, J.; Pinto, J.F.; Temtem, M. Production of nano-solid dispersions using a novel solvent-controlled precipitation process - Benchmarking their in vivo performance with an amorphous micro-sized solid dispersion produced by spray drying. Eur. J. Pharm. Sci., 2016, 93(93), 203-214.
[http://dx.doi.org/10.1016/j.ejps.2016.08.011] [PMID: 27519665]
[14]
Serajuddin, A.T. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci., 1999, 88(10), 1058-1066.
[http://dx.doi.org/10.1021/js980403l] [PMID: 10514356]
[15]
Diab, A. Zhanping You, M. Rheological characteristics of nano sized hydrated lime modified foamed warm mix asphalt. J. Mater. Civ. Eng., 2015, 27, 9.
[http://dx.doi.org/10.1061/(ASCE)MT.1943-5533.0001222]
[16]
Lingyun, Y.; Zhanping, Y.; Dai, Q. Lifeng Zhang. Assessment of nanoparticles dispersion in asphalt during bubble escaping and bursting: Nano hydrated lime modified foamed asphalt. Constr. Build. Mater., 2018, 184, 391-399.
[http://dx.doi.org/10.1016/j.conbuildmat.2018.06.234]
[17]
Bayoumi, A.A. Enhancement of solubility of a poorly soluble antiplatelet aggregation drug by cogrinding technique. Asian J Pharm. Clin. Res. (Alex.), 2018, 11(10), 340-344.
[18]
Sethia, S.; Squillante, E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int. J. Pharm., 2004, 272(1-2), 1-10.
[http://dx.doi.org/10.1016/j.ijpharm.2003.11.025]
[19]
Guo, Y.; Luo, J.; Tan, S.; Otieno, B.O.; Zhang, Z. The applications of Vitamin E TPGS in drug delivery. Eur. J. Pharm. Sci., 2013, 49(2), 175-186.
[http://dx.doi.org/10.1016/j.ejps.2013.02.006]
[20]
Pattnaik, G.; Sinha, B.; Mukherjee, B.; Ghosh, S.; Basak, S.; Mondal, S.; Bera, T. Submicron-size biodegradable polymer-based didanosine particles for treating HIV at early stage: an in vitro study. J. Microencapsul., 2012, 29(7), 666-676.
[http://dx.doi.org/10.3109/02652048.2012.680509] [PMID: 22545676]
[21]
Ghanavati, R.; Taheri, A.; Homayouni, A. Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier. Mater. Sci. Eng. C, 2017, 72(72), 501-511.
[http://dx.doi.org/10.1016/j.msec.2016.11.042] [PMID: 28024614]
[22]
Akhtar, P. Zaheer Khan.; Frynas, J.G.; Tse, Y.K.; Rao-Nicholson, R. Essential micro-foundations for contemporary business operations: top management tangible competencies, relationship-based business networks and environmental sustainability. Br. J. Manage., 2018, 29(1), 43-62.
[23]
Tran, P.; Pyo, Y.C.; Kim, D.H.; Lee, S.E.; Kim, J.K.; Park, J.S. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics, 2019, 11(3), 132.
[http://dx.doi.org/10.3390/pharmaceutics11030132]
[24]
Dhanka, M.; Shetty, C.; Srivastava, R. Injectable methotrexate loaded polycaprolactone microspheres: Physicochemical characterization, biocompatibility, and hemocompatibility evaluation. Mater. Sci. Eng. C, 2017, 81(81), 542-550.
[http://dx.doi.org/10.1016/j.msec.2017.08.055] [PMID: 28888008]
[25]
Cu,i B.; Wang, C.; Zhao, X.; Yao, J.; Zeng, Z.; Wang, Y.; Sun, C.; Liu, G.; Cui, H. Characterization and evaluation of avermectin solid nanodispersion prepared by microprecipitation and lyophilisation techniques. PLoS One, 2018, 13(1)e0191742
[26]
Chakraborty.; Manjusha.; Dasgupta.; Sudip.; Soundrapandian.; Chidambaram.; Chakraborty.; Jui.; Ghosh.; Swapankumar.; Mitra., Manoj, K.; Basu.; Debabrata. Methotrexate intercalated ZnAl-layered double hydroxide. J. of Solid State Chemistry., 2011, 184, 2439-2445.
[27]
Azadi, A.; Hamidi, M.; Rouini, M.R. Methotrexate-loaded chitosan nanogels as ‘Trojan Horses’ for drug delivery to brain: preparation and in vitro/in vivo characterization. Int. J. Biol. Macromol., 2013, 62, 523-530.
[http://dx.doi.org/10.1016/j.ijbiomac.2013.10.004] [PMID: 24120961]
[28]
Siepmann, J.; Peppas, N.A. Higuchi equation: Derivation, applications, use and misuse. Int. J. Pharm., 2011, 418(1), 6-12.
