Xiaona Tian

Galactose-decorated pH-responsive nanogels for hepatoma-targeted delivery of oridonin.

Nanogels based on the polymers of galactosylated chitosan-graft-poly (N-isopropylacrylamide) (Gal-CS-g-PNIPAm) were used as carriers of oridonin (ORI) for tumor targeting. Three ORI-loaded nanogels with various degrees of galactose substitution were prepared, and their characteristics were evaluated. The release behavior of ORI from these nanogels was pH-dependent, and the release could be accelerated under mildly acidic conditions. The cytotoxicity of ORI-loaded nanogels was pH-sensitive. ORI-loaded nanogels exhibited a higher antitumor activity than drug-loaded nanogels without galactosylation, and the anticancer activity increased in relation to increases in the number of galactose moieties of the nanogels in HepG2 cells. In contrast, the cytotoxicity of ORI-loaded nanogels against MCF-7 cells decreased compared with that of drug-loaded nanogels without galactosylation. Results demonstrated that these nanogels could enhance the uptake of ORI into HepG2 cells via asialoglycoprotein receptor-mediated endocytosis. These galactose-decorated pH-responsive nanogels were well-suited for targeted drug delivery to liver cancer cells.

In vitro and in vivo evaluation of paclitaxel-loaded mesoporous silica nanoparticles with three pore sizes

In the present study, mesoporous silica nanoparticles (MSNs) with three pore size were manufactured by the etch method. A typical chemotherapeutic agent, paclitaxel (PTX) was loaded into these MSNs. The in vitro drug release behavior, the in vitro anti-tumor activity, the morphological apoptosis cell changes, cell apoptosis rate and pharmacokinetics were extensively evaluated to clarify the biomedical roles of these MSNs in the application of drug delivery. The results showed that paclitaxel-loaded MSNs not only demonstrated effective drug loading but also exhibited pore-size-dependent drug release performance in vitro. In addition, MSNs exhibited pore-size-dependent anti-tumor activity against breast cancer MCF-7 cells. The apoptosis mechanism study demonstrated that the percentage of early and late apoptosis of all PTX-loaded MSNs treated MCF-7 cells were significantly higher than that of free PTX, and additionally the percentage of apoptosis for PTX-loaded MSNs increased as the pore size of carriers enlarged. The pharmacokinetics results showed that PTX-loaded MSNs with the largest pore size exhibited the pharmacokinetic property similar to the PTX solution and the other drug loaded MSNs displayed sustained release behavior. These results demonstrate that MSNs could be a very promising drug delivery system for pore-size controllable drug release and enhancing the anti-tumor activity.

Redox-responsive catiomer based on PEG-ss-chitosan oligosaccharide-ss-polyethylenimine copolymer for effective gene delivery

The chitosan oligosaccharide-based disulfide-containing polyethylenimine derivative PEG-ss-COS-ss-PEI was synthesized and evaluated as a nonviral gene delivery carrier. The structure of the obtained polymers was confirmed by 1H NMR and FTIR. PEG-ss-COS-ss-PEI copolymers could effectively condense DNA into small particles with average diameters less than 120 nm and the zeta potential of +15.7 mV at the N/P ratio of 15/1. Additionally, the resultant polyplexes showed excellent colloidal stability against 150 mM NaCl and had a better buffering capacity of ∼44%, which was more than double the buffering capacity of PEI1.8k (∼20%). In the presence of 10 mM glutathione (GSH), however, polyplexes of PEG-ss-COS-ss-PEI were rapidly unpacked, as revealed by significant increase of particle sizes to over 800 nm. In vitro experiments revealed that the PEG-ss-COS-ss-PEI copolymers not only had much lower cytotoxicity, but also displayed high transfection efficiency as compared to the control branch 25 kDa PEI. This study indicates that a reducibly degradable copolymer PEG-ss-COS-ss-PEI composed of low molecular weight PEI, chitosan oligosaccharide and PEG via disulfide-containing linkages can be a promising gene delivery carrier.

Preparation and characterization of galactosylated bovine serum albumin nanoparticles for liver-targeted delivery of oridonin

In this study, galactosylated bovine serum albumin (GB), which could be developed for a liver targeting carrier was synthetized and it was identified by Fourier transform infrared (FT-IR) spectrometer. Oridonin loaded bovine serum albumin nanoparticle (ORI-BSA-NP) and oridonin loaded GB nanoparticle (ORI-GB-NP) were prepared and optimized by the desolvation technique. During the preparation of ORI-GB-NP, galactosamine was introduced to end-cap the free aldehyde groups on nanoparticles. The characteristics of ORI-GB-NP such as particle size, zeta potential, particle morphologie, entrapment efficiency and drug loading were evaluated. The nearly spherical nanoparticles, with a narrow size distribution below 200 nm, were negatively charged with zeta potential of about -30 mV. Meanwhile, differential scanning calorimetry (DSC) and X-ray diffraction confirmed the amorphous state of ORI in ORI-GB-NP. The in vitro drug release of ORI from ORI-GB-NP presented a biphasic pattern with an initial burst effect and consequently sustained release. These results implied that the nanoparticles possessed fine physicochemical characteristics and seemed to be a stable delivery system for poorly soluble oridonin.

