Three new cadinene-type sesquiterpenoids from the aerial parts of Ageratina adenophora.

Three new cadinene sesquiterpenoids 1-3, were isolated from the aerial sections of Ageratina adenophora using various chromatographic techniques. Their structures were characterised by comprehensive spectroscopic investigations (including 1D, 2D-NMR and HRMS), and single crystal X-ray diffraction. The cytotoxic activity of new compounds 1-3 were evaluated by testing in vitro tumour growth inhibitory rate against five human tumour cell lines, HL-60, A-549, SMMC-7721, MDA-MB-231, and SW480.

A Facile Way to Increase the Cellular Uptake Efficiency of Hybrid Nanoparticles.

Lipid-polymer hybrid nanoparticles composed of polymer cores and lipid shells have been intensively studied as cancer drug delivery systems. The aim of the present study was to investigate the effect of phosphatidylcholine (PC) on physicochemical properties, stability and cellular uptake of lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticles. Coumarin-6 (cou-6) loaded hybrid nanoparticles (NPs) were prepared using PC with different alkyl chain lengths from C12 to C18, and were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and encapsulation efficiency (EE). The quality and quantity of cellular uptake of NPs were carefully assessed. The NPs were 140-180 nm in size, negatively charged of 7-12 mV and with EE values higher than 80%. NPs remained stable in storage at 4 °C for 28 d. Cell viability rates of NPs were above 90%, and the as-prepared nanoparticles showed excellent biocompatibility by MTT assay. Interestingly, the uptake order was as follows: C12 < C14 < C16-C18. As the alkyl chain length of PC increased, the cellular uptake efficiency of hybrid nanoparticles was enhanced. C16 to C18 saturated PC exhibited the highest cellular uptake efficiency and did not significantly differ. PC had little or no effect on physicochemical properties and stability but did affect cellular uptake of hybrid nanoparticles. The obtained findings could provide a fundamental basis for rational design of hybrid nanoparticles and a facile way to improve the cellular uptake of hybrid nanoparticles.

Progesterone PLGA/mPEG-PLGA Hybrid Nanoparticle Sustained-Release System by Intramuscular Injection.

PURPOSE: To prepare sustained-release PLGA/mPEG-PLGA hybrid nanoparticles of progesterone (PRG), and evaluate the descending required administration dosage in vivo. METHODS: PRG hybrid nanoparticles (PRG H-NPs) based on PLGA/mPEG-PLGA were compared with PRG nanoparticles (PRG-NPs) of pure PLGA as the matrix and PRG-oil solutions. Nanoparticles (NPs) were formed by the method of nanoemulsion, and the pharmacokinetics of the sustained-release PRG H-NPs in male Sprague dawley (SD) rats were investigated. The rats were randomly divided into four groups, each group received: single dose of PRG H-NPs (14.58 mg/kg, i.m.) and PRG-NPs (14.58 mg/kg, i.m.), repeated dosing for 7 days of PRG-oil (2.08 mg/kg, i.m.) solution (Oil-L) and a higher dosage of PRG-oil (6.24 mg/kg, i.m.) solution (Oil-H), respectively. RESULTS: In the pharmacokinetic test, the PRG H-NPs exhibited a comparatively good sustained-release effect against the PRG-NPs without mPEG-PLGA and PRG-oil solution. The pharmacokinetic parameters of the PRG H-NPs, PRG-NPs, Oil-L and Oil-H were AUC0-t(ng·h·mL-1) 8762.1, 1546.1, 1914.5, and 12,138.9, t1/2 (h)52.7, 44.1, 8.4 and 44.6 respectively. CONCLUSIONS: Owing to the modification of PEG, PRG H-NPs can act as safe delivery platforms for sustained-release of drugs with a lower dosage required.

An innovative method for preparation of hydrophobic ion-pairing colistin entrapped poly(lactic acid) nanoparticles: Loading and release mechanism study.

Hydrophobic ion-pairing (HIP) complexation has emerged as an efficient approach to enhance the entrapment of therapeutic peptides in the biodegradable polymer matrix. In the present study, we developed an innovative extraction method for preparation of HIP-colistin (CST, a polycationic peptide) using various water-insoluble anionic lipids. To determine the loading mechanism of HIP-CST entrapped poly(lactic acid) (PLA) nanoparticles (HIP-CST-PLA-NPs), the effects of anionic lipids and PLA molecular weight (Mw) on the unentrapped fraction (uf) of CST in PLA-NPs were investigated. And CST release mechanism from HIP-CST-PLA-NPs was also investigated by evaluating their release behavior and NP swelling. It is showed that HIP-CST retention in the PLA-NPs was imposed by their physical localization in the networks of the PLA chains, rather than the electrostatic attraction between anionic lipid and CST in serum. And HIP-CST-PLA-NPs in serum exhibited the swelling-controlled release behavior with a substantially accelerated release and NP swelling observed in comparison with that in phosphate buffer. Our results can effectively guide the preparation of biodegradable polymer based modified drug release systems with desired properties for peptides delivery.

Electrostatically entrapped colistin liposomes for the treatment of Pseudomonas aeruginosa infection.

The potential use of liposomes for the pulmonary delivery of colistin has been hindered by their phospholipid membrane permeability resulting in a very low entrapment of colistin in the liposomes. To increase the entrapment capacity of colistin in liposomes, the anionic lipid sodium cholesteryl sulfate (Chol-SO4-) was used to enhance the electrostatic attraction between colistin and the lipid membrane. The resulting colistin-entrapped liposomes of Chol-SO4- (CCL) showed significantly greater entrapment efficiency in comparison with liposomes without Chol-SO4-. A time-kill kinetics study showed that colistin could redistribute from the liposomes into a new bacterial cell membrane to exert bactericidal activity. After intratracheal instillation, the CCL exhibited prolonged colistin retention in the lung with less colistin being transferred to the bloodstream and kidney, and the improved biodistribution further resulted in the enhanced therapeutic efficacy in a murine pulmonary Pseudomonas aeruginosa infection model compared with the colistin solution. These results highlight the suitability of applying an electrostatic attraction to entrap colistin in liposomes for pulmonary delivery by increasing colistin retention in the lung, while reducing the systemic exposure.

Colistin-entrapped liposomes driven by the electrostatic interaction: Mechanism of drug loading and in vivo characterization.

The potential in vivo application of liposome for polycationic colistin has been hindered by the poor entrapment efficiency (EE) due to their phospholipid membrane permeability. The objective of this study is to investigate the loading mechanism and validity of applying electrostatic attraction for the colistin entrapment and delivery in liposomes. Anionic lipids with various structures were used for colistin entrapment, and the properties of resulting liposomes (i.e. zeta-potential, EE and release rate) were highly dependent on the structure of anionic lipids. Based on consideration of intermolecular interactions, the retention of electrostatically entrapped colistin is essentially determined by the balance of interfacial hydrophobic attraction and electrostatic repulsion. The liposomal colistin showed the reduced bacterial killing rate, but did not compromise the in vitro antibacterial activity. Specially, the PEGylated liposomal colistin of sodium cholesteryl sulfate (Chol-SO4-) showed the best drug retention, resulting in the significantly increased maximum-tolerated dose, prolonged blood circulation and decreased colistin distribution in kidney after intravenous administration in mice. These results highlight the potential utility of electrostatically entrapped liposome for polycationic colistin delivery.

Preparation and characterisation of the colistin-entrapped liposome driven by electrostatic interaction for intravenous administration.

Potential use of liposome for polycationic colistin is hindered by their phospholipid membrane permeability. In this study, liposomes were modified with sodium cholesteryl sulphate (Chol-SO4(-)) for improving the colistin loading by enhancing the colistin-bilayer electrostatic attraction. We have evaluated two liposomes: colistin-entrapped liposome of Chol-SO4(-) (CCL) and coated Chol-SO4(-)/colistin complex liposome (CCCL). In comparison with CCL which formed large aggregates at Chol-SO4(-)/colistin charge ratio below 2:1, CCCL showed a smaller size less dependent on the charge ratio, probably arising from more colistin entrapped on the inner leaflet of bilayer. Both liposomes exhibited significantly increased entrapment efficiency as compared with the liposome without Chol-SO4(-). But colistin released upon dilution, implying free transfer of colistin through bilayers. Pharmacokinetics results showed the approximately four-fold increase in the plasma AUC0-8 h for CCCL and CCL as compared with colistin solution, showing potential benefit for infectious target localisation by prolonging the systemic circulation of colistin.