Crossing the blood–brain barrier with graphene nanostructures

Therapeutic approaches for the delivery of drugs to the central nervous system are hampered by the presence of the blood–brain barrier (BBB); overcoming this barrier is the clinical goal for the treatment of neurological disorders, including Alzheimer’s disease and Parkinson’s disease. The BBB is a cellular barrier of a highly impermeable nature that is predominantly formed by a tightly bound continuous layer of endothelial cells; it acts as a gatekeeper to restrict the free diffusion of bloodborne pathogens into the central nervous system. Targeted drug delivery systems have been explored over the past decade for crossing the BBB. Very recently, graphene nanostructures have shown great potential for crossing the BBB due to their exceptional features such as high electron mobility, ease of synthesis and functionalization, as well as control over size, shape, and the drug release profile. Graphene is evolving as a system not only to detect diseased lesions but also, in parallel, to treat neurological disorders while demonstrating minimal side effects. Given the rapid developments of innovative graphene-based delivery platforms, the present review sheds light on the status and prospects of graphene for crossing the BBB by improving, preserving, or rescuing brain energetics, with a specific focus on how graphene alters neuronal cell function.     

Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies

The blood–brain barrier (BBB), a unique structure in the central nervous system (CNS), protects the brain from bloodborne pathogens by its excellent barrier properties. Nevertheless, this barrier limits therapeutic efficacy and becomes one of the biggest challenges in new drug development for neurodegenerative disease and brain cancer. Recent breakthroughs in nanotechnology have resulted in various nanoparticles (NPs) as drug carriers to cross the BBB by different methods. This review presents the current understanding of advanced NP-mediated non-invasive drug delivery for the treatment of neurological disorders. Herein, the complex compositions and special characteristics of BBB are elucidated exhaustively. Moreover, versatile drug nanocarriers with their recent applications and their pathways on different drug delivery strategies to overcome the formidable BBB obstacle are briefly discussed. In terms of significance, this paper provides a general understanding of how various properties of nanoparticles aid in drug delivery through BBB and usher the development of novel nanotechnology-based nanomaterials for cerebral disease therapies.     

A novel pH-sensitive magnetic alginate–chitosan beads for albendazole delivery

Background: Drug delivery system using polymer-coated magnetic carriers is considered as an effective strategy for passive targeting, which can not only increase drug utilization but also reduce the adverse reaction. With the carriers, sensitivity to physical stimuli (e.g., magnetic field, pH) has been developed and drugs were conjugated to form incorporating magnetic particles, so that drugs could be located to desire position. Method: Novel magnetic alginate (Alg)–chitosan (CS) beads loaded with albendazole (ABZ) were prepared and evaluated for pH sensitivity and drug release characteristics. The effects of six different factors (Alg concentration, the weight ratio of drug to polymer, the weight ratio of magnetite nanoparticles to polymer, CaCl2 concentration, CS concentration, the volume ratio of Alg to CS) were studied on the swelling ability of the magnetic beads. The magnetic beads were characterized by Fourier transform infrared spectroscopy, scanning electron microscope, and vibrating sample magnetometry. In addition, the delivery behavior of ABZ from the magnetic beads was studied. Result: The magnetic Alg–CS beads had showed unique pH-dependent swelling behaviors and a continuous release of ABZ. From the magnetometer measurements data, the beads also had superparamagnetic property as well as fast magnetic response. Conclusion: The pH-sensitive magnetic beads may be used as a magnetic drug targeting system for ABZ in the gastrointestinal tract.     

Study on crosslinked gelatin–montmorillonite nanoparticles for controlled drug delivery applications

Gelatin, because of its biodegradability and ecofriendly nature, has been the best choice for controlled release applications. Montmorillonite (MMT) clay shows a very important role in controlling drug delivery. Hence, an attempt was made in this work to prepare gelatin–MMT nanoparticles by desolvation method using acetone as precipitating agent, glutaraldehyde (GA) as crosslinking agent, and water as reaction media for controlled delivery of isoniazid, a drug for tuberculosis. Characterization of the MMT and isoniazid-loaded gelatin–MMT nanoparticles was carried out using Fourier transform infrared spectroscopy, X-ray diffraction study, scanning electron microscopy study, and transmission electron microscopy study. The effect of MMT on gelatin nanoparticles was evaluated in terms of water uptake studies, and subsequently to the release of isoniazid drug in buffer solution at pH 1.2 (gastric pH) and pH 7.4 (intestinal pH). Swelling experiment indicated that the gelatin nanoparticles were very sensitive to the pH environment. The release profile of drug was studied by a UV–Visible spectrophotometer. Cytotoxicity study revealed that MMT-containing nanoparticles showed less cytotoxicity than MMT-free nanoparticles.     

