title: Safety, feasibility, and optimization of intra-arterial mitoxantrone delivery to gliomas.
abstract: Mitoxantrone is a highly cytotoxic antineoplastic drug, however, its poor penetration of the blood-brain barrier has limited its role in the treatment of brain cancers. We hypothesize that intra-arterial (IA) delivery of mitoxantrone may enhance its capacity for regional brain deposition thus expanding its potential as a brain tumor therapy agent. In this study we assessed the dose-response characteristics as well as the feasibility and safety of mitoxantrone delivery to the brain and specifically to gliomas in a rodent model. We show that delivery optimization utilizing the technique of intra-arterial transient cerebral hypoperfusion (IA-TCH) facilitates achieving the highest peak- and end- brain drug concentrations as compared to intravenous and IA delivery without hypoperfusion. Additionally, we observed significant tumor-specific uptake of mitoxantrone when delivered by the IA-TCH method. No untoward effects of IA-TCH delivery of mitoxantrone were observed. The IA-TCH method is shown to be a safely tolerated and feasible strategy for delivering mitoxantrone to tumors in the glioma model tested. Additional investigation is warranted to determine if IA-TCH delivery of mitoxantrone produces clinically relevant benefit.
authors: Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA. jae2109@cumc.columbia.edu.
authors: Jason A
authors: JA
authors: Ellis
authors: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors: Johann
authors: J
authors: Cooke
authors: Department of Electrical Engineering, Columbia University, New York, NY, USA.
authors: Rajinder P
authors: RP
authors: Singh-Moon
authors: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors: Mei
authors: M
authors: Wang
authors: Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA.
authors: Jeffrey N
authors: JN
authors: Bruce
authors: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors: Charles W
authors: CW
authors: Emala
authors: Departments of Electrical and Biomedical Engineering, Boston University, Boston, MA, USA.
authors: Irving J
authors: IJ
authors: Bigio
authors: Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors: Shailendra
authors: S
authors: Joshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008942:Mitoxantrone
keywords: Brain tumor; Chemotherapy; Glioblastoma; Targeted therapy