Caiyun Li

Self-assembled nanoparticles based on galactosylated O-carboxymethyl chitosan-graft-stearic acid conjugates for delivery of doxorubicin.

A novel polymer, i.e. galactosylated O-carboxymethyl chitosan-graft-stearic acid (Gal-OCMC-g-SA) was synthesized for liver targeting delivery of doxorubicin. The chemical structure was characterized by FT-IR, (1)H NMR and elemental analysis. Gal-OCMC-g-SA could self-assemble into nanoparticles with diameter of 160 nm by probe sonication in aqueous medium and exhibited a low critical aggregation concentration of 0.047 mg/mL. The DOX-loaded Gal-OCMC-g-SA (Gal-OCMC-g-SA/DOX) self-assembled nanoparticles were almost spherical in shape with an average diameter of less than 200 nm and zeta potential of around -10 mV. In vitro release revealed that the Gal-OCMC-g-SA/DOX nanoparticles exhibited a sustained and pH-dependent drug release manner. Furthermore, the hemolysis test demonstrated the good safety of Gal-OCMC-g-SA in blood-contacting applications. These results indicated that Gal-OCMC-g-SA/DOX nanoparticles were highly potential to be applied in cancer therapy.

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.

Studies on the preparation, characterization and pharmacokinetics of Amoitone B nanocrystals

Amoitone B, as a new derivative of cytosporone B, has been proved to be a natural agonist for Nur77. It exhibits remarkable anticancer activity in vivo and has the potential to be a therapeutic agent for cancer treatment. However, the poor solubility and dissolution rate result in low therapeutic index for injection and low bioavailability for oral administration, therefore limiting its application. In order to magnify the clinical use of Amoitone B, nanocrystal was selected as an application technology to solve the above problems. In this study, the optimized Amoitone B nanocrystals with small and uniform particle size were successfully prepared by microfluidization method and investigated by morphology, size distribution, and zeta potential. The differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed there was no crystalline state changed in the size reduction process. For Amoitone B nanocrystals, an accelerated dissolution velocity and increased saturation solubility were achieved in vitro and a markedly different pharmacokinetic property in vivo was exhibited with retarded clearance and magnified AUC compared with Amoitone B solution. These results implied that developing Amoitone B as nanocrystals is a promising choice for intravenous delivery and further application for cancer therapy.

Galactosylated chitosan nanoparticles for hepatocyte-targeted delivery of oridonin.

In this study, oridonin-loaded nanoparticles coated with galactosylated chitosan (ORI-GC-NP) were prepared for tumor targeting and their characteristics were evaluated for the morphologies, particle size and zeta potential. Oridonin-loaded nanoparticles (ORI-NP) without galactosylated chitosan were prepared as a control. The entrapment efficiency of ORI-GC-NP and ORI-NP were 72.15% and 85.31%, respectively. The in vitro drug release behavior from nanoparticles displayed biphasic drug release pattern with initial burst release and consequently sustained release. Next, the pharmacokinetics and tissue distribution of ORI-GC-NP, ORI-NP and ORI solution were carried out. Pharmacokinetic analysis showed that ORI-GC-NP and ORI-NP could prolong the drug plasma levels compared with ORI solution. Meanwhile, the distribution of ORI-GC-NP to liver was higher than that of ORI-NP and free drug. In conclusion, ORI-GC-NP, as a promising intravenous drug delivery system for ORI, could be developed as an alternative to the conventional ORI preparations.

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.

Preparation, characterization and pharmacokinetics of Amoitone B-loaded long circulating nanostructured lipid carriers.

Amoitone B, chemically synthesized as the derivative of Cytosporone B, is a powerful agonist for Nur77 receptor. It has outstanding anticancer activity in vivo. However, the water-insolubility and short biological half-life lead to poor bioavailability, which limits its application. The aim of this study was to develop polyethylene glycol-coated Amoitone B-loaded nanostructured lipid carriers (AmB-PEG-NLC) for parenteral delivery of Amoitone B to prolong drug circulation time in body and enhance the bioavailability. AmB-PEG-NLC were prepared by emulsion-evaporation and low temperature-solidification method, while Amoitone B-loaded NLC (AmB-NLC) were also prepared as control. The characteristics of AmB-PEG-NLC and AmB-NLC such as particle size, zeta potential, entrapment efficiency and drug loading were investigated in detail. The mean particle size was about 200 nm and the zeta potential value was about -15 mV. The X-ray diffraction analysis demonstrated that Amoitone B was not in crystalline state in NLC (AmB-PEG-NLC and AmB-NLC). Drug release pattern with burst release initially and prolonged release afterwards was obtained in vitro for AmB-PEG-NLC. Furthermore, AmB-PEG-NLC exhibited prolonged MRT (mean residence time) and higher AUC (area under drug concentration-time curve) compared with AmB-NLC as well as Amoitone B solution. These results indicated that AmB-PEG-NLC could be a promising delivery system for Amoitone B to prolong the circulation time in body and thus improve its bioavailability.