Successfully tailoring the pore size of mesoporous silica nanoparticles: Exploitation of delivery systems for poorly water-soluble drugs

A novel approach was applied to fabricate mesoporous silica nanoparticles (MSNs) with different pore size in this study. The pore size of MSNs can be modulated conveniently from 3 nm to 10nm by controlling the etching time of MSNs with the NaBH(4) solution. The as-synthesized MSNs were investigated as carriers for loading and delivery of the model drug paclitaxel (PTX). The characteristics, drug loading capacity, in vitro drug release behavior, anti-tumor activity and the mechanism of cell uptake were systematically studies. The resultant MSNs showed uniform and mono-dispersed sphere with high drug loading capacity (12-21%). The in vitro drug release exhibited that the released rate of PTX from MSNs could be controlled by the pore size and the larger the pore size, the faster the release rate of PTX. The in vitro anti-tumor studies demonstrated that PTX-loaded MSNs produced higher cytotoxicity than free PTX. Besides, the PTX-loaded MSNs with largest pore size showed the highest anti-tumor activity. These results indicated that these MSNs could provide a promising platform for delivering water-insoluble drugs, controlling the release rate of drugs and increasing the anti-tumor activity.

In vitro and in vivo evaluation of oridonin-loaded long circulating nanostructured lipid carriers

The purpose of this study was to develop poly(ethylene glycol)-coated nanostructured lipid carriers (PEG-NLC) for parenteral delivery of oridonin (ORI) to prolong drug circulation time in blood. Oridonin-loaded PEG-NLC (ORI-PEG-NLC) consisting of PEG(2000)-stearate, glycerol monostearate and medium chain triglycerides were prepared by emulsion-evaporation and low temperature-solidification technique. Oridonin-loaded NLC (ORI-NLC) were also prepared as control. ORI-PEG-NLC were observed by transmission election microscope and the morphology was in rotiform shape. The mean particle size of ORI-PEG-NLC was 329.2 nm and entrapment efficacy was 71.18%. The results of differential scanning calorimetry and X-ray diffraction revealed a low-crystalline structure of ORI and verified the incorporation of ORI into the nanoparticles. In vitro drug release of ORI-PEG-NLC exhibited biphasic drug release patterns with burst release initially and prolonged release afterwards. Pharmacokinetic analysis showed that the mean residence time of ORI-PEG-NLC was prolonged and AUC (area under tissue concentration-time curve) value was also improved compared with ORI-NLC and ORI solution. In conclusion, ORI-PEG-NLC could be a potential carrier to get prolonged retention time of oridonin in blood.

Multifunctional mesoporous silica nanoparticles mediated co-delivery of paclitaxel and tetrandrine for overcoming multidrug resistance

The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR.

In vitro and in vivo evaluation of riccardin D nanosuspensions with different particle size.

Riccardin D (RD) is a novel compound extracted from Chinese liverwort Marchantia polymorpha L. It exhibits various anticancer activities and can be used during lung cancer treatment. However, the compounds low solubility hinders its development. Recently nanosuspension has been developed as one of the most promising formulations for poorly water-soluble drugs. In order to understand the dissolution behavior of riccardin D in vitro and in vivo, two nanosuspensions of riccardin D with markedly different sizes were prepared. The particle size of nanosuspension A prepared by bottom-up method was 184.1±3.15 nm, while that of nanosuspension B prepared by top-down method was 815.4±9.65 nm. The main purpose of this study was to investigate the effects of particle size on pharmacokinetics and tissue distribution after intravenous administration. Riccardin D dissolving in organic solution was studied as control group. In pharmacokinetics study in Wistar rats, nanosuspension A showed properties similar to the control group, while nanosuspension B exhibited rather different properties. In tissue distribution research on Kunming strain mice, nanosuspension A had a multi-peak phenomenon because of reticulate endothelial system (RES) while nanosuspension B showed a high uptake in RES organs that passively target to the lungs. In conclusion, particle size of riccardin D nanosuspensions had obvious effects on pharmacokinetics and tissue distribution.

Synthesis, characterization, in vitro and in vivo evaluation of PEGylated oridonin conjugates

Oridonin (ORI), a diterpenoid compound with promising antitumor activity, was proved to possess potent antileukemia efficacies in vitro and in vivo recently. However, the development and application of ORI was limited by its poor solubility and rapid plasma clearance. The purpose of this study was to solve these problems. PEGylated oridonin linked with succinic acid (SA) as spacer moiety (PEG-SA-ORI conjugate) was synthesized. mPEG amines with four specifications of molecular weight (MW) were utilized. All polymeric conjugates showed satisfactory aqueous solubility and in vitro studies implied that the drug solubility and release features of conjugates were relevant to PEGs. The drug solubility increased more when the MW of PEG was lower, while more significant sustained-release effect was shown with higher PEG MW. Moreover, the release behaviors of conjugates showed a pH-sensitive property. In vivo pharmacokinetic studies demonstrated that the elimination half-life was prolonged in comparison with ORI solution. PEGylation could be a promising method to obtain better efficacy in the field of drug delivery system.

Nanosuspension for parenteral delivery of a p-terphenyl derivative: preparation, characteristics and pharmacokinetic studies.

Recently, nanosuspension technology has evolved into a mature drug delivery system, which can enhance the saturation solubility and dissolution velocity of poorly soluble drugs. In this study, nanosuspensions of a p-terphenyl derivative (H2) were prepared by combining microfluidization and precipitation method and transformed into dry powder by lyophilization. The resultant nanosuspensions had a mean particle size of 201.7±5.87nm and a zeta potential of -21.07±0.57mV. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis verified that the crystalline state of H2 was not transformed when it was prepared to nanosuspensions. An increased saturation solubility (1.46ug/ml) and accelerated dissolution velocity were achieved. The percent drug release of bulk H2 and H2 nanosuspension dried powder was 7.16% and 93.5% at 120min point, respectively. The pharmacokinetic test in rats indicated that the area under plasma concentration-time curve (AUC0~∞) value of H2 nanosuspension (5.183mg/Lh) was about 5-fold higher than that of H2 solution (1.094mg/Lh). Additionally, the mean retention time (MRT) value of H2 nanosuspension (2.832h) was significantly longer than that of H2 solution (0.997h).