title: Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats.
abstract: Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival<20months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent chemotherapeutic agent, but its use to treat GBM is limited by severe systemic toxicity and inefficient penetration of brain tumor tissue even when it is placed directly in the brain within standard delivery systems. We describe the development of cisplatin-loaded nanoparticles that are small enough (70nm in diameter) to move within the porous extracellular matrix between cells and that possess a dense polyethylene glycol (PEG) corona that prevents them from being trapped by adhesion as they move through the brain tumor parenchyma. As a result, these "brain penetrating nanoparticles" penetrate much deeper into brain tumor tissue compared to nanoparticles without a dense PEG corona following local administration by either manual injection or convection enhanced delivery. The nanoparticles also provide controlled release of cisplatin in effective concentrations to kill the tumor cells that they reach without causing toxicity-related deaths that were observed when cisplatin was infused into the brain without a delivery system. Median survival time of rats bearing orthotopic glioma was significantly enhanced when cisplatin was delivered in brain penetrating nanoparticles (median survival not reached; 80% long-term survivors) compared to cisplatin in conventional un-PEGylated particles (median survival=40days), cisplatin alone (median survival=12days) or saline-treated controls (median survival=28days).
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, MD 21205, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Nance
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Chisholm
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Center for Biotechnology Education, Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, United States.
authors.forename: Sneha
authors.initials: S
authors.lastname: Berry
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Eberhart
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Suk
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States. Electronic address: hanes@jhu.edu.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D018481:Convection; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Brain tumor; Cisplatin; Convection enhanced delivery; Non-adhesive surface; Therapeutic nanoparticle