'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded With Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice.

Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of Ac4MAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of Ac4MAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (As2O3, ATO)-loaded liposomes inserted with distearoyl phospho-ethanolamine-polyethylene glycol-1000-p-carboxylpheny-α-d-acetylmannosamine (DSPE-PEG-1000-Ac4MAN), which was named Ac4MAN-ATO-LIP. Cytotoxic experiments of liposomes indicated that the toxicity of Ac4MAN-ATO-LIP was lower than that of free ATO but stronger than that of ATO-LIP (without insertion of DSPE-PEG-1000-Ac4MAN). The uptake of vesicles by U87 glioma cells displayed that the cellular uptake of Ac4MAN-Rho-LIP (labeled by rhodamine) was remarkably improved, compared with Rho-LIP. The in vivo biodistribution results showed the superiority of Ac4MAN-Rho-LIP in enhanced intracranial accumulation. Furthermore, the treatment of orthotopic glioma in Balb/c nude mice with Ac4MAN-ATO-LIP elongated the survival time of the animals than that with physiological saline, free ATO, or ATO-LIP, respectively. All the results suggested that the Ac4MAN-ATO-LIP had stronger anti-glioma effects as well as lower toxicities, and may be a promising approach for the treatment of brain cancer.

NaF-loaded core-shell PAN-PMMA nanofibers as reinforcements for Bis-GMA/TEGDMA restorative resins.

A kind of core-shell nanofibers containing sodium fluoride (NaF) was produced and used as reinforcing materials for dimethacrylate-based dental restorative resins in this study. The core-shell nanofibers were prepared by coaxial-electrospinning with polyacrylonitrile (PAN) and poly(methyl methacrylate) (PMMA) solutions as core and shell fluids, respectively. The produced PAN-PMMA nanofibers varied in fiber diameter and the thickness of PMMA shell depending on electrospinning parameters. NaF-loaded nanofibers were obtained by incorporating NaF nanocrystals into the core fluid at two loadings (0.8 or 1.0wt.%). Embedment of NaF nanocrystals into the PAN core did not damage the core-shell structure. The addition of PAN-PMMA nanofibers into Bis-GMA/TEGDMA clearly showed the reinforcement due to the good interfacial adhesion between fibers and resin. The flexural strength (Fs) and flexural modulus (Ey) of the composites decreased slightly as the thickness of PMMA shell increasing. Sustained fluoride releases with minor initial burst release were achieved from NaF-loaded core-shell nanofibers and the corresponding composites, which was quite different from the case of embedding NaF nanocrystals into the dental resin directly. The study demonstrated that NaF-loaded PAN-PMMA core-shell nanofibers were not only able to improve the mechanical properties of restorative resin, but also able to provide sustained fluoride release to help in preventing secondary caries.

The Effects of Lactidyl/Glycolidyl Ratio and Molecular Weight of Poly(D,L -Lactide-co-Glycolide) on the Tetracycline Entrapment and Release Kinetics of Drug-Loaded Nanofibers.

Electrospun tetracycline (Tet)-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanofibers are considered to have great potential as local drug-delivery systems. This study was designed to explore the effects of the lactidyl/glycolidyl (LA/GA) unit ratio and molecular weight of PLGA on Tet entrapment efficiency and in vitro release kinetics. Three kinds of PLGA (PLGA75/25, M w = 100 000 or 50 000; PLGA50/50, M w = 50 000) were examined in this study. Electrospun nanofibers were fabricated containing 3, 5, 10 wt% Tet. The results showed that PLGA50/50 entrapped more Tet than both PLGA75/25 co-polymers, and the PLGA75/25 of M w = 100 000 entrapped the least amount of Tet, suggesting that the lower the molecular weight of PLGA was, the higher the GA content in PLGA was and the higher the resulting Tet entrapment. Tet loading played an important role in Tet release. Nanofibers with 3 and 5 wt% Tet loading exhibited a sustained release for more than 28 days, whereas 10 wt% Tet only lasted 14 days. Loading of 3 wt% Tet resulted in approx. 35% release in the initial 12 h, 5 wt% Tet released approx. 70% and 10 wt% Tet resulted in approx. 85% release. The integrity of Tet incorporated into electrospun PLGA nanofibers was identified by FT-IR spectrum examination and the bacterial inhibition test. The modified Kirby-Bauer test showed dose-dependent inhibition of Staphylococcus aureus growth by Tet, confirming Tet structural stability throughout the electrospinning procedure. MG-63 cells demonstrated good adhesion and proliferation on all PLGA/Tet fibrous membranes. These results indicate that Tet entrapment and release kinetics of PLGA/Tet composite fibrous scaffolds can be tailored by the LA/GA ratios, molecular weights and drug loadings. Tet-loaded fibrous scaffolds show great potential for local drug delivery and bone defect repair.

In vitro hydrolytic and enzymatic degradation of nestlike-patterned electrospun poly(D,L-lactide-co-glycolide) scaffolds.

A common problem in applying electrospun biodegradable polyester matrixes as tissue-engineering scaffolds is their serious shrinkage with degradation to reduce the porosity drastically. To ameliorate this problem, a nestlike-patterned poly(D,L-lactide-co-glycolide) (PLGA) nanofibrous (∼900 nm) matrix was proposed and fabricated by electropinning. Shrinkage studies demonstrated that the dimension change of nestlike-patterned fibrous membrane was much smaller than those of nonwoven and parallel-aligned fibrous membranes. And the robust framework of the patterned matrix helped to maintain its original nestlike topographical structure during degradation. Compared to hydrolytic-degraded specimens, the PLGA nanofibrous matrixes degraded in the presence of lysozyme showed larger weight loss but slower decrease in molecular weight. Besides, porous fibers with intact surface were detected by scanning electron microscopy after 20-week hydrolysis, and fibers with pores both inside and on surface were observed after enzymatic degradation for 12 weeks. Accordingly, the former presented a bimodal gel permeation chromatography (GPC) peak, while no bi or multimodal GPC peaks were found for the latter as degradation proceeded. These results indicated that an acid autocatalytic effect still existed in the hydrolysis of PLGA nanofibrous matrix. The presence of lysozyme could only accelerate the dissolution of degradation products with low molecular weight, but have no contribution to the chain scission.