title: MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound.
abstract: Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a "blood-tumor barrier" (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact blood-brain barrier (BBB). Here, we tested whether brain-penetrating nanoparticles (BPN) that possess dense surface coatings of polyethylene glycol (PEG) and are loaded with cisplatin (CDDP) could be delivered across both the blood-tumor and blood-brain barriers with MR image-guided focused ultrasound (MRgFUS), and whether this treatment could control glioma growth and invasiveness. To this end, we first established that MRgFUS is capable of significantly enhancing the delivery of ~60nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and invasive F98 (28-fold improvement) glioma models. Importantly, BPN delivery across the intact BBB, just beyond the tumor edge, was also markedly increased in both tumor models. We then showed that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of polyaspartic acid (PAA) and heavily PEGylated polyaspartic acid (PAA-PEG), was highly stable, provided extended drug release, and was effective against F98 cells in vitro. These CDDP-BPN were delivered from the systemic circulation into orthotopic F98 gliomas using MRgFUS, where they elicited a significant reduction in tumor invasiveness and growth, as well as improved animal survival. We conclude that this therapy may offer a powerful new approach for the treatment invasive gliomas, particularly for preventing and controlling recurrence.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, 415 Lane Road Building MR5, Charlottesville, VA 22908, United States.
authors.forename: Kelsie F
authors.initials: KF
authors.lastname: Timbie
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Center for Nanomedicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Department of Biochemistry, PMAS-Arid Agriculture University, Shamsabad, Muree Road, Rawalpindi, Pakistan.
authors.forename: Umara
authors.initials: U
authors.lastname: Afzal
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Center for Nanomedicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Date
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Center for Nanomedicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States.
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, University of Virginia, 415 Lane Road Building MR5, Charlottesville, VA 22908, United States.
authors.forename: Ji
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Radiology and Medical Imaging, University of Virginia, 480 Ray C Hunt Drive, Charlottesville, VA 22908, United States.
authors.forename: G
authors.initials: G
authors.lastname: Wilson Miller
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Center for Nanomedicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States.
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Suk
authors.affiliation: Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States; Center for Nanomedicine, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Department of Biomedical Engineering, University of Virginia, 415 Lane Road Building MR5, Charlottesville, VA 22908, United States. Electronic address: rprice@virginia.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Price
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D002103:Cadaverine / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D005910:Glioma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D045423:Microbubbles; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden / Q000187:drug effects; D000069453:Ultrasonic Waves
chemical_list: C569686:Alexa Fluor 647; D000970:Antineoplastic Agents; D002232:Carbocyanines; D005456:Fluorescent Dyes; D010455:Peptides; C017645:polyaspartate; D011092:Polyethylene Glycols; D002103:Cadaverine; D002945:Cisplatin
keywords: Blood-brain barrier; Blood-tumor barrier; Cisplatin; Focused ultrasound; Glioma; Nanoparticle