Lisi Qi

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.

Folate-modified bexarotene-loaded bovine serum albumin nanoparticles as a promising tumor-targeting delivery system

Bexarotene (BEX), a high-affinity agonist for retinoid X receptors (RXRs), shows apparent biological activities and distinct inhibitive efficacy in both cancer therapy and prevention. This study exploited a folate-decorated delivery of bexarotene-loaded bovine serum albumin nanoparticles, which could solubilize the poorly water-soluble drug and overcome the nonspecific targeting disadvantage. Bexarotene-loaded bovine serum albumin nanoparticles (BEX-BSANPs) were optimized by a desolvation technique, subsequently conjugated with folate by carbodiimide reaction. The resultant folate-modified bexarotene-loaded bovine serum albumin nanoparticles (FA-BEX-BSANPs) showed a spherical shape, with a diameter of 195.3 ± 5.6 nm, a zeta potential of -33.64 ± 1.97 mV, and 71.28 ± 1.93 μg folate was coupled per mg BSA. Differential scanning calorimetry and X-ray diffraction analysis confirmed the amorphous state of bexarotene in the folate-conjugates. The in vitro drug release of bexarotene presented a controlled and sustained release pattern. The in vitro cytotoxicity, cell apoptosis and cellular uptake experiments of the nanoparticles were performed by MTT assay, propidium iodide staining, fluorescence microscopy and flow cytometric analysis on A549 and MCF-7 cancer cells. Both the BEX-BSANPs and FA-BEX-BSANPs induced an enhanced cancer cell apoptotic effect in contrast to BEX solution. The cells showed an excellent binding for folate-modified nanoparticles. Especially, the interference effect on the cellular internalization process by an excess folic acid was relatively dramatic for the FR-positive MCF-7 cells in comparison to the modest change seen in the FR-negative A549 cell lines, indicating that the uptake was mediated by the folate receptors. Together these data suggested that the folate-modified bexarotene-loaded delivery system, which demonstrated better biocompatibility and potential superiority, could be an appropriate cancer therapy in targeting tumors in the future.

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.

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.

Preparation, properties and in vivo pharmacokinetic study of drug vesicles composed of diphenhydramine and AOT

In this work we designed a controlled-release drug delivery system formed by a cationic drug (diphenhydramine hydrochloride, DH) and an anionic surfactant (sodium 2-ethylhexyl sulfosuccinate, AOT) and investigated the corresponding physicochemical properties, aggregation behavior and potential application in drug delivery systems. The DH–AOT mixed solutions with different molar ratios of DH and AOT at the same total concentration were prepared and characterized. The aggregation behaviors of the drug/surfactant solutions were studied by transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential techniques. Furthermore, hemolysis testing, and in vitro and in vivo drug release were studied to evaluate the potential use of the as-prepared catanionic aggregates in drug delivery systems. The results indicate that the physicochemical properties, the hemolytic toxicity and the drug release behavior are dependent on the composition of the samples, X1 (X1 = nDH/n(DH+AOT)). The results demonstrated that these drug-participating catanionic aggregates show potential as an efficient and safe sustained drug delivery system.

Preventive and Therapeutic Effects of the Retinoid X Receptor Agonist Bexarotene on Tumors

We present a review of recent investigations of anticancer drug bexarotene in this article. As one of the novel synthetic analogs of retinoids, bexarotene selectively binds to and activates the retinoid X receptor (RXRs) subfamilies, exerting a prophylactic and therapeutic effect on a large series of tumors in vitro and in vivo covering cutaneous lesions, lung and breast cancers, nervous system diseases etc. Bexarotene has been proved to have a specifically favorable therapeutic profile in clinical dermatology or oncology with mild or absent retinoids side effects, especially in combination with other therapies. It is noteworthy that numerous previous outstanding researches have contributed to the chemical, biological, preclinical and clinical examinations of bexarotene during the past decades, with a relatively deficient progress of bexarotene in the field of pharmacy. In this review, the positive therapeutic results of bexarotene used as a monotherapy or combination therapy both in preclinical and clinical studies are reported based on relevant medical data; the distinct acting mechanisms of bexarotene are described; the potential studies and prospects of bexarotene in pharmaceutical domain are discussed. All the reports above collectively present bexarotene as a promising anti-cancer agent.