Yange Wang

Therapeutic effect of folate-targeted and PEGylated phytosomes loaded with a mitomycin C-soybean phosphatidyhlcholine complex.

A mitomycin C (MMC)-soybean phosphatidyhlcholine complex loaded in phytosomes was previously reported for the purpose of developing a MMC drug delivery system (Mol. Pharmaceutics 2013, 10, 90-101), but this approach was limited by rapid elimination from the body and lack of target specificity. In this article, to overcome these limitations, MMC-soybean phosphatidyhlcholine complex-loaded phytosomes (MMC-loaded phytosomes) as drug carriers were surface-functionalized with folate-PEG (FA-PEG) to achieve reduced toxicity and a superior MMC-mediated therapeutic effect. For this purpose, FA was conjugated to DSPE-PEG-NH2, and the resultant DSPE-PEG-FA was introduced into the lipid moiety of the phytosomes via a postinsertion technique. The prepared FA-PEG-functionalized MMC-loaded phytosomes (FA-PEG-MMC-loaded phytosomes) have a particle size of 201.9 ± 2.4 nm, a PDI of 0.143 ± 0.010, a zeta potential of -27.50 ± 1.67 mV, a spherical shape, and sustained drug release. The remarkable features of FA-PEG-MMC-loaded phytosomes included increased cellular uptake in HeLa cells and higher accumulation in H22 tumor-bearing mice over that of the PEG-MMC-loaded phytosomes. Furthermore, FA-PEG-MMC-loaded phytosomes were associated with enhanced cytotoxic activity in vitro and an improved antitumor effect in vivo compared to that resulting from free MMC injection. These results suggest that FA-PEG-MMC-loaded phytosomes may be useful drug delivery systems for widening the therapeutic window of MMC in clinical trials.

Development of multifunctional folate-poly(ethylene glycol)-chitosan-coated Fe3O4 nanoparticles for biomedical applications

AbstractThe efficacy of magnetic nanoparticles (MNPs) for biomedical applications depends on the specic targeting capacity, blood circulation time and magnetic susceptibility. Functionalized chitosan-coated Fe3O4 nanoparticles (CS-coated Fe3O4 NPs) were synthesized by a non-solvent-aided coacervation procedure followed by a chemical crosslinking procedure. The surfaces of CS-coated Fe3O4 NPs were successfully functionalized with folate-poly(ethylene glycol)-COOH (FA-PEG) to obtain novel FA-PEG-CS-coated Fe3O4 NPs endowed with long blood circulation and specic targeting capacity. The as-synthesized NPs were characterized by dynamic light scattering, transmission electron microscope, X-ray diffraction, thermal gravimetric analysis, vibration sample magnetometer, Fourier transform infrared spectroscopy, and confocal laser scanning microscopy. As a result, the novel FA-PEG-CS-coated Fe3O4 NPs showed excellent biocompatibility, magnetic properties, good dispersibility, and proper hydrodynamic sizes in an aqueous medium. The specific targeting capacity of the as-synthesized NPs to cancer cells was also investigated. It was observed that the uptake of the FA-PEG-CS-coated Fe3O4 NPs by HeLa cells was significantly enhanced compared to the CS-coated Fe3O4 NPs and mPEG-CS-coated Fe3O4 NPs. These results clearly indicate that our novel FA-PEG-CS-coated Fe3O4 NPs with remarkable specific targeting capacity, long blood circulation, and superparamagnetism hold great promise for biomedical applications, including targeted drug delivery and hyperthermia therapy.n

Carboxylic Acid Fullerene (C60) Derivatives Attenuated Neuroinflammatory Responses by Modulating Mitochondrial Dynamics

Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60–COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60–COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (ΔΨm) were also significantly inhibited by C60–COOH. Moreover, we also found that C60–COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.

Evaluation of self-assembled HCPT-loaded PEG-b-PLA nanoparticles by comparing with HCPT-loaded PLA nanoparticles

We present a dialysis technique to prepare the 10-hydroxycamptothecin (HCPT)-loaded nanoparticles (NPs) using methoxypolyethylene glycol-poly(d,l-lactide) (PEG-b-PLA) and PLA, respectively. Both HCPT-loaded PEG-b-PLA NPs and HCPT-loaded PLA NPs were characterized by differential scanning calorimetry (DSC), dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The results showed that the HCPT-loaded PEG-b-PLA NPs and HCPT-loaded PLA NPs presented a hydrodynamic particle size of 120.1 and 226.8xa0nm, with a polydispersity index of 0.057 and 0.207, a zeta potential of −31.2 and −45.7xa0mV, drug encapsulation efficiency of 44.52% and 44.94%, and drug-loaded content of 7.42% and 7.49%, respectively. The HCPT-loaded PEG-b-PLA NPs presented faster drug release rate compared to the HCPT-loaded PLA NPs. The HCPT-loaded PEG-b-PLA NPs presented higher cytotoxicity than the HCPT-loaded PLA NPs. These results suggested that the HCPT-loaded PEG-b-PLA NPs presented better characteristics for drug delivery compared to HCPT-loaded PLA NPs.

A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery

We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

Preparation and ocular pharmacokinetics of hyaluronan acid-modified mucoadhesive liposomes

Abstract The aim of this research was to formulate a liposomal preparation of DOX to be applied topically, and to investigate the in vitro and in vivo performance of the prepared liposomes. DOX liposomes were prepared by the solvent evaporation method, and then modified with bioadhesive material HA. Through MTT assay, we found that the safe concentration of liposomes delivered would hit 1u2009mg/mL. Cellular uptake studies showed that DOX liposomes coated with HA are much more targetable to cell nucleus. Their ocular pharmacokinetics in rabbits were investigated through the comparison with those obtained after dosing with non-modified liposomes and DOX solution. The in vitro transcorneal permeability of DOX in both kinds of liposomes was found to be slower than that of the solution because of sustained release. After in vivo instillation in rabbits, HA-modified liposomes had the longest retention time, following with naked liposomes. Significantly, the area under the curve of the aqueous humor concentration–time profiles of DOX liposomes was found to be 1.7-fold higher than that of DOX solution. The confocal experiment confirmed that HA-modified liposomes were able to maintain a higher DOX concentration and residence time than that of non-modified liposomes and free DOX. These results suggest that our liposomal preparation was of great help to improve the bioavailability of DOX.

Optimization of Production of PLA Microbubble Ultrasound Contrast Agents for Hydroxycamptothecin Delivery

In this paper, ultrasound contrast agents based on a high molecular polymer-poly lactic acid (PLA) and loaded with hydroxycamptothecin (HCPT) were prepared by combining ultrasound method and a Shirasu porous glass (SPG) membrane emulsification technique. A special focus was on the optimization of production of HCPT-PLA microbubbles. Different factors, such as the power and the time of ultrasonic action, the ratio of inner aqueous phase against outer oil phase, and the concentration of PLA were evaluated, and the average size of HCPT-PLA microbubbles, the drug carrying efficiency, as well as the acoustically- triggered drug release at 3 kHz ultrasound were determined. The study showed that the HCPT-PLA microbubbles prepared using our optimized conditions, were sphere-like in shape with a mean diameter of 1-7 mum. The drug loading efficiency reached up to 56.48% In vitro, the drug release of HCPT-PLA microbubbles increased significantly at 3 kHz ultrasound for 30 s compared with that of ultrasound-free condition. In conclusion, the HCPT-PLA microbubbles has the characteristics desirable for an intravenously administered ultrasound contrast agent for further clinical use.

Glutathione-responsive self-delivery nanoparticles assembled by curcumin dimer for enhanced intracellular drug delivery

Graphical abstract Figure. No Caption available. Abstract Poor water solubility, short half‐life, and low drug efficacy posed a challenge for clinical application of curcumin (CUR). In this work, a kind of CUR prodrug was synthesized by coupling two CUR molecules with a mono‐thioether linker for glutathione (GSH)‐responsive drug delivery. The synthesized CUR prodrug (CUR‐S‐CUR dimer) could self‐assemble into the homogeneous spherical nanoparticles (NPs) in aqueous solution followed by surface functionalization of trace amounts of DSPE‐PEG. These CUR‐S‐CUR@PEG NPs exhibited a small particle size of ˜100 nm, high CUR‐loading content of ˜78 wt%, and good colloid stability. Moreover, the CUR‐S‐CUR@PEG NPs demonstrated much more efficient cellular uptake and intracellular/nuclear drug delivery compared with free CUR, indicating the advantages of small molecular prodrug assembly. In addition, the GSH with high concentration in tumor cells could trigger the disassembly of CUR‐S‐CUR@PEG NPs. Furthermore, the cytotoxicity assays indicated that the CUR‐S‐CUR@PEG NPs exhibited the comparable inhibition effect of tumor cell proliferation with free CUR due to sustained drug release. Therefore, these stimuli‐responsive CUR‐S‐CUR@PEG NPs might have promising potential for highly efficient intracellular drug delivery and controlled drug release in cancer therapy.