Guixia Ling

Development of novel self-assembled DS-PLGA hybrid nanoparticles for improving oral bioavailability of vincristine sulfate by P-gp inhibition

To improve the encapsulation efficiency and oral bioavailability of vincristine sulfate (VCR), novel self-assembled dextran sulphate-PLGA hybrid nanoparticles (DPNs) were successfully developed using self-assembly and nanoprecipitation method. By introducing the negative polymer of dextran sulphate sodium (DS), VCR was highly encapsulated (encapsulation efficiency up to 93.6%) into DPNs by forming electrostatic complex. In vitro release of VCR solution (VCR-Sol) and VCR-loaded DPNs (VCR-DPNs) in pH 7.4 PBS showed that about 80.4% of VCR released from VCR-DPNs after 96h and burst release was effectively reduced, indicating pronounced sustained-release characteristics. In vivo pharmacokinetics in rats after oral administration of VCR-Sol and VCR-DPNs indicated that the apparent bioavailability of VCR-DPNs was increased to approximate 3.3-fold compared to that of VCR-Sol. The cellular uptake experiments were conducted by quantitative assay of VCR cellular accumulation and fluorescence microscopy imaging of fluorescent labeled DPNs in two human breast cancer cells including MCF-7 and P-glycoprotein over-expressing MCF-7/Adr cells. The relative cellular uptake of VCR-DPNs was 12.4-fold higher than that of VCR-Sol in MCF-7/Adr cells implying that P-glycoprotein-mediated drug efflux was diminished by the introduction of DPNs. The new DPNs might provide an effective strategy for oral delivery of VCR with improved encapsulation efficiency and oral bioavailability.

Novel nanostructured lipid-dextran sulfate hybrid carriers overcome tumor multidrug resistance of mitoxantrone hydrochloride

UNLABELLED Novel nanostructured lipid-dextran sulfate hybrid carriers (NLDCs) were successfully developed for sustained delivery of water-soluble cationic mitoxantrone hydrochloride (MTO) and overcoming multidrug resistance. The introduction of negative polymer of dextran sulfate sodium significantly improved the encapsulation efficiency (97.4%) and sustained the release of MTO (86.9% at 72 hours). In vivo pharmacokinetics in rats after intravenous administration demonstrated that MTO-loaded NLDCs (MTO-NLDCs) had higher area under the curve and longer half-life than MTO solution (MTO-Sol). In the biodistribution study, NLDCs significantly improved the MTO levels in plasma, spleen, and brain, and decreased the distribution of MTO in heart and kidney. In comparison with MTO-Sol, MTO-NLDCs efficiently enhanced cytotoxicity through the higher accumulation of MTO in breast cancer resistance protein (BCRP)-overexpressing MCF-7/MX cells. MTO-NLDCs entered into the resistant cancer cells by the clathrin-mediated endocytosis pathway, which escaped the efflux induced by BCRP transporter and thereby overcame the multidrug resistance of MCF-7/MX cells. FROM THE CLINICAL EDITOR In this study, novel nanostructured lipid-dextran sulfate hybrid carriers were synthesized and utilized for sustained delivery of mitoxantrone hydrochloride. The utilized methods successfully addressed multidrug resistance to this chemotherapy agent.

Liquid Chromatography‐Electrospray Ionization Mass Spectrometric Method for Determination of Gliclazide in Human Plasma

Abstract A rapid, sensitive, and specific liquid chromatography‐electrospray ionization mass spectrometric (LC‐ESI‐MS) method has been developed for quantification of gliclazide in human plasma. The analyte and tolbutamide (internal standard, I.S.) were extracted from plasma samples with n‐hexane–dichloromethane (1:1, v/v) and analyzed on a C18 column. The chromatographic separation was achieved within 4.0 min by using methanol–0.5% formic acid (80:20, v/v) as mobile phase and the flow rate was 1.0 mL/min. Ion signals m/z 324.0 and 271.0 for gliclazide and internal standard were measured in the positive mode, respectively. The method was linear within the range of 2.5–2000 ng/mL. The lower limit of quantification (LLOQ) was 2.5 ng/mL. The intra‐ and inter‐day precisions were lower than 2.8% in terms of relative standard deviation (RSD). The inter‐day relative error (RE) as determined from quality control samples (QCs) ranged from −1.93% to 1.85%. This validated method was successfully applied for the evaluation of pharmacokinetic profiles of gliclazide modified‐release tablets in 20 healthy volunteers.

An LC-MS/MS method for simultaneous determination of vincristine and verapamil in rat plasma after oral administration of a dual agent formulation.

A rapid and sensitive method for simultaneous determination of vincristine and verapamil in rat plasma was first developed and validated, using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode via electrospray ionization (ESI). The method, which required a small sample volume (25 µL) of plasma, was linear in the concentration range of 0.5-500 ng/mL for vincristine and 0.1-100.0 ng/mL for verapamil. Finally, the method was successfully employed in a pharmacokinetic study of vincristine and verapamil in rats after an oral administration of a dual-agent formulation containing vincristine and verapamil.

Nanostructured lipid–carrageenan hybrid carriers (NLCCs) for controlled delivery of mitoxantrone hydrochloride to enhance anticancer activity bypassing the BCRP-mediated efflux

Abstract Novel nanostructured lipid–carrageenan hybrid carriers (NLCCs) were exploited for controlled delivery of water soluble chemotherapeutic agent mitoxantrone hydrochloride (MTO) with high loading capacity, sustained release property, and potential for improving oral bioavailability and antitumor efficacy. By introducing the negative polymer of carrageenan, MTO was highly incorporated into NLCCs with encapsulation efficiency of 95.8% by electrostatic interaction. In vivo pharmacokinetics of MTO solution (MTO-Sol) and MTO-NLCCs in rats demonstrated that the apparent bioavailability of MTO-NLCCs was increased to approximate 3.5-fold compared to that of MTO-Sol. The cytotoxicity investigations by MTT method indicated that NLCCs could significantly enhanced the antitumor efficacy against resistant MCF-7/MX cells. The relative cellular association of MTO-NLCCs was 9.2-fold higher than that of MTO-Sol in breast cancer resistance protein (BCRP) over-expressing MCF-7/MX cells, implying that BCRP-mediated drug efflux was diminished by the introduction of NLCCs. The endocytosis inhibition study implied that the NLCCs entered the MCF-7/MX cells by clathrin-mediated endocytosis process, which can bypass the efflux of MTO mediated by BCRP. The new developed NLCCs provide an effective strategy for oral delivery of water-soluble MTO with improved encapsulation efficiency, oral bioavailability, and cytotoxicity against resistant breast cancer cells.

Synergistic and complete reversal of the multidrug resistance of mitoxantrone hydrochloride by three-in-one multifunctional lipid-sodium glycocholate nanocarriers based on simultaneous BCRP and Bcl-2 inhibition

Multidrug resistance (MDR) is a severe obstacle to successful chemotherapy due to its complicated nature that involves multiple mechanisms, such as drug efflux by transporters (P-glycoprotein and breast cancer resistance protein, BCRP) and anti-apoptotic defense (B-cell lymphoma, Bcl-2). To synergistically and completely reverse MDR by simultaneous inhibition of pump and non-pump cellular resistance, three-in-one multifunctional lipid-sodium glycocholate (GcNa) nanocarriers (TMLGNs) have been designed for controlled co-delivery of water-soluble cationic mitoxantrone hydrochloride (MTO), cyclosporine A (CsA – BCRP inhibitor), and GcNa (Bcl-2 inhibitor). GcNa and dextran sulfate were incorporated as anionic compounds to enhance the encapsulation efficiency of MTO (up to 97.8%±1.9%) and sustain the release of cationic MTO by electrostatic interaction. The results of a series of in vitro and in vivo investigations indicated that the TMLGNs were taken up by the resistant cancer cells by an endocytosis pathway that escaped the efflux induced by BCRP, and the simultaneous release of CsA with MTO further efficiently inhibited the efflux of the released MTO by BCRP; meanwhile GcNa induced the apoptosis process, and an associated synergistic antitumor activity and reversion of MDR were achieved because the reversal index was almost 1.0.

Transdermal Adhesive Patches Loaded with Ketoprofen Evaluated by Dynamic Detection of Percutaneous Absorption

ABSTRACTTopical delivery has many benefits toward NSAIDs administration, and the best-selling transdermal preparation in 2015 was the NSAID patch MOHRUS®. Herein, we report a ketoprofen adhesive patch (KAP) and evaluate the penetration and absorption compared to MOHRUS®. Microdialysis sampling technique was applied to determine drug penetration in the dermis and subcutaneous tissue. Simultaneously, blood samples were withdrawn over time to obtain the drug absorption in plasma. The ketoprofen concentrations in the dermis, subcutaneous tissue, and plasma were compared with the commercially available patch (MOHRUS®). Based on the detection, pharmacokinetic parameters including Cmax, Tmax, and AUC0–8h were determined for both the formulations. No significant differences were found in the dermis, subcutaneous tissue, and plasma in rats according to the bioequivalence assessment. The KAP demonstrated multiple therapeutic advantages including the controlled drug release and the sustained drug concentration in the skin as well as in plasma. The pharmacokinetic study coupled with microdialysis sampling provided an effective strategy to evaluate transdermal delivery.