Electrically controlled drug release of donepezil and BiFeO3 magnetic nanoparticle-loaded PVA microbubbles/nanoparticles for the treatment of Alzheimer's disease
Graphical abstract
Introduction
Alzheimer's disease (AD) is a deadly neurodegenerative disease that is common worldwide and it occurs due to protein accumulation in the brain [1]. The accumulation of beta-amyloid protein in the tissue of nerve cells in the brain increases over time. The connection between nerve cells in the brain is damaged due to protein accumulation, and then nerve cells begin to die. As a result of this situation, symptoms such as memory loss, cognitive impairment, anxiety, confusion, mood swings, and speaking difficulties appear gradually [2,3]. It affects more than 45 million people worldwide. The number of AD patients is estimated to increase to 131.5 million by 2050 [4]. Currently, the drugs approved for the treatment of AD are donepezil, rivastigmine, memantine, galantamine, and tacrine, etc [5,6]. Current medications can improve symptoms, but cannot stop or slow down or prevent the progression of the disease.
Donepezil hydrochloride (DO) is the second well-tolerated drug for the treatment of AD [7]. DO is a centrally effective acetylcholinesterase inhibitor that increases acetylcholine concentration and decreases beta-amyloid availability [8]. It is administered to patients orally and shows significant differences in DO plasma concentrations. Also, gastrointestinal side effects of DO such as anorexia, vomiting, nausea, and abdominal pain are associated with its oral administration. In addition, it is a common problem in elderly patients to forget to take medication due to some reasons such as dementia [9,10]. Treatment failure often occurs because of the negative pharmacodynamic and pharmacokinetic features of the drugs. Various drug delivery systems have been investigated to reduce side effects and dosage frequency, as well as increase the effect of oral AD drugs.
Supercritical fluid technology, pressurized gyration method, electrohydrodynamic technology, and microfluidic technology are traditional approaches to obtain microbubbles and polymeric particles [11,12]. Among these, microfluidic technology has the advantage of creating uniform microbubbles. Microfluidics has affected many applications including chemical synthesis, biological analysis, tissue engineering, and cell analysis. They have many advantages such as being economical, prone to modifications, reproducible, simplicity of device manufacturing, and integration with other technologies [13].
Microfluidic devices are a widely used system that takes attention in the preparation of microbubbles and polymer nanospheres, such as effective and easy control of gas and liquid flow [14]. Also, microfluidic systems play an essential role in biomedical research and clinical applications with narrower size distributions, homogenous size distribution, reproducibility, and high encapsulation efficiency [15,16]. Traditionally, microfluidic devices include three different types: flow focusing, co-flow geometry, and T-junction. The T-junction microfluidic device has significant advantages such as good operability, reusability, simplicity, and cost-effectiveness. It has properties such as the controllability of the flow rate to produce microbubbles and the repetition of the microbubble formation process. It is one of the easiest methods used to create continuous and uniform microbubbles and polymeric nanoparticles [17,18].
Microbubble production has many applications in the fields of pharmacology, medicine, cosmetics, materials science, and the food industry [19]. Microbubbles with a diameter of 1–1000 μm are used as application tools for targeted therapy, contrast agents for ultrasound imaging, and gas carriers for blood substitution [20,21].
Nanocarriers can be made of various materials such as carbon nanotubes, metals, polymers, ceramics, lipids, etc [22,23]. They are colloidal systems containing a therapeutic agent ranging in diameter from 1 to 300 nm [24]. It can accommodate active ingredients such as chemotherapeutics, contrast agents, proteins, and nucleic acids for biomedical applications. Unlike other compositions, polymeric nanoparticles are versatile, stable, have the best combination of characteristics, and allow high loading of many substances, and control over drug release kinetics [25]. Nanoparticles are also taken into the cell more than microparticles due to their nanoscale structure [26]. The release of drugs is slowed for pre-clinically and clinically usage with the help of polymeric carriers, which are also used for targetting the treatment area in some diseases such as cancer, diabetes, or neurodegenerative disorders [4]. One of the important parameters governing the biodistribution of the particles is their size and it plays a crucial role in the bioavailability of drugs [27,28].
