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1.  Nanoscale drug delivery systems and the blood–brain barrier 
The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.
doi:10.2147/IJN.S52236
PMCID: PMC3926460  PMID: 24550672
apoE; blood–brain barrier; CNS; drug targeting; liposomes; nanoparticles
2.  Synthesis, characterization, controlled release, and antibacterial studies of a novel streptomycin chitosan magnetic nanoantibiotic 
This study describes the preparation, characterization, and controlled release of a streptomycin-chitosan-magnetic nanoparticle-based antibiotic in an effort to improve the treatment of bacterial infections. Specifically, chitosan-magnetic nanoparticles were synthesized by an incorporation method and were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and vibrating sample magnetometry. Streptomycin was incorporated into the nanoparticles to form a streptomycin-coated chitosan-magnetic nanoparticle (Strep-CS-MNP) nanocomposite. The release profiles showed an initially fast release, which became slower as time progressed. The percentage of drug released after 350 minutes was around 100%, and the best fit mathematical model for drug release was the pseudo-second order model. The Strep-CS-MNP nanocomposite showed enhanced antibacterial activity against methicillin-resistant Staphylococcus aureus. This study forms a significant basis for further investigation of the Strep-CS-MNP nanocomposite in the treatment of various bacterial infections.
doi:10.2147/IJN.S53079
PMCID: PMC3897325  PMID: 24549109
magnetic nanoparticles; streptomycin; nanoantibiotics; chitosan; release; antimicrobial activity; methicillin-resistant Staphylococcus aureus
3.  Novel kojic acid-polymer-based magnetic nanocomposites for medical applications 
Iron oxide magnetic nanoparticles (MNPs) were synthesized by the coprecipitation of iron salts in sodium hydroxide followed by coating separately with chitosan (CS) and polyethylene glycol (PEG) to form CS-MNPs and PEG-MNPs nanoparticles, respectively. They were then loaded with kojic acid (KA), a pharmacologically bioactive natural compound, to form KA-CS-MNPs and KA-PEG-MNPs nanocomposites, respectively. The MNPs and their nanocomposites were characterized using powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, vibrating sample magnetometry, and scanning electron microscopy. The powder X-ray diffraction data suggest that all formulations consisted of highly crystalline, pure magnetite Fe3O4. The Fourier transform infrared spectroscopy and thermogravimetric analysis confirmed the presence of both polymers and KA in the nanocomposites. Magnetization curves showed that both nanocomposites (KA-CS-MNPs and KA-PEG-MNPs) were superparamagnetic with saturation magnetizations of 8.1 emu/g and 26.4 emu/g, respectively. The KA drug loading was estimated using ultraviolet–visible spectroscopy, which gave a loading of 12.2% and 8.3% for the KA-CS-MNPs and KA-PEG-MNPs nanocomposites, respectively. The release profile of the KA from the nanocomposites followed a pseudo second-order kinetic model. The agar diffusion test was performed to evaluate the antimicrobial activity for both KA-CS-MNPs and KA-PEG-MNPs nanocomposites against a number of microorganisms using two Gram-positive (methicillin-resistant Staphylococcus aureus and Bacillus subtilis) and one Gram-negative (Salmonella enterica) species, and showed some antibacterial activity, which could be enhanced in future studies by optimizing drug loading. This study provided evidence for the promise for the further investigation of the possible beneficial biological activities of KA and both KA-CS-MNPs and KA-PEG-MNPs nanocomposites in nanopharmaceutical applications.
doi:10.2147/IJN.S53847
PMCID: PMC3890966  PMID: 24453486
chitosan; polyethylene glycol; magnetic nanoparticle; kojic acid; controlled release; biological activity
4.  Induction of apoptosis in cancer cells by NiZn ferrite nanoparticles through mitochondrial cytochrome C release 
The long-term objective of the present study was to determine the ability of NiZn ferrite nanoparticles to kill cancer cells. NiZn ferrite nanoparticle suspensions were found to have an average hydrodynamic diameter, polydispersity index, and zeta potential of 254.2 ± 29.8 nm, 0.524 ± 0.013, and −60 ± 14 mV, respectively. We showed that NiZn ferrite nanoparticles had selective toxicity towards MCF-7, HepG2, and HT29 cells, with a lesser effect on normal MCF 10A cells. The quantity of Bcl-2, Bax, p53, and cytochrome C in the cell lines mentioned above was determined by colorimetric methods in order to clarify the mechanism of action of NiZn ferrite nanoparticles in the killing of cancer cells. Our results indicate that NiZn ferrite nanoparticles promote apoptosis in cancer cells via caspase-3 and caspase-9, downregulation of Bcl-2, and upregulation of Bax and p53, with cytochrome C translocation. There was a concomitant collapse of the mitochondrial membrane potential in these cancer cells when treated with NiZn ferrite nanoparticles. This study shows that NiZn ferrite nanoparticles induce glutathione depletion in cancer cells, which results in increased production of reactive oxygen species and eventually, death of cancer cells.
doi:10.2147/IJN.S50061
PMCID: PMC3817022  PMID: 24204141
NiZn ferrite nanoparticles; cancer cells; reactive oxygen species; cytochrome C; mitochondrial membrane potential; p53
5.  Sn doping induced enhancement in the activity of ZnO nanostructures against antibiotic resistant S. aureus bacteria 
Highly ionic metal oxide nanostructures are attractive, not only for their physiochemical properties but also for antibacterial activity. Zinc oxide (ZnO) nanostructures are known to have inhibitory activity against many pathogens but very little is known about doping effects on it. The antibacterial activity of undoped ZnO and tin (Sn) doped ZnO nanostructures synthesized by a simple, versatile, and wet chemical technique have been investigated against Escherichia coli, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa bacterial strains. It has been interestingly observed that Sn doping enhanced the inhibitory activity of ZnO against S. aureus more efficiently than the other two bacterial strains. From cytotoxicity and reactive oxygen species (ROS) production studies it is found that Sn doping concentration in ZnO does not alter the cytotoxicity and ROS production very much. It has also been observed that undoped and Sn doped ZnO nanostructures are biosafe and biocompatible materials towards SH-SY5Y Cells. The observed behavior of ZnO nanostructures with Sn doping is a new way to prevent bacterial infections of S. aureus, especially on skin, when using these nanostructures in creams or lotions in addition to their sunscreen property as an ultraviolet filter. Structural investigations have confirmed the formation of a single phase wurtzite structure of ZnO. The morphology of ZnO nanostructures is found to vary from spherical to rod shaped as a function of Sn doping. The excitation absorption peak of ZnO is observed to have a blue shift, with Sn doping leading toward a significant tuning in band gap.
doi:10.2147/IJN.S45439
PMCID: PMC3792850  PMID: 24109181
nanostructures; Sn doped ZnO; S. aureus; antibacterial activity
6.  Biogenic silver nanoparticles using Rhinacanthus nasutus leaf extract: synthesis, spectral analysis, and antimicrobial studies 
Nanotechnology is gaining momentum due to its ability to transform metals into nanoparticles. The synthesis, characterization, and applications of biologically synthesized nanomaterials have become an important branch of nanotechnology. Plant extracts are a cost-effective, ecologically friendly, and efficient alternative for the large-scale synthesis of nanoparticles. In this study, silver nanoparticles (AgNps) were synthesized using Rhinacanthus nasutus leaf extract. After exposing the silver ions to the leaf extract, the rapid reduction of silver ions led to the formation of AgNps in solution. The synthesis was confirmed by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy. The in vitro antimicrobial activity of the AgNps synthesized using R. nasutus leaf extract was investigated against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Aspergillus niger, and Aspergillus flavus using a disc diffusion method. The AgNps showed potential activity against all of the bacterial strains and fungal colonies, indicating that R. nasutus has the potential to be used in the development of value-added products in the biomedical and nanotechnology-based industries.
doi:10.2147/IJN.S49000
PMCID: PMC3771748  PMID: 24039419
R. nasutus; silver nanoparticles; TEM; antimicrobial activities
7.  Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer’s disease 
Background
To sustain the effect of rivastigmine, a hydrophilic cholinesterase inhibitor, nanobased formulations were prepared. The efficacy of the prepared rivastigmine liposomes (RLs) in comparison to rivastigmine solution (RS) was assessed in an aluminium chloride (AlCl3)-induced Alzheimer’s model.
Methods
Liposomes were prepared by lipid hydration (F1) and heating (F2) methods. Rats were treated with either RS or RLs (1 mg/kg/day) concomitantly with AlCl3 (50 mg/kg/day).
Results
The study showed that the F1 method produced smaller liposomes (67.51 ± 14.2 nm) than F2 (528.7 ± 15.5 nm), but both entrapped the same amount of the drug (92.1% ± 1.4%). After 6 hours, 74.2% ± 1.5% and 60.8% ± 2.3% of rivastigmine were released from F1 and F2, respectively. Both RLs and RS improved the deterioration of spatial memory induced by AlCl3, with RLs having a superior effect. Further biochemical measurements proved that RS and RLs were able to lower plasma C-reactive protein, homocysteine and asymmetric dimethy-larginine levels. RS significantly attenuated acetylcholinesterase (AChE) activity, whereas Na+/K+-adenosine triphosphatase (ATPase) activity was enhanced compared to the AlCl3-treated animals; however, RLs succeeded in normalization of AChE and Na+/K+ ATPase activities. Gene-expression profile showed that cotreatment with RS to AlCl3-treated rats succeeded in exerting significant decreases in BACE1, AChE, and IL1B gene expression. Normalization of the expression of the aforementioned genes was achieved by coadministration of RLs to AlCl3-treated rats. The profound therapeutic effect of RLs over RS was evidenced by nearly preventing amyloid plaque formation, as shown in the histopathological examination of rat brain.
Conclusion
RLs could be a potential drug-delivery system for ameliorating Alzheimer’s disease.
doi:10.2147/IJN.S39232
PMCID: PMC3558309  PMID: 23378761
rivastigmine; Alzheimer’s disease; liposomes; rats; gene expression
8.  Effect of compositions in nanostructured lipid carriers (NLC) on skin hydration and occlusion 
Purpose
To study the effects of varying lipid concentrations, lipid and oil ratio, and the addition of propylene glycol and lecithin on the long-term physical stability of nanostructured lipid nanocarriers (NLC), skin hydration, and transepidermal water loss.
Methods
The various NLC formulations (A1–A5) were prepared and their particle size, zeta potential, viscosity, and stability were analyzed. The formulations were applied on the forearms of the 20 female volunteers (one forearm of each volunteer was left untreated as a control). The subjects stayed for 30 minutes in a conditioned room with their forearms uncovered to let the skin adapt to the temperature (22°C ± 2°C) and humidity (50% ± 2%) of the room. Skin hydration and skin occlusion were recorded at day one (before treatment) and day seven (after treatment). Three measurements for skin hydration and skin occlusion were performed in each testing area.
Results
NLC formulations with the highest lipid concentration, highest solid lipid concentration, and additional propylene glycol (formulations A1, A2, and A5) showed higher physical stability than other formulations. The addition of propylene glycol into an NLC system helped to reduce the particle size of the NLC and enhanced its long-term physical stability. All the NLC formulations were found to significantly increase skin hydration compared to the untreated controls within 7 days. All NLC formulations exhibited occlusive properties as they reduced the transepidermal water loss within 7 days. This effect was more pronounced with the addition of propylene glycol or lecithin into an NLC formulation, whereby at least 60% reduction in transepidermal water loss was observed.
Conclusion
NLCs with high lipid content, solid lipid content, phospholipid, and lecithin are a highly effective cosmetic delivery system for cosmetic topical applications that are designed to boost skin hydration.
doi:10.2147/IJN.S35648
PMCID: PMC3534299  PMID: 23293516
nanostructured lipid carriers; transepidermal water loss; skin hydration; particle size
9.  Comparative study of Mg/Al- and Zn/Al-layered double hydroxide-perindopril erbumine nanocomposites for inhibition of angiotensin-converting enzyme 
The intercalation of a drug active, perindopril, into Mg/Al-layered double hydroxide for the formation of a new nanocomposite, PMAE, was accomplished using a simple ion exchange technique. A relatively high loading percentage of perindopril of about 36.5% (w/w) indicates that intercalation of the active took place in the Mg/Al inorganic interlayer. Intercalation was further supported by Fourier transform infrared spectroscopy, and thermal analysis shows markedly enhanced thermal stability of the active. The release of perindopril from the nanocomposite occurred in a controlled manner governed by pseudo-second order kinetics. MTT assay showed no cytotoxicity effects from either Mg/Al-layered double hydroxide or its nanocomposite, PMAE. Mg/Al-layered double hydroxide showed angiotensin-converting enzyme inhibitory activity, with 5.6% inhibition after 90 minutes of incubation. On incubation of angiotensin-converting enzyme with 0.5 μg/mL of the PMAE nanocomposite, inhibition of the enzyme increased from 56.6% to 70.6% at 30 and 90 minutes, respectively. These results are comparable with data reported in the literature for Zn/Al-perindopril.
doi:10.2147/IJN.S32267
PMCID: PMC3418079  PMID: 22904631
magnesium; aluminum; layered double hydroxide; perindopril erbumine; ion exchange; angiotensin-converting enzyme; Chang cells line
10.  Cationized dextran nanoparticle-encapsulated CXCR4-siRNA enhanced correlation between CXCR4 expression and serum alkaline phosphatase in a mouse model of colorectal cancer 
Purpose:
The failure of colorectal cancer treatments is partly due to overexpression of CXCR4 by tumor cells, which plays a critical role in cell metastasis. Moreover, serum alkaline phosphatase (ALP) levels are frequently elevated in patients with metastatic colorectal cancer. A polysaccharide, dextran, was chosen as the vector of siRNA. Spermine was conjugated to oxidized dextran by reductive amination process to obtain cationized dextran, so-called dextran-spermine, in order to prepare CXCR4-siRNAs/dextran-spermine nanoparticles. The fabricated nanoparticles were used in order to investigate whether downregulation of CXCR4 expression could affect serum ALP in mouse models of colorectal cancer.
Methods:
Colorectal cancer was established in BALB/C mice following injection of mouse colon carcinoma cells CT.26WT through the tail vein. CXCR4 siRNA for two sites of the target gene was administered following injection of naked siRNA or siRNA encapsulated into nanoparticles.
Results:
In vivo animal data revealed that CXCR4 silencing by dextran-spermine nanoparticles significantly downregulated CXCR4 expression compared with naked CXCR4 siRNA. Furthermore, there was correlation between CXCR4 expression and serum ALP.
Conclusion:
CXCR4 siRNA/dextran-spermine nanoparticles appear to be highly effective, and may be suitable for further in vivo applications. Further research evaluation will be needed to determine the effect of CXCR4 silencing on serum ALP levels, which may be a useful marker to predict liver metastasis in colorectal cancer.
doi:10.2147/IJN.S29823
PMCID: PMC3415322  PMID: 22888250
nanoparticles; cationized dextran; colorectal cancer; serum ALP enzyme; CXCR4; siRNA
11.  Controlled-release formulation of antihistamine based on cetirizine zinc-layered hydroxide nanocomposites and its effect on histamine release from basophilic leukemia (RBL-2H3) cells 
A controlled-release formulation of an antihistamine, cetirizine, was synthesized using zinc-layered hydroxide as the host and cetirizine as the guest. The resulting well-ordered nanolayered structure, a cetirizine nanocomposite “CETN,” had a basal spacing of 33.9 Å, averaged from six harmonics observed from X-ray diffraction. The guest, cetirizine, was arranged in a horizontal bilayer between the zinc-layered hydroxide (ZLH) inorganic interlayers. Fourier transform infrared spectroscopy studies indicated that the intercalation takes place without major change in the structure of the guest and that the thermal stability of the guest in the nanocomposites is markedly enhanced. The loading of the guest in the nanocomposites was estimated to be about 49.4% (w/w). The release study showed that about 96% of the guest could be released in 80 hours by phosphate buffer solution at pH 7.4 compared with about 97% in 73 hours at pH 4.8. It was found that release was governed by pseudo-second order kinetics. Release of histamine from rat basophilic leukemia cells was found to be more sensitive to the intercalated cetirizine in the CETN compared with its free counterpart, with inhibition of 56% and 29%, respectively, at 62.5 ng/mL. The cytotoxicity assay toward Chang liver cells line show the IC50 for CETN and ZLH are 617 and 670 μg/mL, respectively.
doi:10.2147/IJN.S30809
PMCID: PMC3405893  PMID: 22848164
cetirizine hydrochloric acid; nanocomposite; zinc-layered hydroxide; histamine release; rat basophilic leukemia (RBL-2H3) cells
12.  Controlled release and angiotensin-converting enzyme inhibition properties of an antihypertensive drug based on a perindopril erbumine-layered double hydroxide nanocomposite 
Background
The intercalation of perindopril erbumine into Zn/Al-NO3-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation.
Results
Perindopril was intercalated into the interlayers and formed a well ordered, layered organic-inorganic nanocomposite. The basal spacing of the products was expanded to 21.7 Å and 19.9 Å by the ion-exchange and coprecipitation methods, respectively, in a bilayer and a monolayer arrangement, respectively. The release of perindopril from the nanocomposite synthesized by the coprecipitation method was slower than that of its counterpart synthesized by the ion-exchange method. The rate of release was governed by pseudo-second order kinetics. An in vitro antihypertensive assay showed that the intercalation process results in effectiveness similar to that of the antihypertensive properties of perindopril.
Conclusion
Intercalated perindopril showed better thermal stability than its free counterpart. The resulting material showed sustained-release properties and can therefore be used as a controlled-release formulation.
doi:10.2147/IJN.S30461
PMCID: PMC3356206  PMID: 22619549
perindopril erbumine; layered double hydroxides; ion-exchange; coprecipitation; sustained release; angiotensin-converting enzyme
13.  Human facial neural activities and gesture recognition for machine-interfacing applications 
The authors present a new method of recognizing different human facial gestures through their neural activities and muscle movements, which can be used in machine-interfacing applications. Human–machine interface (HMI) technology utilizes human neural activities as input controllers for the machine. Recently, much work has been done on the specific application of facial electromyography (EMG)-based HMI, which have used limited and fixed numbers of facial gestures. In this work, a multipurpose interface is suggested that can support 2–11 control commands that can be applied to various HMI systems. The significance of this work is finding the most accurate facial gestures for any application with a maximum of eleven control commands. Eleven facial gesture EMGs are recorded from ten volunteers. Detected EMGs are passed through a band-pass filter and root mean square features are extracted. Various combinations of gestures with a different number of gestures in each group are made from the existing facial gestures. Finally, all combinations are trained and classified by a Fuzzy c-means classifier. In conclusion, combinations with the highest recognition accuracy in each group are chosen. An average accuracy >90% of chosen combinations proved their ability to be used as command controllers.
doi:10.2147/IJN.S26619
PMCID: PMC3260039  PMID: 22267930
neural system; neural activity; electromyography; machine learning; muscle activity
14.  Blood cleaner on-chip design for artificial human kidney manipulation 
A novel design of a blood cleaner on-chip using an optical waveguide known as a PANDA ring resonator is proposed. By controlling some suitable parameters, the optical vortices (gradient optical fields/wells) can be generated and used to form the trapping tools in the same way as optical tweezers. In operation, the trapping force is formed by the combination between the gradient field and scattering photons by using the intense optical vortices generated within the PANDA ring resonator. This can be used for blood waste trapping and moves dynamically within the blood cleaner on-chip system (artificial kidney), and is performed within the wavelength routers. Finally, the blood quality test is exploited by the external probe before sending to the destination. The advantage of the proposed kidney on-chip system is that the unwanted substances can be trapped and filtered from the artificial kidney, which can be available for blood cleaning applications.
doi:10.2147/IJN.S19077
PMCID: PMC3124399  PMID: 21720507
optical trapping; blood dialysis; blood cleaner; human kidney manipulation

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