Hejian Guo

Preparation of new 5-fluorouracil-loaded zein nanoparticles for liver targeting

This study proposes a new zein nanoparticle (ZP) encapsulated 5-fluorouracil (5-FU) that target liver through intravenous delivery. The ZPs were prepared by phase separation process and optimized using uniform experimental design. The physical properties, in vitro drug release and stability of optimal drug-loaded ZPs were studied. The biodistribution and the target efficiency of the particles were investigated in a mouse model. The highest drug loading was obtained using zein: 5-FU, 3:1 (v/v); zein concentration, 12.5mg/ml, pH 9.18, mixing time, 3h and ethanol concentration, 40%. The encapsulation efficiency and the drug loading were 60.7 ± 1.74 and 9.17 ± 0.11 respectively. The size of ZPs and zeta potential were 114.9 ± 59.4 nm and -45 ± 0.3 mV respectively. Differential scanning calorimetry (DSC) demonstrated that the drug was encapsulated within the ZPs. A sustained release profile of 5-FU was observed from ZPs. The more stable storage condition of ZPs was at a temperature of 4 °C. In vivo, ZPs was mostly accumulated in liver following intravenous injection, and the targeting efficiency increased 31.33%. The relative uptake rate of liver was 2.79. Also, nano-sized ZPs were beneficial for prolonged blood residence (7.2-fold increase). These demonstrated that the drug-loaded ZPs could be efficiently targeted at the liver by intravenous delivery.

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.

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.

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.

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.

Bexarotene nanocrystal-Oral and parenteral formulation development, characterization and pharmacokinetic evaluation.

Bexarotene (Targretin®) is a synthetic retinoid that selectively activates the retinoid X receptor subfamily of retinoid receptors and exhibits potent anti-tumor activity. However, the poor solubility and bioavailability limit its application. The main aim of this study is to investigate the potential of oral and parenteral nanocrystals in enhancing the bioavailability of bexarotene. In this work, the orthogonal design was used to screen the optimum stabilizers and precipitation-combined microfluidization method was employed to obtain the optimal nanocrystals. According to DSC, X-ray diffraction analysis and Raman examination, the nanocrystals were still in crystalline state after the preparation procedure. By reducing the particle size, the in vitro dissolution rate of bexarotene was increased significantly. The in vivo test was carried out in rats and pharmacokinetic parameters of the bexarotene solution and bexarotene nanocrystals were compared after gavage and intravenous administration. The higher AUC and lower Cmax indicated that oral bexarotene nanocrystals significantly increased the bioavailability of bexarotene and decreased its side effects. Compared to the oral nanocrystals, the intravenous nanocrystals cut losses and increased bioavailability because of the absence of first pass effect and enterohepatic circulation.

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.

A novel zein-based dry coating tablet design for zero-order release

The purpose of this study was to design zero-order release of dry-coated tablets using pure zein powder, zein granule and zein blend containing two common pharmaceutical excipients such as microcrystalline cellulose (MCC) or starch in different proportions as coating material. The 5-fluorouracil (5-FU) was used as a model drug. The physical characterization and drug release behaviors of dry-coated tablets were investigated. The surface structure of the tablets was examined by a scanning electron microscopy. The correlation coefficient (R) was used as indicator of the best fitting of the zero-order model for drug release. It was found that zein formed a gelatinous layer fast and its network prevented disintegration of the tablet during dissolution process. Zein-based dry coating tablets had good physical properties such as compactibility and friability. All formulations fit the zero-order model well. The mechanism for zero-order release of these dry-coated tablets was solvent penetration into the dosage form and dissolving the drug, the dissolving core formed an apex in the center of the tablets and the drug diffused out. The apex of zein-coated tablets worked as orifice of an osmotic system and released the drug in zero-order profile.