title: pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas.
abstract: Nanoparticle-mediated delivery of chemotherapeutics has demonstrated potential in improving anticancer efficacy by increasing serum half-life and providing tissue specificity and controlled drug release to improve biodistribution of hydrophobic chemotherapeutics. However, suboptimal drug loading, particularly for solid core nanoparticles (NPs), remains a challenge that limits their clinical application. In this study we formulated a NP coated with a pH-sensitive polymer of O6-methylguanine-DNA methyltransferase (MGMT) inhibitor analog, dialdehyde modified O6-benzylguanosine (DABGS) to achieve high drug loading, and polyethylene glycol (PEG) to ameliorate water solubility and maintain NP stability. The base nanovector consists of an iron oxide core (9 nm) coated with hydrazide functionalized PEG (IOPH). DABGS and PEG-dihydrazide were polymerized on the iron oxide nanoparticle surface (IOPH-pBGS) through acid-labile hydrazone bonds utilizing a rapid, freeze-thaw catalysis approach. DABGS polymerization was confirmed by FTIR and quantitated by UV-vis spectroscopy. IOPH-pBGS demonstrated excellent drug loading of 33.4 ± 5.1% by weight while maintaining small size (36.5 ± 1.8 nm). Drug release was monitored at biologically relevant pHs and demonstrated pH dependent release with maximum release at pH 5.5 (intracellular conditions), and minimal release at physiological pH (7.4). IOPH-pBGS significantly suppressed activity of MGMT and potentiated Temozolomide (TMZ) toxicity in vitro, demonstrating potential as a new treatment option for glioblastomas (GBMs).
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Stephen
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Gebhart
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Jeon
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Allison A
authors.initials: AA
authors.lastname: Blair
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ellenbogen
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
authors.affiliation: Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Miqin
authors.identifier: 0000-0001-8974-1494
authors.initials: M
authors.lastname: Zhang
mesh_terms: D001932:Brain Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005909:Glioblastoma / Q000628:therapy*; D006151:Guanosine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D011108:Polymers / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D000077204:Temozolomide
chemical_list: D011108:Polymers; D006151:Guanosine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide