Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers

Abstract

Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200 nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P-gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p ≤ 0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers.

PLA/PLGA nanoparticles for delivery of drugs across the blood-brain barrier

“…Glutathione-coated PEG-PLGA NPs (237 nm) with entrapped paclitaxel showed significantly higher therapeutic efficiency than uncoated NPs and paclitaxel solution. Tubulin immunofluorescent and Western blotting studies also confirmed the enhanced therapeutic efficacy of paclitaxel entrapped in glutathione-coated NPs [32] .…”

“…A number of in vitro experiments have demonstrated that surface functionalized NPs enhanced the therapeutic efficacy of antitumor drugs against the glioma cells such as RG2 and C6 glioma cells when compared with that of free drugs in solution and unmodified NPs with entrapped drugs [17,20,28,32,37,41] . Besides cell viability, IC 50 , the concentration of the drug required to kill 50 % of the incubated cells over a fixed time period, was employed to quantify and evaluate the cytotoxicity of NPs loaded with chemotherapeutic drugs, and their therapeutic efficiency.…”

“…PEG-containing NPs were demonstrated to have advantages such as stabi lity, prolonged blood circulation time, reduced liver distribution and enhanced brain uptake as PEG chains can help adsorb less opsonins and immunoglobulin G, but more apolipoprotein (Apo) E/B [3] . PEGylated NPs PEG-PLGA and PEG-PLA were reported in 10 papers [19,21,25,26,28,32,35,37,39,41] , and were included in the discussion.…”

“…Among 29 papers cited in this review, 9 papers performed in vitro studies [20,23,24,31,33,37,38,40] , 8 papers focused on in vivo studies [13,15,16,18,21,25,27,30] , and 12 papers did both in vitro and in vivo studies [14,17,19,22,26,28,29,32,34,35,39,41] .…”

Nanomaterials for biomedical applications

“…Systemically-administered poly(lactic acid) (PLA) NPs, loaded with breviscapine (a flavonoid), have been shown to penetrate the BBB (Liu et al 2008). Geldenhuys et al (2011) have demonstrated that surface modification of paclitaxel-loaded PLGA NPs with glutathione may also improve BBB bypass. Surface functionalization with PEG-PLA NPs with lectins like wheat gram protein, which specifically bind to the sialic acid present in large amounts in nasal cavities, have shown to increase brain uptake enormously (Gao et al 2006).…”