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 96 h 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.

Graphical abstractNovel self-assembled dextran sulphate-PLGA hybrid nanoparticles (DPNs) were successfully developed with improved encapsulation efficiency, sustained-release characteristics, and oral bioavailability enhancement effect by P-glycoprotein inhibition for vincristine sulfate.Figure optionsDownload full-size imageDownload as PowerPoint slide