Both synthetic and natural polymers such as poly (lactide-co-glycolide) acid, poly (lactic acid), polycaprolactone, poly (D, L-glycolide), polyvinyl alcohol (PVA), gelatin, collagen, alginate, and chitosan can be used to manufacture nanoparticle delivery systems. Hydrophilic nanoparticles can reduce opsonization reactions that cause rapid clearance of drugs before reaching target tissues [29]. PVA, which has a simple chemical structure, is a synthetic and water-soluble polymer. It is widely used for drug delivery systems in pharmaceutical and biomedical applications due to its properties such as biodegradable, biocompatible, non-toxic, non-immunogenic, and excellent mechanical and chemical stability [30,31]. In addition, PVA has three important properties for its use as a carrier system: High surface stabilization, low protein adsorption properties, and chelating properties resulting in low cell adhesion compared to other polymers. In addition, the highly hydrophilic nature of PVA increases its solubility when conjugated with carriers and drugs [32].
NIR radiation, UV- and visible wavelength light, magnetic field, ultrasound, and electrical stimulation are the recent advances to enhance drug release from smart materials [33,34]. These techniques provide more effective control on drug delivery among the drug delivery systems that are based on unchangeable passive delivery. To provide controlled drug delivery, nanoparticle drug carriers are under investigation further for their advantages such as their excellent structure and adjustable properties [35]. Studies in recent years show that materials with both magnetic and electrical properties have attracted attention to create new materials or structures due to their controllable possession [36]. These materials are known as multiferroic materials and exhibit both ferroelectric and ferromagnetic effects at the same time. Bismuth ferrite (BiFeO3, BFO), known as multiferroic, is a unique material with a polar R3c space group [37,38]. Bismuth ferrite can be synthesized with many techniques which are the sol-gel, solid-state, hydrothermal, mechanochemical, sonomechanical, and co-precipitation methods [39]. Bedir et al. successfully produced BiFeO3 particles by the co-precipitation method and showed that the cells are aligned towards BiFeO3 under electric stimulation. In this work, we investigated the effect of BiFeO3 nanoparticles produced by the co-precipitation method for electrically controlled drug release [40].
In this study, PVA, PVA/BiFeO3, PVA/BiFeO3/DO monodisperse polymer nanoparticles were manufactured with bursting microbubbles by a T-junction device. Structural analysis (XRD), morphological (SEM), molecular interaction (FT-IR), and physical analysis were performed after the production of nanoparticles. The electrically controlled release behavior of PVA/BiFeO3/DO nanoparticles were investigated at different voltages (0 V, −1.0 V, −0.5 V, +0.5 V, +1.0 V), different currents (−50 μA, −100 μA, −200 μA, and −300 μA), and 200 rpm. The kinetics of drug release from PVA/BiFeO3/DO nanoparticles were investigated at different conditions with five mathematical models.
Section snippets
Materials
Bismuth (III) nitrate (Bi5O(OH)9(NO3)4, MW = 1.461,99 g/mol), iron (III) nitrate nonahydrate (Fe(NO3)3, Mw = 403.95 g/mol), and nitric acid (65%) were bought from Merck KGaA, Germany. Ammonia solution (25%, MW = 35.05 g/mol) was purchased from ISOLAB (Wertheim, Germany). Polyvinyl alcohol (PVA, Mw = 89,000–98,000, 99% hydrolyzed) was purchased from Sigma Aldrich (United Kingdom). Distilled water is ensured by a water distiller (Liston). Donepezil hydrochloride was kindly taken from Abdi Ibrahim
Characterization of polymeric solutions
In this study, a variety of monodisperse polymeric PVA, PVA/BiFeO3, and PVA/BiFeO3/DO nanoparticles were manufactured by exploding microbubbles by a T-junction device. Two different components, consisting of liquid and gas phases coming from two independent feed channels, were infused into the mixing area to form microbubbles. The less-dense polymer solution encapsulated the high-density N2 gas. A series of microbubble clusters form in the outlet channel. The shapes and sizes of these bubbles
Conclusions
In this study, three different particles were manufactured with bursting microbubbles by a T-junction device: PVA, PVA/BiFeO3, and PVA/BiFeO3/DO. When SEM images of the obtained nanoparticles were examined, it was seen that they had a smooth and monodisperse structure. Besides, the diameters of PVA, PVA/BiFeO3, and PVA/BiFeO3/DO nanoparticles were 148 ± 15 nm, 159 ± 21 nm, and 164 ± 12 nm, respectively. XRD and FTIR results demonstrated that BiFeO3 magnetic nanoparticles and DO were
Author statement
Oguzhan Gunduz: Conceptualization, Methodology, Reviewing Sumeyye Cesur: Methodology, Investigation, Experiment, Draft preparation Muhammet Emin Cam: Methodology and Investigation Fatih Serdar Sayin: Investigation and Editing.
Declaration of competing interest
The following authors declare no conflict of interest.
