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Additional file 1: Figure S1. 1H-NMR study showing the existence of Ang conjugated to DSPE-PEG. Figure S2. Size distribution of exosomes derived from U87-MG cells by nanoparticle tracking analysis. Figure S3. DTX release profiles for different nanoformulations. Figure S4. Storage stability of different nanoparticles. Figure S5. Serum levels of ALT, AST, BUN and Cr in mice with GBM after treatment. Figure S6. H&E staining of major organs of mice with GBM after treatment. Scale bar = 200 ��m. Table S1. Drug loading properties of nanoparticles.

Jun-Yong Wu,1–3* Yong-Jiang Li,1–3* Xin-Yi Liu,1–3 Jia-Xin Cai,1–3 Xiong-Bin Hu,1–3 Jie-Min Wang,1–3 Tian-Tian Tang,1–3 Da-Xiong Xiang1–3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drug, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Da-Xiong XiangDepartment of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of ChinaEmail xiangdaxiong@csu.edu.cnBackground: 3,5,4′-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated.Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated.Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues.Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.Keywords: 3,5,4′-trimethoxy-trans-stilbene, bioavailability, colon cancer, drug delivery, micelles

Xiong-Bin Hu,1–3 Tian-Tian Tang,1–3 Yong-Jiang Li,1–3 Jun-Yong Wu,1–3 Jie-Min Wang,1–3 Xin-Yi Liu,1–3 Da-Xiong Xiang1–31Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drug, Changsha, Hunan Province, 410011, People’s Republic of ChinaPurpose: The aim of this research was to develop a phospholipid complex based nanoemulsion system for oral insulin delivery.Methods: Insulin-phospholipid complex (IPC) was firstly prepared by an anhydrous co-solvent lyophilization method, and then encapsulated into the oil phase of nanoemulsion to obtain the IPC-based nanoemulsion (IPC-NE). Both water-in-oil (W/O) IPC-NE and oil-in-water (O/W) IPC-NE were formulated and evaluated for comparison.Results: The obtained W/O IPC-NE and O/W IPC-NE were both spherical in shape with a mean particle size of 18.6±0.79 nm and 27.3±1.25 nm, respectively. While both IPC-NEs exhibited enhanced Caco-2 cell monolayers permeability than IPC and insulin solution, W/O IPC-NE showed relatively greater protective effects against enzymatic degradation than O/W IPC-NE. Moreover, oral administration of W/O IPC-NE exhibited significant hypoglycemic effects, with 12.4-fold and 1.5-fold higher oral bioavailability compared with insulin solution and O/W IPC-NE, respectively.Conclusion: IPC-NEs, especially the W/O IPC-NE showed promising efficiency in vitro and in vivo, thus could be a potential strategy for oral insulin delivery.Keywords: insulin, phospholipid complex, oral drug delivery, nanoemulsion, hypoglycemic effect

Jun-Yong Wu,1–3,* Yong-Jiang Li,1–3,* Ting-Ting Liu,1–3 Ge Ou,1–3 Xiong-Bin Hu,1–3 Tian-Tian Tang,1–3 Jie-Min Wang,1–3 Xin-Yi Liu,1–3 Da-Xiong Xiang1–3 1Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drugs, Changsha, Hunan, People’s Republic of China *These authors contributed equally to this work Background: 8-methoxypsoralen (8-MOP) is one of the most commonly utilized drugs in psoralen-ultraviolet A therapy for treatment of vitiligo. However, poor skin retention and systemic side effects limit the clinical application of 8-MOP. Methods: Microemulsions (MEs) and chitosan derivative-coated 8-MOP MEs were developed and compared for dermal delivery of 8-MOP. Ex vivo skin retention/permeation study was performed to select the ME formulation with the highest retention:permeation ratio. Four different chitosan-coated MEs were prepared and compared with the ME formulation for their ability to distribute 8-MOP in the skin.Results: Among various ME formulations developed, a formulation containing 2.9% ethyl oleate, 17.2% Cromophor EL35, 8.6% ethanol and 71.3% water showed the highest ex vivo skin retention:permeation ratio (1.98). Of four chitosan-coated MEs prepared, carboxymethyl chitosan-coated MEs (CC-MEs) and hydroxypropyl chitosan-coated MEs (HC-MEs) showed higher ex vivo skin retention:permeation ratio (1.46 and 1.84). and were selected for in vivo pharmacokinetic study. AUCskin (0–12 h) for 8-MOP MEs (4578.56 h·ng·mL-1) was higher than HC-MEs (3422.47 h·ng·mL-1), CC-MEs (2808.51 h·ng·mL-1) and tincture (1500.16 h·ng·mL-1). Also, AUCplasma (0–12 h) for MEs (39.35±13.90 h·ng·mL-1) was significantly lower than HC-MEs (66.32 h·ng·mL-1), CC-MEs (59.70 h·ng·mL-1) and tincture (73.02 h·ng·mL-1).Conclusion: These combined results suggested that the MEs developed could be a promising and safe alternative for targeted skin delivery of 8-MOP. Keywords: 8-methoxypsoralen, microemulsion, chitosan-coated microemulsion, ex vivo permeation, microdialysis, pharmacokinetics

5000kM high-speed railway with 350km/h speed will be constructed in China in the next five years. Traction substations convert the high voltage electricity from the public power system to 25kV single phase electricity, which are implemented to support the high-speed locomotives through the catenary system. These substations and the catenary system form the Traction Power Supply System (TPSS). Researches show that the reliability of TPSS is mainly dependent upon the catenary system [2] which is essentially a multi-component mechanical system. Three types of maintenance actions have been categorized: (1a)-maintenance (mechanical service), (1b)-maintenance (repair) and (2p)-maintenance (replacement).

5000kM high-speed railways with speed of 350km/h are being constructed in China in the next five years. A high-speed railway has many traction power substations (TPS) which convert the high voltage electricity of the public bulk power system to 25kV single phase electricity and supply it to the high-speed locomotives through the catenary system. These substations and the catenary system form the traction power supply system (TPSS) of the high-speed railway and its Reliability, Availability, Maintenance and Safety (RAMS) evaluation become a critical issue in China now. A novel reliability evaluation approach using Monte Carlo simulation is discussed in this paper. This analysis approach is proposed for a bulk power system for the traction power supply system of a high-speed railway. The traction substations of a railway are taken as composite loads of the bulk power system. Different from the traditional generation and transmission reliability evaluation, these loads are not independent. The traction substations are designed to have section-crossing power supplying ability. When one substation is down the adjacent two substations can extend their power supplying sections to the blackout part and the railway can still operate as normal. Four reliability indices for the individual TPSs and five indices for the entire railway considering the section-crossing ability of the substations have been proposed. The analytical expressions of these reliability indices and their sensitivities with respect to power system component reliability parameters have been deduced. In order to calculate the practical shedding loads of each TPS, a heuristic load shedding strategy has also been suggested which simulates the actions of the grid operators. When the reliability of TPSS is evaluated at the first time, the Monte Carlo simulation approach is used. This procedure is somewhat time-consuming. After that, the analytical expressions of the reliability indices have been determined. When the reliability performance of the power system changes all these reliability indices can be calculated directly through the analytical expressions without simulation so the evaluation is sped up. RBTS benchmark model[17] and IEEE RTS79[18] have been used and the results show that the proposed approach is correct and effective.