[29]
Vuddanda, P.R.; Rajamanickam, V.M.; Yaspal, M.; Singh, S. Investigations on agglomeration and haemocompatibility of vitamin E TPGS surface modified berberine chloride nanoparticles. BioMed Res. Int., 2014, 2014951942
[http://dx.doi.org/10.1155/2014/951942] [PMID: 25162037]
[30]
Singh, V.K.; Subudhi, B.B. Development and characterization of lysine-methotrexate conjugate for enhanced brain delivery. Drug Deliv., 2016, 23(7), 2327-2337.
[http://dx.doi.org/10.3109/10717544.2014.984369] [PMID: 25475953]
[31]
Cagno, E.; Trianni, A. Analysis of the most effective energy efficiency opportunities in manufacturing primary metals, plastics, and textiles small- and medium-sized enterprises. J. Energy Resour. Technol., 2012, 134(2)021005
[http://dx.doi.org/10.1115/1.4006043]
[32]
Mingan, Yu.; Sun, L. Wei Li.; Zuopin Lan.; Bibo Li.;Liqing Tan.; Ming Li.; Xueheng Yang. Investigation of structure and dissolution properties of a solid dispersion of lansoprazole in Polyvinylpyrrolidone. J. Mol. Struct., 2011, 1005, 70-77.
[http://dx.doi.org/10.1016/j.molstruc.2011.08.019]
[33]
Kuo, Y-M.; Kuthati, Y.; Kankala, R.K.; Wei, P.R.; Weng, C.F.; Liu, C.L.; Sung, P.J.; Mou, C.Y.; Lee, C.H. Layered double hydroxide nanoparticles to enhance organ-specific targeting and the anti-proliferative effect of cisplatin. J. Mater. Chem. B Mater. Biol. Med., 2015, 3(17), 3447-3458.
[http://dx.doi.org/10.1039/C4TB01989J] [PMID: 32262227]
[34]
Ausprunk, D.H.; Knighton, D.R.; Folkman, J. Vascularization of normal and neoplastic tissues grafted to the chick chorioallantois. Role of host and preexisting graft blood vessels. Am. J. Pathol., 1975, 79(3), 597-618.
[PMID: 1094838]
[35]
Niemelä, E.; Desai, D.; Niemi, R.; Doroszko, M.; Özliseli, E.; Kemppainen, K.; Rahman, N.A.; Sahlgren, C.; Törnquist, K.; Eriksson, J.E.; Rosenholm, J.M. Nanoparticles carrying fingolimod and methotrexate enables targeted induction of apoptosis and immobilization of invasive thyroid cancer. Eur. J. Pharm. Biopharm., 2020, 148, 1-9.
[http://dx.doi.org/10.1016/j.ejpb.2019.12.015] [PMID: 31917332]
[36]
Fernández, C.A.; Butterfield, C.; Jackson, G.; Moses, M.A. Structural and functional uncoupling of the enzymatic and angiogenic inhibitory activities of tissue inhibitor of metalloproteinase-2 (TIMP-2). J. Biol. Chem., 2003, 278(42), 40989-40995.
[37]
Moses, M.A.; Sudhalter, J.; Langer, R. Identification of an inhibitor of neovascularization from cartilage. Science, 1990, 248(4961), 1408-1410.
[http://dx.doi.org/10.1126/science.1694043]
[38]
Liu, Z.; Wu, Y.; Guo, Z.; Liu, Y.; Shen, Y.; Zhou, P.; Lu, X. Effects of Internalized Gold Nanoparticles with Respect to Cytotoxicity and Invasion Activity in Lung Cancer Cells PLoS One, 2014, 9(6)e99175
[39]
Ye, W.L.; Du, J.B.; Zhang, B.L.; Na, R.; Song, Y.F.; Mei, Q.B.; Zhao, M.G.; Zhou, S.Y. Cellular uptake and antitumor activity of dox-hyd-pegfa nanoparticles. PLoS One, 2014, 9(5)e97358
[40]
Taheri, A. Nanoparticles of conjugated methotrexate-human serum albumin: preparation and cytotoxicity evaluations. J. Nanomater., 2011, 2011(2), 5.
[41]
Zhao, Y.; Guo, Y.; Li, R.; Wang, T.; Han, M.; Zhu, C.; Wang, X. Methotrexate nanoparticles prepared with codendrimer from polyamidoamine (pamam) and oligoethylene glycols (oeg) dendrons: antitumor efficacy in vitro and in vivo. Sci. Rep., 2016, 6, 28983.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 21
ISSUE: 2
Year: 2021
Published on: 04 September, 2020
Page: [140 - 150]
Pages: 11
DOI: 10.2174/1568026620999200904120241
Price: $65

Article Metrics

PDF: 32
HTML: 5