The "perivascular pump" driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain.
We investigated the movement of interstitially infused macromolecules within the central nervous system (CNS) in rats with high and low blood pressure (BP)/heart rate and in rats euthanized immediately before infusion (no heart action). Adeno-associated virus 2 (AAV2), fluorescent liposomes, or bovine serum albumin was infused into rat striatum (six hemispheres per group) by convection-enhanced delivery (CED). After infusion, distribution volumes were evaluated. The rats with high BP/heart rate displayed a significantly larger distribution of the infused molecules within the injected site and more extensive transport of those molecules to the globus pallidus. This difference was particularly apparent for AAV2, for which a 16.5-fold greater distribution of viral capsids was observed in the rats with high BP/heart rate than in the rats with no heartbeat. Similar results were observed for liposomes, despite their larger diameter. The distribution of all infused molecules in all rats that had low or no blood flow was confined to the space around brain blood vessels. These findings show that fluid circulation within the CNS through the perivascular space is the primary mechanism by which viral particles and other therapeutic agents administered by CED are spread within the brain and that cardiac contractions power this process.
Hadaczek
Piotr
P
Laboratory of Molecular Therapeutics, Department of Neurological Surgery, UCSF, MCB, 1855 Folsom Street, Room 226, San Francisco, CA 94103, USA. piotr.hadaczek@ucsf.edu
Yamashita
Yoji
Y
Mirek
Hanna
H
Tamas
Laszlo
L
Bohn
Martha C
MC
Noble
Charles
C
Park
John W
JW
Bankiewicz
Krystof
K
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D018481:Convection; D000229:Dependovirus / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D006339:Heart Rate / Q000502:physiology; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics; D018810:Magnetic Resonance Angiography; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics
D008081:Liposomes; D012710:Serum Albumin, Bovine