Lipid-sugar particles for intracranial drug delivery: safety and biocompatibility.
Controlled release of drugs to specific locales in the brain has engendered considerable interest. Here we evaluate the safety and biocompatibility of 6-microm diameter particles composed of dipalmitoylphosphatidylcholine and chondroitin sulfate A, when delivered into the cerebral parenchyma and ventricles, and in the case of intravascular injection. Some particles were loaded with fluorescein-labeled albumin to facilitate detection. Particles placed in medium with cultured murine primary cortical neurons did not increase cell death at concentrations as high as 4 mg/ml. When particles (100 microg in 2 microl) were placed stereotactically in the striatum and lateral ventricles, there was no histological evidence on hematoxylin-eosin stained sections of tissue injury outside of the needle track in any animal 3, 7, and 14 days after injection (n=6 each), and no inflammation. Ventricular size was not significantly different between animals given intraventricular injections of particles and albumin solution at those time points (n=4 each). Intracarotid injection of particles at concentrations of 0.2 and 1 mg/ml (n=4 each) did not affect relative cerebral blood flow, and there were no embolic events on histology. In one animal in the group injected with 5 mg/ml (n=3), there was a profound decrease in rCBF, with patchy emboli on histology. These novel biodegradable particles are biocompatible in and around the brain, and may be safe for intracranial sustained drug delivery either in the parenchyma or into the CSF.
Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Daniel S
DS
Kohane
Nikolaus
N
Plesnila
Sunu S
SS
Thomas
Dean
D
Le
Robert
R
Langer
Michael A
MA
Moskowitz
D015060:1,2-Dipalmitoylphosphatidylcholine; D000418:Albumins / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects; D001921:Brain / Q000187:drug effects*; D002241:Carbohydrates; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002809:Chondroitin Sulfates; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005079:Excipients; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D007276:Injections, Intraventricular; D008055:Lipids; D008297:Male; D008422:Materials Testing; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010316:Particle Size
D000418:Albumins; D001672:Biocompatible Materials; D002241:Carbohydrates; D004337:Drug Carriers; D005079:Excipients; D005456:Fluorescent Dyes; D008055:Lipids; D015060:1,2-Dipalmitoylphosphatidylcholine; D002809:Chondroitin Sulfates; D016650:Fluorescein-5-isothiocyanate