Journal
BRAIN RESEARCH
Volume 1035, Issue 2, Pages 139-153Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2004.12.007
Keywords
cationic lipid; DNA; PEG; rodent; tumor; rat
Categories
Funding
- NCI NIH HHS [NIH R01CA107268, R01 CA107268, NIH CA-85356] Funding Source: Medline
- NIBIB NIH HHS [NIH 8R01EB002047] Funding Source: Medline
- NINDS NIH HHS [NIH NS42927] Funding Source: Medline
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We have investigated the role of diameter, charge, and steric shielding on the brain distribution of liposomes infused by convection enhanced delivery (CED) using both radiolabeled and fluorescent-labeled particles. Liposomes of 40 and 80-nm diameter traveled the same distance but penetrated significantly less than a 10-kDa dextran; whereas 200-nm-diameter liposomes penetrated less than 80 nm liposomes. A neutral liposome shielded by polyethylene glycol (PEG; 2 kDa; 10% by mole) penetrated significantly farther than an unshielded liposome. Even when shielded with PEG, positive surface charge (10% by mole) significantly reduced the penetration radius compared to a neutral or negative charged liposome (10% by mole). A mathematical CED model including a term for liposome cell binding was applied to analyze the radius of particle penetration. Neutral liposomes had a binding constant of k = 0.0010 +/- 0.0002 min(-1), whereas for positive charged liposomes k increased 50-fold. The binding constant was independently verified using a degradable lipid radiolabel that eliminated from the brain with a 9.9 +/- 2.0 h half-life, equivalent to the calculated elimination constant k = 0.0012 +/- 0.0002 min(-1). During CED, liposomes accumulated in a subpopulation of perivascular cells within the brain. A non-degradable lipid radiolabel showed that lipid components remained within these perivascular brain cells for at least 2 days. To reduce this uptake, 100-fold molar excess of non-labeled liposomes were co-infused with labeled liposomes, which significantly increased liposome penetration. These studies suggest that optimization of therapeutic CED using particles such as drug-loaded liposomes, polymeric nanoparticles, non-viral DNA complexes, and viruses will require a strategy to overcome particle binding and clearance by cells within the CNS. (c) 2004 Elsevier B.V. All rights reserved.
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