title: Treatment of Invasive Brain Tumors Using a Chain-like Nanoparticle.
abstract: Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment.
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: Pubudu M
authors: PM
authors: Peiris
authors: Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio. Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio.
authors: Aaron
authors: A
authors: Abramowski
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: James
authors: J
authors: Mcginnity
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: Elizabeth
authors: E
authors: Doolittle
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: Randall
authors: R
authors: Toy
authors: Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: Ramamurthy
authors: R
authors: Gopalakrishnan
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio.
authors: Shruti
authors: S
authors: Shah
authors: Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio. Department of Physics, Case Western Reserve University, Cleveland, Ohio.
authors: Lisa
authors: L
authors: Bauer
authors: Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, Texas. Department of Radiology, Baylor College of Medicine, Houston, Texas.
authors: Ketan B
authors: KB
authors: Ghaghada
authors: University Hospitals Case Medical Center, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Christopher
authors: C
authors: Hoimes
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio.
authors: Susann M
authors: SM
authors: Brady-Kalnay
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: James P
authors: JP
authors: Basilion
authors: Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Mark A
authors: MA
authors: Griswold
authors: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. Department of Radiology, Case Western Reserve University, Cleveland, Ohio. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. stathis@case.edu.
authors: Efstathios
authors: E
authors: Karathanasis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D005290:Ferric Compounds; D039302:Integrin alphaVbeta3; C000499:ferric oxide; D004317:Doxorubicin
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