In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2′-(ethylenedioxy)-bis-(ethylamine) (EDBE) through the conjugation with folic acid. The conjugation has been analyzed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The resultant nanoparticles with an average size less then 200 nm measured by dynamic light scattering and transmission electron microscopy. Confocal microscopy and flow cytometric analysis have revealed that folate-mediated targeting significantly enhances the cellular uptake of the nanoparticle and thus facilitates apoptosis of cancer cells (HeLa, B16F1). For the application of the nanoparticles as a drug carrier, Doxorubicin a potent anticancer drug has been loaded into the nanoparticles, with the drug loading amount and the drug release pattern observed.     

Study of the growth process of magnetic nanoparticles obtained via the non-aqueous sol–gel method

The growth process of iron oxide nanoparticles during synthesis via the non-aqueous sol–gel method has been analyzed. Samples obtained after reaching reaction temperature T _R = 200 °C and during the following 23 h of synthesis were characterized in detail by X-ray diffraction measurements, transmission electron microscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, Mössbauer spectroscopy, and magnetization measurements. The results show that the iron oxide nanocrystals are majorly composed of maghemite and grow in a faceted shape. The particle size increases gradually during the synthesis, and the structural and magnetic properties improve primarily during the first 6 h of reaction.     

Investigation of the iron doping on the structural,optical, and magnetic properties of Fe-doped ZnO nanoparticles synthesized by sol–gel method

Journal of Materials Science: Materials in Electronics - In this work, the compatibility of zinc oxide for spintronic applications motivated the development of single-phase Fe/ZnO nanostructures by...     

Bioactive magnetic nanoparticles of Fe–Ga synthesized by sol–gel for their potential use in hyperthermia treatment

Hyperthermia is one of the most recents therapies for cancer treatment using particles with nanometric size and appropriate magnetic properties for destroying cancer cells. Magnetic nanoparticles (MNP’s) of Fe–Ga and synthesized using a polycondensation reaction by sol–gel method were obtained. MNP’s of Fe_1.4Ga_1.6O₄ that posses an inverse spinel structure were identified by X-Ray Diffraction, Transmission Electron Microscopy, Scanning Electron Microscopy and Energy Dispersive Spectroscopy. The results showed that the MNP’s are composed only by Fe, Ga and O and their size is between 15 and 20 nm. The magnetic properties measured by Vibration Sample Magnetometry demonstrated a saturation magnetization value of 37.5 emu/g. To induce the MNP’s bioactivity, a biomimetic method was used which consisted in the immersion of MNP’s in a Simulated Body Fluid (SBF) for different periods of time (7, 14 and 21d) along with a wollastonite disk. The formation of a bioactive layer, which closely resembles that formed on the existing bioactive systems and with a Ca/P atomic ratio within a range of 1.37–1.73 was observed on the MNP’s. Cytotoxicity of MNP’s was evaluated by in vitro hemolysis testing using human red blood cells at concentrations between 0.25 and 6.0 mg/mL. It was found that the MNP’s were not cytotoxic at none of the concentrations used. The results indicate that Fe–Ga MNP’s are potential materials for cancer treatment of both hard and soft tissue by hyperthermia and drug carriers, among other applications.     

Structural, vibrational, optical and magnetic properties of sol–gel derived Nd doped ZnO nanoparticles

Nd doped ZnO (Zn_1-xNd_xO, x = 0.0, 0.03, 0.06 and 0.10) nanoparticles were prepared by sol–gel method. Phase identification and effect of Nd ions substitution in ZnO lattice were confirmed by Rietveld analysis of XRD patterns. UV–Visible absorption spectra of pure and Nd doped ZnO nanoparticles showed the variation of the band gap in the range of 3.31–3.26 eV. The FTIR analysis of pure and Nd doped ZnO nanoparticles exhibited similar patterns in Zn/Nd–O bond length as obtained from the Rietveld refinement. Raman analysis confirmed the formation of a wurtzite structure wherein the local structure of ZnO nanoparticles is distorted due to Nd substitution. Magnetization-magnetic field hysteresis curves for pure and Nd doped ZnO nanoparticles revealed diamagnetic and paramagnetic behaviour, respectively. The paramagnetic behaviour of doped ZnO nanoparticles increased with increasing Nd concentration. However, the weak ferromagnetic behaviour of doped ZnO nanoparticles is observed after subtracting paramagnetic components, whereas the ferromagnetic behavior increased up to x = 0.06 samples, which further declined for x = 0.10 sample due to competition between paramagnetic and ferromagnetic ordering. The reduction in the ferromagnetic behavior for x = 0.10 sample indicates that the solubility limit of Nd atoms in ZnO lattice has been reached and paramagnetically coupled Nd atoms increased due to the increasing secondary phases.     

Preparation of N,N-p-phenylene bismethacryl amide as a novel cross-link agent for synthesis and characterization of the core–shell magnetic molecularly imprinted polymer nanoparticles

Novel magnetic molecularly imprinted nanoparticles (MMIPs) using N,N-p-phenylene bismethacryl amide as a cross linker and super paramagnetic core–shell nanoparticle as a supporter for use in controlled release were prepared by precipitation polymerization. Novel cross-linking agents were synthesized by the reaction of methacryloyl chloride with p-phenylenediamine. Then, the Fe₃O₄ nanoparticles were encapsulated with a SiO₂ shell and functionalized with –CH=CH₂ and MMIPs were further prepared by using methacrylic acid as a functional monomer, N,N-p-phenylene bismethacryl amide as a cross-linking agent and betamethasone as template. Magnetic non-MIPs were also prepared with the same synthesis procedure as with MMIPs only without the presence of the template. The obtained MMIPs were characterized by using transmission electron microscopy, Fourier transform infrared spectrum, X-ray diffraction, energy-dispersive X-ray spectroscopy, and the vibrating sample magnetometer. The performance of the MMIPs for the controlled release of betamethasone was assessed and results indicated that the magnetic MIPs also had potential applications in drug controlled release.     

Lipid nanoparticles of zaleplon for improved oral delivery by Box–Behnken design: optimization,in vitro and in vivo evaluation

Purpose: Zaleplon (ZL) is a hypnotic drug prescribed for the management of insomnia and convulsions. The oral bioavailability of ZL was low (～30%) owing to poor water solubility and hepatic first-pass metabolism. The cornerstone of this investigation is to develop and optimize solid lipid nanoparticles (SLNs) of ZL with the aid of Box–Behnken design (BBD) to improve the oral bioavailability.

Methods: A design space with three formulation variables at three levels were evaluated in BBD. Amount of lipid (A₁), amount of surfactant (A₂) and concentration of co-surfactant (%) (A₃) were selected as independent variables, whereas, particle size (B₁), entrapment efficiency (B₂) and zeta potential (ZP, B₃) as responses. ZL-SLNs were prepared by hot homogenization with ultrasonication method and evaluated for responses to obtain optimized formulation. Morphology of nanoparticles was observed under SEM. DSC and XRD studies were examined to understand the native crystalline behavior of drug in SLN formulations. Further, in vivo studies were performed in Wistar rats.

Results: The optimized formulation with 132.89?mg of lipid, 106.7?mg of surfactant and 0.2% w/v of co-surfactant ensued in the nanoparticles with 219.9?±?3.7?nm of size, ?25.66?±?2.83?mV surface charge and 86.83?±?2.65% of entrapment efficiency. SEM studies confirmed the spherical shape of SLN formulations. The DSC and XRD studies revealed the transformation of crystalline drug to amorphous form in SLN formulation. In conclusion, in vivo studies in male Wistar rats demonstrated an improvement in the oral bioavailability of ZL from SLN over control ZL suspension.

Conclusions: The enhancement in the oral bioavailability of ZL from SLNs, developed with the aid of BBD, explicated the potential of lipid-based nanoparticles as a potential carrier in improving the oral delivery of this poorly soluble drug.     

Ceramide–palmitic acid complex based Curcumin solid lipid nanoparticles for transdermal delivery: pharmacokinetic and pharmacodynamic study

Curcumin is an important anti-inflammatory natural compound with low bioavailability which is due to poor solubility and absorption. Solid lipid nanoparticles (SLNs) loaded with Curcumin were formulated and evaluated for physical parameters and in vitro/ex vivo permeation. Further the optimised SLN was assessed for pharmacokinetic/pharmacodynamic considerations. SLNs were formulated by emulsion-solvent evaporation technique and evaluated for physical properties and in vitro drug release. Selected SLNs were evaluated for stability and then characterised for pharmacokinetic parameters and anti-inflammatory activity with reference to a commercial formulation. Spherical SLNs were obtained in the size range of 102–156 nm with negative potential. C-SLN category has shown highest entrapment efficiency. The order of drug release was S-SLN > G-SLN > C-SLN. Selected SLN formulation C-SLN-3 has shown good stability under various conditions. C-SLN-3 has demonstrated highest drug permeation through human skin and 171.623 mg drug content permeated in 24 h. It has also shown lowest lag time 0.375 h. Similarly, it has shown maximum value for C_max in in vivo determination and increased the bioavailability upto 68.12%. C-SLN-3 provided 90.75% edema inhibition in 6 h. Present study shows that nature of lipids and its physical-chemical properties are critical for SLN formulation and can be used for designing better drug delivery systems with optimum transdermal permeation.     

Folate-modified–chitosan-coated liposomes for tumor-targeted drug delivery

In this study, a folate-modified–chitosan-coated liposome (FCCL) was prepared for tumor-targeted drug delivery. The folate–chitosan conjugates were characterized using ¹H NMR and infrared spectrum analysis. The properties of folate–chitosan-coated liposomes (FCCLs) were studied and compared with those of traditional liposomes and chitosan-coated liposomes (CCLs). FCCLs were spherical in shape with a classic core–shell structure. Compared with conventional liposomes, FCCLs had larger size (average diameter: 182.0 nm), higher zeta potential (10.1 mV), prolonged drug release behaviors (55.76 % after 24 h), and better physical stability when stored at 25 °C, all similar to the properties of CCLs. With fluorescein as a model drug, fluorescein-loaded liposomes, CCLs, and FCCLs were prepared and their tumor targeting ability was evaluated according to the in vitro cellular uptake of fluorescein loaded nanoparticles by MCF-7 and HUVEC cells. Results demonstrated that FCCLs had a significant higher uptake by folate receptor positive cells (MCF-7) as compared to traditional liposomes and CCLs, which indicated that the FCCLs were promising nano-carriers for tumor-targeted drug delivery.     

Optimization of the lyophilization process for long-term stability of solid–lipid nanoparticles

Objectives: To optimize a lyophilization protocol for solid–lipid nanoparticles (SLNs) loaded with dexamethasone palmitate (Dex-P) and to compare the long-term stability of lyophilized SLNs and aqueous SLN suspensions at two storage conditions.

Materials and Methods: The effect of various parameters of the lyophilization process on SLN redispersibility was evaluated. A three month stability study was conducted to compare changes in the particle size and drug loading of lyophilized SLNs with SLNs stored as aqueous suspensions at either 4°C or 25°C/60% relative humidity (RH).

Results and Discussion: Of nine possible lyoprotectants tested, sucrose was shown to be the most efficient at achieving SLN redispersibility. Higher freezing temperatures, slower freezing rates, and longer secondary drying times were also shown to be beneficial. Loading of the SLNs with Dex-P led to slightly larger particle size and polydispersity index increases, but both parameters remained within an acceptable range. Drug loading and particle shape were maintained following lyophilization, and no large aggregates were detected. During the stability study, significant growth and drug loss were observed for aqueous SLN suspensions stored at 25°C/60% RH. In comparison, lyophilized SLNs stored at 4°C exhibited a consistent particle size and showed <20% drug loss. Other storage conditions led to intermediate results.

Conclusions: A lyophilization protocol was developed that allowed SLNs to be reconstituted with minimal changes in their physicochemical properties. During a three month period, lyophilized SLNs stored at 4°C exhibited the greatest stability, showing no change in the particle size and a minimal reduction in drug retention.     

Effect of ‘Zn’ substitution on structural,morphological, magnetic and optical properties of Co–Zn ferrite nanoparticles for ferrofluid application

Journal of Materials Science: Materials in Electronics - The Co1?xZnxFe2O4 (Co–Zn) ferrite nanoparticles with x varying from 0.0 to 0.4 have been manufactured by facile chemical...     

Interfacial magnetic coupling between Fe nanoparticles in Fe–Ag granular alloys

The role of the interface in mediating interparticle magnetic interactions has been analysed in Fe50Ag50 and Fe55Ag45 granular thin films deposited by the pulsed laser deposition technique (PLD). These samples are composed of crystalline bcc Fe (2–4 nm) nanoparticles and fcc Ag (10–12 nm) nanoparticles, separated by an amorphous Fe50Ag50 interface, occupying around 20% of the sample volume, as determined by x-ray diffraction (XRD), x-ray absorption spectroscopy (XAS), and high resolution transmission electron microscopy (HRTEM). Interfacial magnetic coupling between Fe nanoparticles is studied by dc magnetization and x-ray magnetic circular dichroism (XMCD) measurements at the Fe K and Ag L2,3 edges. This paper reveals that these thin films present two magnetic transitions, at low and high temperatures, which are strongly related to the magnetic state of the amorphous interface, which acts as a barrier for interparticle magnetic coupling.     

Preparation and characterization of marine sponge collagen nanoparticles and employment for the transdermal delivery of 17β-estradiol-hemihydrate

Background: Transdermal administration of estradiol offers advantages over oral estrogens for hormone replacement therapy regarding side effects by bypassing the hepatic presystemic metabolism. Aim: The objective of this study was to develop nanoparticles of Chondrosia reniformis sponge collagen as penetration enhancers for the transdermal drug delivery of 17β-estradiol-hemihydrate in hormone replacement therapy. Method: Collagen nanoparticles were prepared by controlled alkaline hydrolysis and characterized using atomic force microscopy and photon correlation spectroscopy. Estradiol-hemihydrate was loaded to the nanoparticles by adsorption to their surface, whereupon a drug loading up to 13.1% of sponge collagen particle mass was found. After incorporation of drug-loaded nanoparticles in a hydrogel, the estradiol transdermal delivery from the gel was compared with that from a commercial gel that did not contain nanoparticles. Results: Saliva samples in postmenopausal patients showed significantly higher estradiol levels after application of the gel with nanoparticles. The area under the curve (AUC) for estradiol time–concentration curves over 24 hours was 2.3- to 3.4-fold higher and estradiol levels 24 hours after administration of estradiol were at least twofold higher with the nanoparticle gel. Conclusions: The hydrogel with estradiol-loaded collagen nanoparticles enabled a prolonged estradiol release compared to a commercial gel and yielded a considerably enhanced estradiol absorption. Consequently, sponge collagen nanoparticles represent promising carriers for transdermal drug delivery.     

Layered dielectric–magnetic composite structures for Rf-applications

In this paper multilayer magnetic–dielectric composite structures for high frequency applications are introduced. The 0–3 type dielectric and magnetic composites with homogeneously distributed ceramic inclusions were fabricated by mixing extrusion and injection moulding. Magnetic Yttrium Iron Garnet (YIG) and Z-type Hexaferrite (HexaZ) as well as paraelectric Barium Strontium Titanate (BST) powders were used to enhance the permittivity and permeability of the composites. The magnetic–dielectric multilayer composites were constructed by hot-laminating magnetic and dielectric layers in turn to create a solid 2-2 type composite structure. The microstructure, high frequency dielectric and magnetic properties of individual layers and 2-2 composites were investigated and measured. The measurement results indicate that such multimaterial multilayer structures are good candidates for components with reduced dielectric and magnetic losses. Moreover, the observed good frequency stability and the cut-off frequencies above 1 GHz suggested that the composites could be utilized in, e.g., sophisticated functional circuit boards and RF devices.