Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform

The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core–shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core–shell-type lipid–polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics.From the Clinical EditorThis comprehensive review covers the current applications of core–shell-type lipid–polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.     

Cartilage regeneration using a novel gelatin–chondroitin–hyaluronan hybrid scaffold containing bFGF-impregnated microspheres

Cartilage engineered from chondrocytes requires a scaffold to keep the cells in the cartilage defect and to act as a support for inducing hyaline cartilage formation on occasion. In this study, we developed a novel three-dimensional special scaffold in combination with a controlled release of bFGF, which provided structural support and stimulated repair. Gelatin microspheres loaded with bFGF (GM-bFGF) showed a fast release at the initial phase (28.23%) and the ultimate accumulated release was 92.9% by day 14. Three-dimensional gelatin–chondroitin–hyaluronan hybrid scaffolds seeded with cultured autologous chondrocytes were transplanted into the defects in rabbit knees and analyzed histologically at 12 and 24 weeks after the operation. Our findings showed that the defects were filled with smooth, shiny white cartilaginous tissue macroscopically and hyaline-like cartilage histologically 24 weeks postoperatively. The present study implied the great potential of the novel scaffold with GM-bFGF as a new way to promote the retention of chondrocytes and it might serve as a desirable cartilaginous tissue scaffolds to enhance the chondrogenesis.     

Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG–PCCL-modified magnetic iron oxide nanoparticles

Background: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl–poly(?-caprolactone) modified MNP (PEG–PCCL-MNP) suitable for magnetic targeting based on our previous studies.

Methods: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated.

Results: The size of PEG–PCCL-MNP was 79.6?±?0.945?nm. PEG–PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field.

Discussion: PEG–PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.     

Tamoxifen-loaded nanoparticles based on a novel mixture of biodegradable polyesters: characterization and in vitro evaluation as sustained release systems

Nanoparticles (NP) from mixtures of two poly(D,L-lactide-co-caprolactone) (PLC) copolymers, PLC 40/60 and PLC 86/14, with poly(D,L-lactide) (PDLLA) and PCL were prepared: PLC 40/60-PCL (25:75), PLC 86/14-PCL (75:25) and PLC 86/14-PLA (75:25). Tamoxifen was loaded with encapsulation efficiency between 65% and 75% (29.9-36.3?μg TMX/ mg NP). All selected systems showed spherical shape and nano-scale size. TMX-loaded NPs were in the range of 293-352?nm. TMX release from NP took place with different profiles depending on polymeric composition of the particles. After 60 days, 59.81% and 82.65% of the loaded drug was released. The cytotoxicity of unloaded NP in MCF7 and HeLa cells was very low. Cell uptake of NP took place in both cell types by unspecific internalization in a time dependent process. The administration of 6 and 10?μm TMX by TMX-loaded NP was effective on both cellular types, mainly in MCF7 cells.     

A poly(γ-glutamic acid)–amphiphile complex as a novel nanovehicle for drug delivery system

Recently, many studies have focused on biomedical and pharmaceutical applications of self-assembled nanoparticles. In addition, several biodegradable nanoparticles have been reported to possess poor dispersion stability and poor size-controllability. However, these nanoparticles require complicated fabrication procedures using synthesis techniques. We developed an efficient method for producing nanoparticles derived from a biological origin of molecule poly(γ-glutamic acid) (γ-PGA), a cationic lipid, and doxorubicin (Dox). The complex had a size of 510?nm and was able to encapsulate over 90% of the added Dox. An in vivo assay of antitumor activity demonstrated that the complex had significant antitumor activity in sarcoma 180–bearing mice, and was effectively accumulated in solid tumors based on the EPR effect. The data suggested that this complex is a promising formulation of γ-PGA for targeted delivery to solid tumors. γ-PGA–12GP2 complexes may possess several unique advantages, including simplicity of nanoparticle preparation, high drug-carrying capacity, appropriate size to allow deeper penetration based on EPR effect into solid tumors, and lack of necessity to modify the chemical structure of the drugs. These data indicate that the γ-PGA–12GP2 complexes are potentially useful in cancer chemotherapy.     

Enhanced drug encapsulation and extended release profiles of calcium–alginate nanoparticles by using tannic acid as a bridging cross-linking agent

Abstract

Calcium alginate nanoparticles (NPs) suffer from sub-optimal stability in bio-relevant media leading to low drug encapsulation efficiency and uncontrolled release profiles. To sort out these drawbacks, a novel approach is proposed herein based on introducing tannic acid into these NPs to act as a bridging cross-linking aid agent. Calcium–alginate NPs were prepared by the ionotropic gelation method and loaded with diltiazem hydrochloride as a model drug. These NPs were characterized in terms of particle size, zeta potential, and morphology, and results were explained in accordance with Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). The incorporation of tannic acid led to more than four folds increase in drug encapsulation efficiency (i.e. from 15.3% to 69.5%) and reduced burst drug release from 44% to around 10% within the first 30?min. These findings suggest the possibility of improving the properties of Ca–alginate NPs by incorporating cross-linking aid agents under mild conditions.     

−NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor–cognitive impairments in Parkinsonism

Background: Parkinsonism describes Parkinson’s disease and other associated degenerative changes in the brain resulting in movement disorders. The motor cortex, extrapyramidal tracts and nigrostriatal tract are brain regions forming part of the motor neural system and are primary targets for drug or chemotoxins induced Parkinsonism. The cause of Parkinsonism has been described as wide and elusive, however, environmental toxins and drugs accounts for large percentage of spontaneous cases in humans. A common mechanism in the cause and progression of drug/chemotoxin induced Parkinsonism involves calcium signalling in; oxidative stress, autophagy, cytoskeletal instability and excitotoxicity

.Aim: This study sets to investigate the effect of targeting calcium controlling receptors, specifically activation of Vitamin D₃ receptor (VDR) and inhibition of N-Methyl-D-Aspartate Receptor (NMDAR) in the motor cortex of mice model of drug induced Parkinsonism. Also we demonstrated how these interventions improved neural activity, cytoskeleton, glia/neuron count and motor–cognitive functions in vivo.

Methods: Adult mice were separated into six groups of n?=?5 animals each. Body weight (5?mg/kg) of haloperidol was administered intraperitoneally for 7 days to block dopaminergic D₂ receptors and induce degeneration in the motor cortex following which an intervention of VDR agonist (VDRA), and (or) NMDAR inhibitor was administered for 7 days. A set of control animals received normal saline while a separate group of control animals received the combined intervention of VDRA and NMDAR inhibitor without prior treatment with haloperidol. Behavioral tests for motor and cognitive functions were carried out at the end of the treatment and intervention periods. Subsequently, neural activity in the motor cortex was recorded in vivo using unilateral wire electrodes. We also employed immunohistochemistry to demonstrate neuron, glia, neurofilament and proliferation in the motor cortex after haloperidol treatment and the intervention.

Result/Discussion: We observed a decline in motor function and memory index in the haloperidol treatment group when compared with the control. Similarly, there was a decline in neural activity in the motor cortex (a reduced depolarization peak frequency). General cell loss (neuron and glia) and depletion of neurofilament were characteristic anatomical changes seen in the motor cortex of this group. However, Vitamin D₃ intervention facilitated an improvement in motor–cognitive function, neural activity, glia/neuron survival and neurofilament expression. NMDAR inhibition and the combined intervention improved motor–cognitive functions but not as significant as values observed in VDRA intervention. Interestingly, animals treated with the combined intervention without prior haloperidol treatment showed a decline in motor function and neural activity.

Conclusion: Our findings suggest that calcium mediated toxicity is primary to the cause and progression of Parkinsonism and targeting receptors that primarily modulates calcium reduces the morphological and behavioral deficits in drug induced Parkinsonism. VDR activation was more effective than NMDAR inhibition and a combined intervention. We conclude that targeting VDR is key for controlling calcium toxicity in drug/chemotoxin induced Parkinsonism.     

(–)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1 (NDM-1) inhibitor

The β-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health. We have previously screened out (–)-epicatechin gallate (ECG) as a potent NDM-1 inhibitor. We further discussed its inhibitory effect and action mode in the present study. According to our results, ECG reversibly inactivated NDM-1 in a non-competitive mode, with an IC₅₀ value of 4.48 μM. ECG effectively recovered the activity of several β-lactam antibiotics against resistant strain harboring blaNDM-1. Especially, the effects on carbapenems were worth mentioning. The zinc supplement assay indicated a zinc-related mechanism of ECG. Different from traditional chelating agents, it showed low toxicity both in vivo and in vitro. In a word, our findings provided a promising NDM-1 inhibitor, ECG, which was able to assist carbapenems against NDM-1-producing strain.     

Production of nZVI–Cl nanocomposite as a novel eco–friendly adsorbent for efficient As(V) ions removal from aqueous media: Adsorption modeling by response surface methodology

By combination of the nano zero–valent iron (nZVI) nanoparticles and clinoptilolite (Cl) natural zeolite and by chemical reduction method, the nZVI–Cl nanocomposite was produced. The physical and chemical characteristics of the produced nanocomposite were examined using FE–SEM, EDX, VSM and zeta potential analyses and its fine structure was confirmed. The produced nanocomposite was applied for efficient As(V) heavy metal ions removal from aqueous media as a novel eco–friendly adsorbent. The adsorption process was optimized using a minimum number of designed experiments by Design–Expert software using central composite design (CCD) and response surface methodology (RSM) and the adsorption optimum conditions were determined as solution pH of 4, nZVI–Cl dosage of 1 g L^?1 and As(V) concentration of 50 mg L^?1 by the numerical optimization of the software. In these conditions, the removal efficiency was 88.10% and desirability parameter was 0.986. The adsorption kinetic study showed that the chemisorption effectively controls the adsorption process by a better fit of pseudo–second order model with the experimental data. The adsorption isotherms study demonstrated that the Langmuir model had the best fit with the experimental data, proving homogeneous surface of nZVI–Cl adsorbent and monolayer adsorption of As(V) ions on it. The adsorption thermodynamic study illustrated that the adsorption is thermodynamically spontaneous and exothermic in nature. Also, the adsorbent reusability test verified the adsorbent stability after five consecutive adsorption–desorption cycles without a tangible reduction in removal efficiency.     

Separation and structural elucidation of a novel analogue of vardenafil included as an adulterant in a dietary supplement by liquid chromatography–electrospray ionization mass spectrometry,infrared spectroscopy and nuclear magnetic resonance spectroscopy

MEGATON, a dietary supplement, was analyzed in order to detect PDE-5 inhibitors and their analogues. A new analogue of vardenafil could be detected by high-performance liquid chromatography (HPLC) analysis with a photodiode array detector (PDA). This compound was compared with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues such as hongdenafil and homosildenafil. The structure of this compound was elucidated by mass spectrometry (MS), infrared (IR) spectroscopy and one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. When compared with vardenafil to verify the structural difference, this compound had an acetyl group instead of a sulfonyl group in the pyrazolopyrimidine portion without any substitution in the piperazine ring of the molecule. This compound was identified as 2-(2-ethoxy-5-(2-(4-ethylpiperazin-1-yl)acetyl)phenyl)-5-methyl-7-propyl-imidazo(5,1-f)-(1,2,4)triazin-4(3H)-one, which is also called acetylvardenafil.