title: Distribution of polymer nanoparticles by convection-enhanced delivery to brain tumors.
abstract: Glioblastoma multiforme (GBM) is a fatal brain tumor characterized by infiltration beyond the margins of the main tumor mass and local recurrence after surgery. The blood-brain barrier (BBB) poses the most significant hurdle to brain tumor treatment. Convection-enhanced delivery (CED) allows for local administration of agents, overcoming the restrictions of the BBB. Recently, polymer nanoparticles have been demonstrated to penetrate readily through the healthy brain when delivered by CED, and size has been shown to be a critical factor for nanoparticle penetration. Because these brain-penetrating nanoparticles (BPNPs) have high potential for treatment of intracranial tumors since they offer the potential for cell targeting and controlled drug release after administration, here we investigated the intratumoral CED infusions of PLGA BPNPs in animals bearing either U87 or RG2 intracranial tumors. We demonstrate that the overall volume of distribution of these BPNPs was similar to that observed in healthy brains; however, the presence of tumors resulted in asymmetric and heterogeneous distribution patterns, with substantial leakage into the peritumoral tissue. Together, our results suggest that CED of BPNPs should be optimized by accounting for tumor geometry, in terms of location, size and presence of necrotic regions, to determine the ideal infusion site and parameters for individual tumors.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Saucier-Sawyer
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Gaudin
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Quijano
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sawyer
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Huttner
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA. Electronic address: mark.saltzman@yale.edu.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018481:Convection; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011916:Rats, Inbred F344; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden
chemical_list: D049452:Green Fluorescent Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Convection-enhanced delivery (CED); Poly(lactide-co-glycolide); Polymer nanoparticles