Electrically controlled drug release of donepezil and BiFeO3 magnetic nanoparticle-loaded PVA microbubbles/nanoparticles for the treatment of Alzheimer's disease

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Abstract

Nanocarriers are used to deliver bioactive substances in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD). These nanocarriers have shown many benefits over traditional treatments due to their properties such as efficient distribution and controlled release of bioactive material to the brain and loading of various drugs simultaneously. In this study, polyvinyl alcohol (PVA), PVA/bismuth ferrite (BiFeO3), and PVA/BiFeO3/donepezil hydrochloride (DO) monodisperse polymeric nanoparticles were manufactured with bursting microbubbles by a T-junction device. Here, BiFeO3 nanoparticles were synthesized by the co-precipitation method, and these magnetic nanoparticles and DO were loaded in PVA nanoparticles. Nanoparticles had a smooth and monodisperse structure according to SEM images. Also, the diameters of PVA, PVA/BiFeO3, and PVA/BiFeO3/DO nanoparticles were 148 ± 15 nm, 159 ± 21 nm, and 164 ± 12 nm, respectively. It was confirmed by X-ray diffraction and infrared spectroscopy that BiFeO3 magnetic nanoparticles and DO were successfully loaded into nanoparticles produced with PVA. There was no cytotoxic effect on healthy L929 cells for all nanoparticle samples. A systematic electrical circuit has been established to investigate the electrically controlled release behaviour of PVA/BiFeO3/DO nanoparticles 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. To apply electric stimulus increased the release except for +1.0 V and the release of DO increased at more negative voltages with a total release of 68.9% of DO after 15 stimulus with −1.0 V. Higher R2 values were obtained with the Higuchi model for almost all conditions and DO was released from nanoparticles through the non-Fickian diffusion mechanism (0.45 < n < 1). The possibility of affecting the release of DO by modifying the current and voltage in the presence of BiFeO3 leads to an immensely controllable and delicately tunable drug release for AD treatment.

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.

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