Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.

The dose-effect relationship of folic acid on human umbilical vein endothelial cells in vitro / 天津医药

Objective To investigate the protective effects of folic acid on the oxidative damage that ox-LDL (oxi?dized low-density lipoprotein receptor 1) render to human umbilical vein endothelial cells (HUVEC). Methods HUVECs were injured by ox-LDL (120 mg/L) for 24 h while they were incubated with various concentration of folic acid (0,15, 60, 150, 225, 300, 375 nmol/L). Then HUVECs were cultured in media contains same concentration of folic acid but without ox-LDL for 72 hours. Finally, HUVECs were harvested after 24, 48, 72 and 96 h. The morphological changes were observed us?ing inverted microscope and cell viability were examined by MTT. Results Various concentrations of folic acid (0,15, 50, 100, 200 and 500 nmol/L) has no obvious promotion or inhibition effect in growth of normal HUVEC (P>0.05). However, compared with the ox-FA-def group, 150, 225, 300 and 375 nmol/L of folic acid promoted proliferation of HUVECs with 96 and 120 hours of incubations (P < 0.05). Folic acid of 60, 150, 225, 300 and 375 nmol/L promoted the proliferation of HUVECs with 72 h and 96 hours of incubation (P<0.05). Conclusion High dose folic acid can reduce the ox-LDL oxida?tive damage on HUVEC in a concentration dependent manner.

The influence of the structure and the composition of water/AOT-Tween 85/IPM microemulsion system on transdermal delivery of 5-fluorouracil.

The purpose of this study was to investigate the influence of the structure and the composition of water/Aerosol-OT (AOT)-Tween 85/isopropylmyristate (IPM) microemulsion system (WATI) on transdermal delivery of 5-fluorouracil (5-FU). The structure of WATI was characterized by measuring surface tension, density, viscosity, electric conductivity, and differential scanning calorimetry. The effect of the drug loading, water content, component compositions and the amount of mixed surfactant on permeation of 5-FU through mice skin was evaluated by using Franz-type diffusion cells. The results in vitro implied that WATI was W/O microemulsion when the water content was below 20 wt% at fixed 20 wt% of mixed surfactant at 25°C, then might be transformed to a bicontinuous structure, finally, formed O/W microemulsion with water content over 30 wt%. Increase of the drug loading can directly facilitate the penetration of the drug across the skin. Drug diffusion after 12 h from the bicontinuous microemulsion (795.1 ± 22.3 µg·cm(-2)) would be fastest compared to that from the W/O microemulsion (650.2 ± 11.7 µg·cm(-2)) and the O/W microemulsion (676.6 ± 14.8 µg·cm(-2)). The combination of AOT and IPM could bring about synergistic effect on the skin enhancement, however, Tween 85 in WATI decreased the cumulative permeation amount of 5-FU. The content of mixed surfactant had no effect on the permeation of 5-FU at fixed surfactant/cosurfactant ratio (K(m) = 2). Thus, the increased transdermal delivery the hydrophilic drug of 5-FU was found to be concerned with both of the structure and the composition of WATI.

Preparation and pharmacokinetics in beagle dogs of once-a-day tetramethylpyrazine phosphate sustained-release pellets.

In this study, once-a-day tetramethylpyrazine phosphate (TMPP) sustained-release pellets were successfully prepared. The pellets cores were carried out in extrusion-spheronization machine and then coated in fluidized-bed. To optimize cumulative release profile, two different coating systems with the same the TMPP pellets cores were employed. The first coating system consisted of surlease, containing HPMC E5 (0.1% w/w), i.e., P1. The second coating system only consisted of surlease, i.e., P2. The two kinds of coating systems were both given coating levels in terms of weight gain of 10%. The resulted once-a-day TMPP sustained-release pellets (OTSP), the mixture of P1 and P2 with the weight proportion of 1:1, were filled in a capsule (150 mg TMPP/capsule). The relative bioavailability of OTSP was studied in six beagle dogs after oral administration using a commercial TMPP tablets as a reference. The C(max) and T(max) for OTSP and TMPP tablets were 213.06 ng/mL, 2.50 h and 3402.13 ng/mL, 0.33 h, respectively and the relative bioavailability of P3 was 97.18% compared with TMPP tablets. Based on the results, it was indicated that TMPP sustained-release pellets and TMPP conventional tablets were bioequivalent.

Preparation of multivariant-phospholipid complex of Ginkgo biloba extract / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare Ginkgo biloba extract multivariant-phospholipid complex(MGBP) and improve the vitro dissolution of ginkgo total flavonoids by adding another water-soluble carrier in phospholipid complex.</p><p><b>METHOD</b>MGBP was prepared using solvent evaporation method with Poloxamer-188 as the carrier and the multivariant complex was analyzed by DSC and X-diffraction technique. The physicochemical properties of the MGBP we also studied, including apparent oil-water distribution coefficients in different pH aqueous solution and its release in vitro.</p><p><b>RESULT</b>The in vitro dissolution of ginkgo total flavonoids was significantly increased while the apparent oil-water distribution coefficient was improved after been made into multivariant-phospholipid complex.</p><p><b>CONCLUSION</b>The preparation technology of MGBP is simple and economic. MGBP can significantly increase the vitro dissolution of ginkgo total flavonoids and improve oil-water distribution coefficients, which can be the reference for the bioavailability in vivo in the further researches.</p>

Microemulsion-based gel of fluorouracil for transdermal delivery / 药学学报

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.

