title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical Unviersity, Rootstown, OH 44272, USA.
authors.forename: Werner
authors.initials: W
authors.lastname: Geldenhuys
authors.forename: Thomas
authors.initials: T
authors.lastname: Mbimba
authors.forename: Thong
authors.initials: T
authors.lastname: Bui
authors.forename: Kimberly
authors.initials: K
authors.lastname: Harrison
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Sutariya
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010316:Particle Size; D010539:Permeability; D051381:Rats; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D014404:Tubulin / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D003692:Delayed-Action Preparations; D013844:Thiazoles; D014404:Tubulin; C517282:coumarin 6; D000251:Adenosine Triphosphatases; D005978:Glutathione; D017239:Paclitaxel