Acknowledgments
The authors thanks to Marmara University Scientific Research Committee (Project Number: FDK-2020-10118) for their financial support.
References (66)
- et al.
Study of the theory of microbubble bursting to obtain bio-inspired alginate nanoparticles
Colloids Surf. A Physicochem. Eng. Asp.
(2020) - et al.
An easily assembled double T-shape microfluidic devices for the preparation of submillimeter-sized polyacronitrile (PAN) microbubbles and polystyrene (PS) double emulsions
Colloids Surf. A Physicochem. Eng. Asp.
(2015) - et al.
Polymeric nanoparticles for drug delivery to the central nervous system
Adv. Drug Deliv. Rev.
(2012) - et al.
Bioinspired preparation of alginate nanoparticles using microbubble bursting
Mater. Sci. Eng. C
(2015) - et al.
Controlled release of donepezil intercalated in smectite clays
Int. J. Pharm.
(2008) - et al.
Construction of functional targeting daunorubicin liposomes used for eliminating brain glioma and glioma stem cells
J. Biomed. Nanotechnol.
(2016) - et al.
Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer's disease
Eur. J. Pharmaceut. Sci.
(2016) Camellia sinensis leaves hydroalcoholic extract improves the Alzheimer's disease-like alterations induced by type 2 diabetes in rats
Clin. Exp. Health Sci.
(2020)- et al.
Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer's disease mice model
J. Contr. Release
(2019) - et al.
Magnetic nanoparticles associated PEG/PLGA block copolymer targeted with anti-transferrin receptor antibodies for Alzheimer's disease
J. Biomed. Nanotechnol.
(2018)
Donepezil treatment in patients with depression and cognitive impairment on stable Antidepressant treatment: a randomized controlled trial
Am. J. Geriatr. Psychiatr.
Preparation, characterization, and in vivo pharmacokinetic evaluation of polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogels for transdermal delivery of donepezil HC1
Pharmaceutics
Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer's disease
Eur. J. Pharm. Biopharm.
A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis
Int. J. Pharm.
Biopolymer-Based Transdermal Films of Donepezil as an Alternative Delivery Approach in Alzheimer's Disease Treatment
Recent progress of microfluidic reactors for biomedical applications
Chem. Eng. J.
Microfluidic technologies for accelerating the clinical translation of nanoparticles
Nat. Nanotechnol.
Novel preparation of monodisperse microbubbles by integrating oscillating electric fields with microfluidics
Micromachines
Current developments and applications of microfluidic technology toward clinical translation of nanomedicines
Adv. Drug Deliv. Rev.
Microfluidic-assisted fabrication of carriers for controlled drug delivery
Lab Chip
Functional microgels tailored by droplet-based microfluidics
Macromol. Rapid Commun.
Generation of microbubbles with applications to industry and medicine
Annu. Rev. Fluid Mech.
Combining microfluidic devices with coarse capillaries to reduce the size of monodisperse microbubbles
RSC Adv.
A device for the fabrication of multifunctional particles from microbubble suspensions
Mater. Sci. Eng. C
Experimental and theoretical investigation of the fluid behavior during polymeric fiber formation with and without pressure
Appl. Phys. Rev.
Resveratrol-Loaded Levan Nanoparticles Produced by Electrohydrodynamic Atomization Technique
Design of polymeric nanoparticles for biomedical delivery applications
Chem. Soc. Rev.
The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent
Pharm. Res.
Controlled and tunable polymer particles' production using a single microfluidic device
Appl. Nanosci.
Role of nanoparticle size, shape and surface chemistry in oral drug delivery
J. Contr. Release
In vitro sustained release study of gallic acid coated with magnetite-PEG and magnetite-PVA for drug delivery system
Sci. World J.
Controlled release of metformin loaded polyvinyl alcohol (PVA) microbubble/nanoparticles using microfluidic device for the treatment of type 2 diabetes mellitus
Polyvinyl alcohol based-drug delivery systems for cancer treatment
Int. J. Pharm.
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2022, Process BiochemistryCitation Excerpt :For example, both polyethylene imine and poly diallyl dimethyl ammonium chloride can be grafted onto BC to give it a positive charge [19,20]. Other polymers and nanoparticles are also available, including collagen, chitosan, poly−L−lysine, fibrin, peptides, amino acids, trimethyl ammonium beta-hydroxypropyl, etc. [21–24]. ECMs are primarily constructed by D−chiral collagen, and it has been shown that D−chiral materials have higher efficiencies in promoting the differentiation of nerve cells [25].