Combined system of sinomenine hydrochloride sustained-release pellets / 中国药科大学学报

Aim: To establish a linear additive model for the predication of in vitro sinomenine hydrochloride release from the combination of immediate release, enteric-coated and sustained-release pellets based on the release profiles of each pellet type. Methods: Immediate release pellets were manufactured by extrusion/spher-onization technology. The operation of bottom-spraying in the fluid-bed equipment was conducted to enteric-coating using Eudragit~(R) L-30D-55 and sustained-release coating using Surelease~(R) . In vitro sinomenine hydrochloride release profiles of both uncoated and coated pellets were fitted to the chosen mathematical equations offered by the curve fitting toolbox of Matlab~(R) before a linear additive model was created based upon the best-to-fitting equations. The proportion of each pellet type in the combined format to generate the desired 24 h sinomenine hydrochloride release profile was solved by Matlab~(R). The predicted and assayed sinomenine hydrochloride release from the polled pellets was compared. Results: It was shown that the actual sinomenine hydrochloride release profiles of each pellet type were approximate to those of predicted ones. A linear additive model of the appropriate mathematical equations of each pellet was proven to be capable of controlling in vitro release of sinomenine hydrochloride multiple-unit pellets. Conclusion: A multiple-unit combined system of the selected pellets, as a novel sustained-release system, was successfully prepared. In vitro release performance of the calculated combination of each pellet type could be guaranteed by this approach in designing sustained-release drug delivery system.

The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats.

The aim of the present study was to find a way of prepare silybin-phospholipid complex to make oral bioavailability of silybin increase and to study its physicochemical properties and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine in rats. Using ethanol as a reaction medium, silybin and phospholipids were resolved into the medium, after the organic solvent was removed under vacuum condition, silybin-phospholipid complex was formed. The new complex's physicochemical properties including scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), solubility, dissolution, etc., were tested. The concentrations of silybin after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine at different time in rats were determined by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. Our data showed that silybin and phospholipids in the silybin-phospholipid complex were combined by non-covalent-bond, not forming a new compound and the solubility of silybin-phospholipid complex in water and in n-octanol was effectively enhanced. We found that mean plasma concentration-time curve of silybin after oral administration of silybin-phospholipid complex and silybin-N-methylglucamine in rats was both in accordance with open single-compartment model with first-order absorption. Pharmacokinetic parameters of silybin in rats were Tmax 10 and 5 min; Cmax 126.72 and 104.29 ng ml(-1); AUC(0-infinity) 1020.33 and 235.81 ng ml(-1)h, respectively. The bioavailability of silybin in rats was increased remarkably after oral administration of silybin-phospholipid complex comparing to silybin-N-methylglucamine. This was mainly due to an impressive improvement of the lipophilic property of silybin-phospholipid complex and improvement of the biological effect of silybin.

Pharmacokinetics of oleanolic acid liposomes in rats / 中成药

AIM: To study the pharmacokinetics of oleanolic acid liposomes in rats.METHODS: Oleanolic acid liposomes were prepared by ethanol injection-sonication;The pharmaceutical properties including morphology,encapsulation efficiency,particle size,zeta potential were determined.Rats were injected with oleanolic acid lipo-somes and oleanolic acid solution via the tail,respectively.The plasma concentrations of sample in rats were assayed by RP-HPLC.The pharmacokinetic parameters were computered by 3P97 program package.RESULTS: Oleanolic acid liposomes showed almost spherical,the mean diametre was(206.4 ? 4.7) nm.The encapsulation efficiency of oleanolic acid liposomes could be more than 90% based on orthogonal design,and no haemolyticus existed.The plasma concentration-time curves of the oleanolic acid liposomes conformed to a two-compartment model.T1/2? of oleanolic acid liposomes was(33.59 ? 12.53) min,AUC was(240.13 ? 23.62)(?g/mL.min),obviously higher than that of the control preparation.CONCLUSION: The oleanolic acid liposomes with high entrapment efficiency and even size has a good pharmacokinetic parameters by comparison with non-liposomes.

Establishment and evaluation of liver fibrosis model induced by bile duct ligation in mouse / 重庆医科大学学报

Objective:To establish and evaluate liver fibrosis model induced by bile duct ligation in mouse.Methods:The bile ducts of the mice were occluded by ligation.Serum AST,ALT,ALP,TBIL and DBIL were determined;the morphological observation was done by HE staining and Sirius red staining,expressions of ?-SMA and CK-19 were analyzed by immunohistochemistry staining;mRNA expression of ?-SMA and Collagen-1 in liver tissues were assayed by real-time PCR.A sham-operation group was used as a control.Results:Chocolate brown cells with positive expression of CK-19 and ?-SMA significantly proliferated 2 weeks after bile duct ligation.Serum AST,ALT,ALP,TBIL and DBIL levels of model group were much higher than those of control group;mRNA expression of ?-SMA and Collagen-1 in liver tissue by real-time PCR were increased significantly in model group.Conclusion:The mouse liver fibrosis model can be established successfully by bile duct ligation.