Abstract
In this study, a system was investigated for controlled delivery of gemcitabine (GEM), an anti-cancer drug with short biological half-life time (8–17 min), using graphene oxide (GO)/montmorillonite (MMT)/chitosan (CS) nanocomposite. The structure, morphology, zeta potential, and thermal stability of the nanocomposite were evaluated by FT-IR, XRD, zeta potential analyzer, FESEM, and TGA. The results revealed that the GO interacted with positively charged GEM and CS surface. Also, the drug was intercalated between the silicate layers of MMT, and this phenomenon is responsible for more protection of the drug from burst release. The positive zeta potential of GO/GEM/CS/MMT nanocomposite (+ 16.5 mV) promotes physical stability and interaction with the negative domains of the cell membrane. A significant synergistic effect of GO and MMT on the controlled release of GEM from the drug delivery system-based chitosan matrix has been obtained. The nanocomposite with 17 wt% MMT in the release media with pH of 7.4 provided the optimal combination of drug release rate and drug release content, whereas the time for GEM 50% release (T50%) was obtained about 2 h. The non-Fickian diffusion mechanism and Korsmeyer–Peppas kinetic model were confirmed for release of GEM from drug-loaded nanocomposites. Finally, to investigate the efficiency of nanocomposite as an anti-cancer drug delivery system, an in vitro cytotoxicity assay was also carried out using breast cancer cell line MDA-MB-231. Results confirmed that the prepared nanocomposite could be used as a potential breast cancer therapy system for the controlled delivery of GEM.
Graphic abstract
Similar content being viewed by others
Availability of data and materials
Not applicable.
Code availability
Not applicable.
References
Yang Y, Jiang J, Du B, Gan ZF, Qian M, Zhang P (2009) Preparation and properties of a novel drug delivery system with both magnetic and bimolecular targeting. J Mater Sci Mater Med 20:301–307
Zhang D, Lv P, Zhou C, Zhao Y, Liao X, Yang B (2019) Cyclodextrin-based delivery systems for cancer treatment. Mater Sci Eng C 96:872–886
Li N, Zhao L, Qi L, Li Z, Luan Y (2016) Polymer assembly: promising carriers as co-delivery systems for cancer therapy. Prog Polym Sci 58:1–26
Huang P, Plunkett W (1995) Fludarabine-and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Can Chemother Pharmacol 36:181–188
Parsian M, Unsoy G, Mutlu P, Yalcın S, Tezcaner A, Gunduz U (2016) Loading of gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug. Eur J Pharmacol 5:121–128
Safdar R, Omar AA, Arunagiri A, Regupathi I, Thanabalan M (2019) Potential of Chitosan and its derivatives for controlled drug release applications—a review. J Drug Deliv Sci Technol 49:642–659
Liu Z, Robinson JT, Tabakman SM, Yang K, Dai H (2011) Carbon materials for drug delivery and cancer therapy. Mater Today 14:316–323
Bekaroğlu MG, Nurili F, İşçi S (2018) Montmorillonite as imaging and drug delivery agent for cancer therapy. Appl Clay Sci 162:469–477
Shi Y, Xiong Z, Lu X, Yan X, Cai X, Xue W (2016) Novel carboxymethyl chitosan-graphene oxide hybrid particles for drug delivery. J Mater Sci Mater Med 27:169
Pan Q, Lv Y, Williams GR, Tao L, Yang H, Li H, Zhu L (2016) Lactobionic acid and carboxymethyl chitosan functionalized graphene oxide nanocomposites as targeted anticancer drug delivery systems. Carbohydr Polym 151:812–820
Zhang H, Yan T, Xu S, Feng S, Huang D, Fujita M, Gao XD (2017) Graphene oxide-chitosan nanocomposites for intracellular delivery of immunostimulatory CpG oligodeoxynucleotides. Mater Sci Eng C 37:144–151
Bernkop-Schnürch A, Dünnhaupt S (2012) Chitosan-based drug delivery systems. Eur J Pharm Biopharm 3:463–469
Zhang H, Chen S, Zhi C, Yamazaki T, Hanagata N (2013) Chitosan-coated boron nitride nanospheres enhance delivery of CpG oligodeoxynucleotides and induction of cytokines. Int J Nanomed 8:1783–1793
Bao H, Pan Y, Ping Y, Sahoo NG, Wu T, Li L, Li J, Gan LH (2011) Chitosan-functionalized graphene oxide as a nanocarrier for drug and gene delivery. Small 11:1569–1578
Zhang SA, Yang K, Feng LZ, Liu Z (2011) In vitro and in vivo behaviors of dextran functionalized graphene. Carbon 12:4040–4049
Yadav M, Ahmad S (2015) Montmorillonite/graphene oxide/chitosan composite: synthesis, characterization and properties. Int J Biol Macromol 79:923–933
Georgakilas V, Otyepka M, Bourlinos AB, Chandra V, Kim N, Kemp KC, Hobza P, Zboril R, Kim KS (2012) Functionalization of graphene: covalent and non-covalent approaches. Deriv Appl Chem Rev 112(11):6156–6214
Zhang C, Tjiu WW, Fan W, Yang Z, Huang S, Liu TX (2011) Aqueous stabilization of graphene sheets using exfoliated montmorillonite nanoplatelets for multifunctional free-standing hybrid films via vacuum-assisted self-assembly. J Mater Chem 21(44):18011–18017
Prashanth SN, Teradal NL, Seetharamappa J, Satpati AK, Reddy AVR (2014) Fabrification of electroreduced graphene oxide−bentonite sodium composite modified electrode and its sensing application for linezolid. Electrochim Acta 133:49–56
Farshi Azhar F, Olad A (2014) A study on sustained release formulations for oral delivery of 5-fluorouracil based on alginate–chitosan/montmorillonite nanocomposite systems. Appl Clay Sci 101:288–296
Liu Q, Liu Y, Xiang S, Mo X, Su S, Zhang J (2011) Apoptosis and cytotoxicity of oligo (styrene-co-acrylonitrile)-modified montmorillonite. Appl Clay Sci 51:214–219
Kevadiya BD, Patel TA, Jhala DD, Thumbar RP, Brahmbhatt H, Pandya MP, Rajkumar S, Jena PK, Joshi GV, Gadhia PK, Tripathi CB, Bajaj HC (2012) Layered inorganic nanocomposites: a promising carrier for 5-fluorouracil (5-FU). Eur J Pharm Biopharm 81:91–101
Darder M, Colilla M, Ruiz-Hitzky E (2003) Biopolymer-clay nanocomposites based on chitosan intercalated in montmorillonite. Chem Mater 15:3774–3780
Derakhshandeh K, Fathi S (2012) Role of chitosan nanoparticles in the oral absorption of Gemcitabine. Int J Pharm 437:172–177
Betsiou M, Bantsis G, Zoi I, Sikalidis C (2012) Adsorption and release of gemcitabine hydrochloride and oxaliplatin by hydroxyapatite. Ceram Int 38:2719–2724
Betsiou M, Bantsis G, Sikalidis C (2013) Loading and delivery of anticancer drugs using montmorillonite. Int J Appl Ceram Technol 11:92–99
Garg NK, Dwivedi P, Campbell C, Tyagi RK (2012) Site specific/targeted delivery of gemcitabine through anisamide anchored chitosan/poly ethylene glycol nanoparticles: an improved understanding of lung cancer therapeutic intervention. Eur J Pharm Sci 47:1006–1014
Wade SJ, Zuzic A, Foroughi J, Talebian S, Aghmesheh M, Moulton SE, Vine KL (2017) Preparation and in vitro assessment of wet-spun gemcitabine-loaded polymeric fibers: towards localized drug delivery for the treatment of pancreatic cancer. Pancreatology 17:795–804
Chen G, Svirskis D, Lu W, Ying M, Huang Y, Wen J (2018) N-trimethyl chitosan nanoparticles and CSKSSDYQC peptide: N-trimethyl chitosan conjugates enhance the oral bioavailability of gemcitabine to treat breast cancer. J Control Release 277:142–153
Xing J, Deng L, Dong A (2010) Chitosan/alginate nanoparticles stabilized by poloxamer for the controlled release of 5-fluorouracil. J Appl Polym Sci 117:2354–2359
Higuchi T (1963) Mechanism of sustained medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 84:1464–1477
Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA (1983) Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 15:25–35
Serra L, Doménech J, Peppas NA (2006) Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid- g-ethylene glycol) hydrogels. Biomaterials 27:5440–5451
Costa P, Sousa Lobo JM (2001) Modeling and comparison of dissolution profiles. Eur J Pharm Sci 13:123–133
Pasparakis G, Bouropoulos N (2006) Swelling studies and in vitro release of verapamil from calcium alginate and calcium alginate-chitosan beads. Int J Pharm 323:34–42
Farshi Azhar F, Olad A, Salehi R (2014) Fabrication and characterization of chitosan–gelatin/nanohydroxyapatite–polyaniline composite with potential application in tissue engineering scaffolds. Des Monomers Polym 17:654–667
Olad A, Farshi Azhar F (2014) A study on the adsorption of chromium (VI) from aqueous solutions on the alginate-montmorillonite/polyaniline nanocomposite. Desalin Water Treat 52:2548–2559
Iglesias GR, Reyes-Ortega F, Fernandez Ch, Delgado A (2018) Hyperthermia-triggered gemcitabine release from polymer-coated magnetite nanoparticles. Polymers 10(269):430–445
Olad A, Bakht Khosh Hagh H, Mirmohseni A, Farshi Azhar F (2019) Graphene oxide and montmorillonite enriched natural polymeric scaffold for bone tissue engineering. Ceram Int 45:15609–15619
Olad A, Farshi Azhar F (2014) The synergetic effect of bioactive ceramic and nanoclay on the properties of chitosan–gelatin/nanohydroxyapatite–montmorillonite scaffold for bone tissue engineering. Ceram Int 40:10061–10072
Ogawa K, Hirano S, Miyanishi T, Yui T, Watanabe T (1984) A new polymorph of chitosan. Macromolecules 17:973–975
Farshi Azhar F, Olad A, Mirmohseni A (2014) Development of novel hybrid nanocomposites based on natural biodegradable polymer–montmorillonite/polyaniline: preparation and characterization. Polym Bull 71:1591–1610
Arya G, Vandana M, Acharya S, Sahoo SK (2011) Enhanced antproliferative activity of Herceptin (HER2)-conjugated gemcitabine-loaded chitosan nanoparticle in pancreatic cancer therapy. Nanomed Nanotechnol 7:859–870
Wang SF, Shen L, Tong YJ, Chen L, Phang IY, Lim PQ, Liu TX (2005) Biopolymer chitosan/montmorillonite nanocomposites: preparation and characterization. Polym Degrad Stab 90:123–131
Karimtehrani M, Ehsani NP, Ghasemi I (2017) Functionalization of graphene nanoplatelet and the shape memory properties of nanocomposite based on thermoplastic elastomer polyurethane/poly(vinyl chloride)/graphene nanoplateletes. Iran J Polym Sci Technol (Persian) 30:287–297
Hunter RJ (2013) Zeta potential in colloid science: principles and applications. Academic Press, Cambridge
Chow EKH, Ho D (2013) Cancer nanomedicine: from drug delivery to imaging. Sci Transl Med 5:216rv214
He C, Yin L, Tang C, Yin C (2012) Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. Biomaterials 33:8569–8578
Win KY, Feng SS (2005) Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 26:2713–2722
Seema Monika Datta SM (2013) Clay–polymer nanocomposites as a novel drug carrier: synthesis, characterization and controlled release study of propranolol hydrochloride. Appl Clay Sci 80–81:85–92
Malekmohammadi S, Hadadzadeh H, Farrokhpour H, Amirghofran Z (2018) Immobilization of gold nanoparticles on folate-conjugated dendritic mesoporous silica-coated reduced graphene oxide nanosheets: a new nanoplatform for curcumin pH-controlled and targeted delivery. Soft Matter 14:2400–2410
Acknowledgements
We are most grateful the continuing financial support of this research project by the Azarbaijan Shahid Madani University.
Funding
The authors declare that there is no funding regarding the publication of this article.
Author information
Authors and Affiliations
Contributions
Not applicable.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Farshi Azhar, F., Rezaei, M., Olad, A. et al. The effect of montmorillonite in graphene oxide/chitosan nanocomposite on controlled release of gemcitabine. Polym. Bull. 79, 5861–5883 (2022). https://doi.org/10.1007/s00289-021-03774-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00289-021-03774-y