title: Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration.
abstract: Poor drug distribution and short drug half-life within tumors strongly limit efficacy of chemotherapies in most cancers, including primary brain tumors. Local or targeted drug delivery via controlled-release polymers is a promising strategy to treat infiltrative brain tumors, which cannot be completely removed surgically. However, drug penetration is limited with conventional local therapies since small-molecule drugs often enter the first cell they encounter and travel only short distances from the site of administration. Nanoparticles that avoid adhesive interactions with the tumor extracellular matrix may improve drug distribution and sustain drug release when applied to the tumor area. We have previously shown model polystyrene nanoparticles up to 114 nm in diameter were able to rapidly diffuse in normal brain tissue, but only if coated with an exceptionally dense layer of poly(ethylene glycol) (PEG) to reduce adhesive interactions. Here, we demonstrate that paclitaxel (PTX)-loaded, poly(lactic-co-glycolic acid) (PLGA)-co-PEG block copolymer nanoparticles with an average diameter of 70 nm were able to diffuse 100-fold faster than similarly sized PTX-loaded PLGA particles (without PEG coatings). Densely PEGylated PTX-loaded nanoparticles significantly delayed tumor growth following local administration to established brain tumors, as compared to PTX-loaded PLGA nanoparticles or unencapsulated PTX. Delayed tumor growth combined with enhanced distribution of drug-loaded PLGA-PEG nanoparticles to the tumor infiltrative front demonstrates that particle penetration within the brain tumor parenchyma improves therapeutic efficacy. The use of drug-loaded brain-penetrating nanoparticles is a promising approach to achieve sustained and more uniform drug delivery to treat aggressive gliomas and potentially other brain disorders.
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, ‡Department of Biomedical Engineering, ∥Department of Ophthalmology, #Deparments of Oncology, Pharmacology and Molecular Sciences, and Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nance
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Shih
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Xu
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Schuster
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy*; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D053758:Nanoparticles; D017239:Paclitaxel / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: brain cancer; drug delivery; nanomedicine; particle tracking