Generic placeholder image

Current Nanomedicine


ISSN (Print): 2468-1873
ISSN (Online): 2468-1881

Research Article

Azacitidine Loaded PLGA Nanoparticles and their Dual Release Mechanism

Author(s): Kanchan Kashyap, Mayank Handa and Rahul Shukla*

Volume 10, Issue 3, 2020

Page: [280 - 289] Pages: 10

DOI: 10.2174/2468187310666200225120130

Price: $65


Background: Glioblastoma multiforme (GBM) is a belligerent brain tumor constituting about 67% of primary brain tumours. The current therapy for glioblastoma multiforme is surgery, radiations and chemotherapy though the success rate is quite limited. Azacitidine is a hydrophilic anti-cancer agent which acts by demethylation and is used in the treatment of both acute and chronic myelomonocytic leukaemia along with GBM.

Objective: Formulation of stable Azacitidine loaded poly-lactide-co-glycolide (PLGA) nanoparticles (NPs) with tailor-made release profiles.

Methods: Preparation of Azacitidine loaded PLGA nanoparticles was done by double emulsion (w/o/w) solvent evaporation technique. PLGA was used in the formulation, as it is biocompatible and biodegradable. Polyvinyl alcohol worked as an emulsifier while Span 80 decreased the interfacial tension among two immiscible phases (aqueous and organic), resulting in increased stability of the formulation.

Results: Polymer concentration was directly proportional to the entrapment and drug loading and inversely proportional to particle size. Azacitidine loaded PLGA NPs showed a biphasic release model. At the first stage, burst release was observed, followed by sustained release. About 43.93 ± 0.69% drug was released in 1 hour and the remaining drug was released in 48 hours.

Conclusion: Dual release behavior first delivered an ample amount of dose which provided cytotoxic dose, followed by the maintenance dose for sustaining the cytotoxic drug levels. Future prospective requires In-vitro cell viability evaluation of tailor-made polymeric nanoparticles along with In-vivo evaluation for therapeutic intervention in a glioblastoma tumor model.

Keywords: Azacitidine, PLGA, nanoparticles, glioblastoma, sustained release, burst release.