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.

In Vitro and In Vivo Study of Gal-OS Self-Assembled Nanoparticles for Liver-Targeting Delivery of Doxorubicin

A liver-targeting drug delivery system for doxorubicin (DOX), that is, DOX-loaded self-assembled nanoparticles based on galactosylated O-carboxymethyl chitosan-graft-stearic acid conjugates (Gal-OS/DOX), has been prepared. The objective of the present study was to investigate the preparation, in vitro release, in vivo pharmacokinetics, and tissue distribution of Gal-OS/DOX nanoparticles. The drug-loaded nanoparticles were spherical in shape with mean size of 181.9 nm. In vitro release profiles indicated that the release of DOX from Gal-OS/DOX nanoparticles behaved with a sustained and pH-dependent drug release. Pharmacokinetics study revealed Gal-OS/DOX nanoparticles exhibited a higher AUC value and a prolonged residence time of drug in the blood circulation than those of DOX solution. Furthermore, Gal-OS/DOX nanoparticles increased the uptake of DOX in liver and spleen, but decreased uptake in heart, lung, and kidney in the tissue distribution study. These results suggested that the Gal-OS/DOX nanoparticles could prolong blood circulation time, enhance the liver accumulation, and reduce the side effect especially the cardiotoxicity of DOX. In conclusion, Gal-OS/DOX nanoparticles could be a promising drug delivery system for liver cancer therapy.

Design and characterization of Amoitone B-loaded nanostructured lipid carriers for controlled drug release.

Abstract Amoitone B, a novel compound chemically synthesized as the analogue of cytosporone B, has been proved to own superior affinity with Nur77 than its parent compound and exhibit notable anticancer activity. However, its application is seriously restricted due to the water-insolubility and short biological half-time. The aim of this study was to construct an effective delivery system for Amoitone B to realize sustained release, thus prolong drug circulation time in body and improve the bioavailability. Nanostructured lipid carriers (NLC) act as a new type of colloidal drug delivery system, which offer the advantages of improved drug loading and sustained release. Amoitone B-loaded NLC (AmB-NLC) containing glyceryl monostearate (GMS) and various amounts of medium chain triglycerides (MCT) were successfully prepared by emulsion-evaporation and low temperature-solidification technology with a particle size of about 200 nm and a zeta potential value of about −20 mV. The results of X-ray diffraction and DSC analysis showed amorphous crystalline state of Amoitone B in NLC. Furthermore, the drug entrapment efficacy (EE) was improved compared with solid lipid nanoparticles (SLN). The EE range was from 71.1% to 84.7%, enhanced with the increase of liquid lipid. In vitro drug release studies revealed biphasic drug release patterns with burst release initially and prolonged release afterwards and the release was accelerated with augment of liquid lipid. These results demonstrated that AmB-NLC could be a promising delivery system to control drug release and improve loading capacity, thus prolong drug action time in body and enhance the bioavailability.

Research on the in vitro anticancer activity and in vivo tissue distribution of Amoitone B nanocrystals

Amoitone B, a natural agonist to Nur77, is a promising anticancer drug. However, its application is seriously restricted due to the water-insolubility and short biological half-life. Amoitone B nanocrystals (AmB-NC) were formulated by microfluidization method to overcome the above obstacles. This study aims to evaluate the cytotoxicity and tissue distribution of AmB-NC. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay revealed the improved in vitro antitumor activity of AmB-NC against stomach, colon, liver and lung cancer cells compared with Amoitone B solution. Meanwhile, observation of morphological changes, cell cycle and apoptosis examination using flow cytometry exhibited that AmB-NC could induce G1 cycle arrest and markedly enhance the apoptosis of human gastric cancer BGC-823 cell line. Tissue distribution study demonstrated that AmB-NC had a higher distribution in liver and lung, which was helpful for relevant cancer treatment. In conclusion, AmB-NC could be a potential delivery system for treatment of human cancer.