[Pharmacokinetic Study on Brucine in Different Administration Methods of Liposome in Rats].

OBJECTIVE: To compare the pharmacokinetic differences of brucine in rats after different administration methods of brucine liposome. METHODS: To determine brucine in rat plasma at different points in time by HPLC after oral administration, intramuscular injection, subcutaneous injection and intravenous injection of brucine liposome, respectively. The pharmacokinetic parameters were calculated and analyzed by DAS 3.0. RESULTS: Compared with other groups, AUC(0 --> t) of subcutaneous injection were higher, C(max) were lower and MRT(0 --> 1), were significantly improved. The pharmacokinetics parameters and absolute bioavailability of brucine show that bioavailability in rats after different administration methods of brucine liposome is subcutaneous injection > intramuscular injection > oral administration.

Biomaterials for local drug delivery in central nervous system.

The central nervous system (CNS) is a vital part of human body which coordinate the actions by transmitting signals. Because of the existence of the blood-brain barrier and the blood-spinal cord barrier, diseases in CNS can hardly be directly intervened by non-invasive methods. While systemic delivery usually requires extravagant drug dosage and leads into toxicity in unexpected tissues, local drug delivery in CNS tissues provides a solution for the problems of physiological barriers and systematic side effects. Biomaterials are applied in local drug delivery system (LDDS) for CNS disease therapy with aims of tuning the drug release property and improving bioavailability, solubility, stability and safety of pharmaceutics. The indispensable importance and distinct physiological structure of cerebrospinal area bring about challenges to biomaterials in LDDS. Thus, properties of drug delivery systems are necessitated with prudently concern. In this review, the development of LDDS utilizing biomaterials will be presented, including sustained release, local parameter-responsible release, and regional cell-selective active targeting release. Studies on biomaterials employed as pharmaceuticals will give rise to a more efficacious method and the better understanding of LDDS design in CNS.

ScreenFect A: an efficient and low toxic liposome for gene delivery to mesenchymal stem cells.

Mesenchymal stem cells (MSCs) hold great promise in variety of therapeutic applications including tissue engineering and cancer therapy. Genetic modification of MSCs can be used to enhance the therapeutic effect of MSCs by facilitating a specific function or by transforming MSCs into more effective gene therapy tools. However, the successful generation of genetically modified MSCs is often limited by the poor transfection efficiency or high toxicity of available transfection reagents. In our previous study, we used thiol-yne click chemistry to develop new liposomal vectors, including ScreenFect(®) A (SF) (Li et al., 2012). In this study, we investigated the transfection performance of SF on MSCs. A comparative evaluation of transfection efficiency, cell viability and cellular DNA uptake was performed using the Lipofectamine™ 2000 (L2K) as a control, and the results show that SF is superior to L2K for MSC transfection. The presence of serum did not significantly influence the transfection efficiency of either SF or L2K but greatly reduced the viability of MSC transfected by L2K. The higher efficiency of SF-mediated transfection compared to L2K was also correlated with better proliferation of cells. These results were supported by monitoring the intracellular fate of DNA, which confirmed stable transportation of DNA from lysosomes and efficient nuclear localization. TGF-ß1 gene delivery by SF promoted MSC osteogenic differentiation in an osteogenic induction condition. As the first study of SF lipofection on stem cells, this study highlights a promising role of SF in gene delivery to MSCs as well as other stem cells to facilitate tissue engineering and other therapeutic effects based on genetically modified stem cells.

Synergistic effects of co-administration of suicide gene expressing mesenchymal stem cells and prodrug-encapsulated liposome on aggressive lung melanoma metastases in mice.

The success of conventional suicide gene therapy for cancer treatment is still limited because of lack of efficient delivery methods, as well as poor penetration into tumor tissues. Mesenchymal stem cells (MSCs) have recently emerged as potential vehicles in improving delivery issues. However, these stem cells are usually genetically modified using viral gene vectors for suicide gene overexpression to induce sufficient therapeutic efficacy. This approach may result in safety risks for clinical translation. Therefore, we designed a novel strategy that uses non-viral gene vector in modifying MSCs with suicide genes to reduce risks. In addition, these cells were co-administrated with prodrug-encapsulated liposomes for synergistic anti-tumor effects. Results demonstrate that this strategy is effective for gene and prodrug delivery, which co-target tumor tissues, to achieve a significant decrease in tumor colonization and a subsequent increase in survival in a murine melanoma lung metastasis model. Moreover, for the first time, we demonstrated the permeability of MSCs within tumor nests by using an in vitro 3D tumor spheroid model. Thus, the present study provides a new strategy to improve the delivery problem in conventional suicide gene therapy and enhance the therapeutic efficacy. Furthermore, this study also presents new findings to improve our understanding of MSCs in tumor-targeted gene delivery.

Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes.

Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.

Evaluation of pluronic nanosuspensions loading a novel insoluble anticancer drug both in vitro and in vivo.

To improve the solubility, stability and the antitumor activity of a novel anticancer drug, 3-(4-bromopheny l)-2-(ethyl-sulfonyl)-6-methylquinoxaline1,4-dioxide (Q39), a poloxamer nanosuspension was developed by precipitation combined with high pressure homogenization in present study. In vitro characterizations of Q39 nanosuspension (Q39/NS), including particle size, polydispersity index (PI), morphology, crystalline, saturation solubility, stability and releases were evaluated. BABL/c nude mice bearing HepG2 cells were used as in vivo tumor models to evaluate the anti-tumor activity of Q39/NS after intravenous administration. The particle size and PI for Poloxamer188 nanosuspension (P188/NS) were (304±3) nm, and (0.123±0.005) respectively, and it was (307±5) nm and (0.120±0.007) for Poloxamer85 nanosuspension (P85/NS) correspondingly. The morphology of P188/NS was spherical shape while elliptoid shape for P85/NS. The crystalline of Q39/NS did not change as shown by the X-ray diffraction analysis. The stability of Q39/NS improved compared with the solution. The solubility of Q39 in P188/NS was 7.3 times higher than the original solubility, while it was 6 times for P85/NS. Sustained release as shown from the in vitro release test, together with the tumor-targeting as shown from in vivo NS distribution, may contribute to the enhanced in vivo antitumor activity of Q39/NS.