Graphical Abstract
Kleihues P, Sobin LH. World Health Organization classification of tumors. Cancer 2000; 88(12): 2887.
[<2887:AID-CNCR32>3.0.CO;2-F] [PMID: 10870076]
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016; 131(6): 803-20.
[] [PMID: 27157931]
Alifieris C, Trafalis DT. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol Ther 2015; 152: 63-82.
[] [PMID: 25944528]
Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med 2015; 3(9): 121.
[PMID: 26207249]
Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med 2014; 6(11): 1359-70.
[] [PMID: 25312641]
Zhang X, Zhang W, Mao XG, et al. Targeting role of glioma stem cells for gliobastoma multiforme. Curr Med Chem 2013; 20: 1974-84.
Willems E, Lombard A, Dedobbeleer M, Goffart N, Rogister B. The unexpected roles of aurora a kinase in gliobastoma recurrences. Target Oncol 2017; 12(1): 11-8.
[] [PMID: 27573024]
Rekers NH, Sminia P, Peters GJ. Towards tailored therapy of glioblastoma multiforme. J Chemother 2011; 23(4): 187-99.
[] [PMID: 21803695]
Khasraw M, Bell D, Wheeler H. Long-term use of temozolomide: could you use temozolomide safely for life in gliomas? J Clin Neurosci 2009; 16(6): 854-5.
[] [PMID: 19303779]
Beljanski V. Azacitidine. xPharm: The Comprehensive Pharmacology Reference 2008.
Sullivan M, Hahn K, Kolesar JM. Azacitidine: a novel agent for myelodysplastic syndromes. Am J Health Syst Pharm 2005; 62(15): 1567-73.
[] [PMID: 16030365]
Kratzsch T, Kuhn SA, Joedicke A, et al. Treatment with 5-azacitidine delay growth of glioblastoma xenografts: a potential new treatment approach for glioblastomas. J Cancer Res Clin Oncol 2018; 144(5): 809-19.
[] [PMID: 29427211]
Kratzsch T, Vajkoczy P, Hanisch UK, Kuhn S. Azacitidine delays growth of patient-derived glioma xenografts and could be a novel treatment approach against glioblastoma multiforme by epigenetic remodeling: V640. Onkologie 2013; 36: 187-8.
[] [PMID: 29427211]
Pardhi VP, Verma T, Flora SJS, et al. Nanocrystals: An overview of fabrication, characterization and therapeutic applications in drug delivery. Curr Pharm Des 2019; 24: 5129-46.
[] [PMID: 30767737]
Shukla R, Handa M, Lokesh SB, et al. Conclusion and future prospective of polymeric nanoparticles for cancer therapy. Polymeric nanoparticles as a promising tool for anti-cancer therapeutics 2019; 389-408.
[ 6.00018-2]
Singh A, Vaishagya K. K Verma R, Shukla R. Temperature/pH-Triggered PNIPAM-Based smart nanogel system loaded with anastrozole delivery for application in cancer chemotherapy. AAPS PharmSciTech 2019; 20(5): 213.
[] [PMID: 31165298]
Tafaghodi M, Abolghasem Sajadi Tabassi S, Jaafari MR, Zakavi SR, Momen-Nejad M. Evaluation of the clearance characteristics of various microspheres in the human nose by gamma-scintigraphy. Int J Pharm 2004; 280(1-2): 125-35.
[] [PMID: 15265553]
Shukla R, Gupta J, Shukla P, et al. Chitosan coated alginate micro particles for the oral delivery of antifilarial drugs and combinations for intervention in Brugia malayi induced lymphatic filariasis. RSC Advances 2015; 5: 69047-56.
Shukla R, Kumar J, Dwivedi P, et al. Microparticles of diethylcarbamazine citrate for the treatment of lymphatic filariasis. Asian J Chem 2013; 25: S302-4.
Agrawal M, Saraf S, Saraf S, et al. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release 2018; 281: 139-77.
[] [PMID: 29772289]
Bitter C, Suter-Zimmermann K, Surber C. Nasal drug delivery in humans. Curr Probl Dermatol 2011; 40: 20-35.
[] [PMID: 21325837]
Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid( PLGA) as biodegradable controlled drug delivery carrier. Polymers 3 2011; 3: 1377-97.
Di Gioia S, Trapani A, Mandracchia D, et al. Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles. Eur J Pharm Biopharm 2015; 94: 180-93.
[] [PMID: 26032293]
van Woensel M, Wauthoz N, Rosière R, et al. Formulations for intranasal delivery of pharmacological agents to combat brain disease: A new opportunity to tackle GBM? Cancers (Basel) 2013; 5(3): 1020-48.
[] [PMID: 24202332]
Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000; 11(1): 1-18.
[] [PMID: 10913748]
Rassu G, Soddu E, Cossu M, et al. Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. J Control Release 2015; 201: 68-77.
[] [PMID: 25620068]
Mundargi RC, Babu VR, Rangaswamy V, Patel P, Aminabhavi TM. Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives. J Control Release 2008; 125(3): 193-209.
[] [PMID: 18083265]
McCall RL, Sirianni RW. PLGA nanoparticles formed by single- or double-emulsion with vitamin E-TPGS. J Vis Exp 2013; (82): 51015.
[] [PMID: 24429733]
Singodia D, Kansal S, Verma A, et al. Development of nevirapine loaded novel surfactant free polymeric emulsion and investigations for its suitability as drug delivery vehicle. J Bionanosci 2010; 4(1-2): 66-73.
Raza K, Singh B, Lohan S, et al. Nano-lipoidal carriers of tretinoin with enhanced percutaneous absorption, photostability, biocompatibility and anti-psoriatic activity. Int J Pharm 2013; 456(1): 65-72.
[] [PMID: 23973754]
Venkateswarlu V, Manjunath K. Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J Control Release 2004; 95(3): 627-38.
[] [PMID: 15023472]
Musumeci T, Ventura CA, Giannone I, et al. PLA/PLGA nanoparticles for sustained release of docetaxel. Int J Pharm 2006; 325(1-2): 172-9.
[] [PMID: 16887303]
Avgoustakis K, Beletsi A, Panagi Z, Klepetsanis P, Karydas AG, Ithakissios DS. PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. J Control Release 2002; 79(1-3): 123-35.
[] [PMID: 11853924]
Sahoo SK, Panyam J, Prabha S, Labhasetwar V. Residual polyvinyl alcohol associated with poly (D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J Control Release 2002; 82(1): 105-14.
[] [PMID: 12106981]
Peltonen L, Hirvonen J, Yliruusi J. The behavior of sorbitan surfactants at the water-oil interface: Straight-chained hydrocarbons from pentane to dodecane as an oil phase. J Colloid Interface Sci 2001; 240(1): 272-6.
[] [PMID: 11446810]
Santini E, Liggieri L, Sacca L, et al. Interfacial rheology of Span 80 adsorbed layers at paraffin oil-water interface and correlation with the corresponding emulsion properties. Colloids Surf A Physicochem Eng Asp 2007; 309: 270-9.
Bannunah AM, Vllasaliu D, Lord J, Stolnik S. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge. Mol Pharm 2014; 11(12): 4363-73.
[] [PMID: 25327847]
Danhier F, Lecouturier N, Vroman B, et al. Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation. J Control Release 2009; 133(1): 11-7.
[] [PMID: 18950666]
Fonseca C, Simões S, Gaspar R. Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity. J Control Release 2002; 83(2): 273-86.
[] [PMID: 12363453]
Andrews GP, Laverty TP, Jones DS. Mucoadhesive polymeric platforms for controlled drug delivery. Eur J Pharm Biopharm 2009; 71(3): 505-18.
[] [PMID: 18984051]
Kashyap K, Shukla R. Drug delivery and targeting to the brain through nasal route: Mechanisms, Applications and Challenges. Curr Drug Deliv 2019; 16(10): 887-901.
[] [PMID: 31660815]
Handa M, Sharma A, Verma RK, Shukla R. Polycaprolactone based nano-carrier for co-administration of moxifloxacin and rutin and its In-vitro evaluation for sepsis. J Drug Deliv Sci Technol 2019; 54101286
Ujjwal RR, Purohit MP, Patnaik S, Ojha U. General reagent free route to pH responsive polyacryloyl hydrazide capped metal nanogels for synergistic anticancer therapeutics. ACS Appl Mater Interfaces 2015; 7(21): 11497-507.
[] [PMID: 25961335]
Jahanfar F, Hasani A, Shanebandi D, Rahmati M, Hamishehkar H. Enhanced in vitro anti-tumor activity of 5-azacytidine by entrapment into solid lipid nanoparticles. Adv Pharm Bull 2016; 6(3): 367-75.
[] [PMID: 27766220]
Handa M, Ujjwal RR, Shukla R. Fabrication of donepezil encumbered mannose assisted polycyanoacrylate nanocarriers. In Conference on Drug Design and Discovery Technologies. R Soc Chem 2019: 335; 219.

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy