The effect of circulation lifetime and drug-to-lipid ratio of intravenously administered lipid nanoparticles on the biodistribution and immunostimulatory activity of encapsulated CpG-ODN.
The encapsulation of conventional drugs in lipid nanoparticles (LNs) has been extensively utilized to enhance therapeutic activity by altering their pharmacokinetic (PK) and biodistribution (BD) properties. We have previously shown that the immunostimulatory activity of unmethylated cytidine-guanosine (CpG)-containing immunostimulatory oligodeoxynucleotides (ODN) is greatly enhanced when encapsulated in an LN (LN CpG-ODN). Here, we investigate the effect of circulation lifetime (determined by lipid composition) and drug-to-lipid (D/L) ratio of intravenously (i.v.) administered LN CpG-ODN on PK, BD, and cellular uptake and correlate these parameters with the immunostimulatory activity. Results from these studies show that despite significant differences in the circulation lifetime and the D/L ratio, the immune response is similar with respect to immune cell activation and cytolytic activity in the spleen and the blood compartments. Our findings indicate that the benefits of liposomal nanoparticles for the delivery of immunomodulatory drugs such as CpG-ODN are defined by a different paradigm than that for conventional drugs.
Raney
Sameersingh G
SG
Tekmira Pharmaceuticals Corporation, Burnaby, British Columbia, Canada. raney@aya.yale.edu
Wilson
Kaley D
KD
Sekirov
Laura
L
Chikh
Ghania
G
de Jong
Susan D
SD
Cullis
Pieter R
PR
Tam
Ying K
YK
D000818:Animals; D001483:Base Sequence; D018899:CpG Islands; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007262:Infusions, Intravenous; D008055:Lipids / Q000008:administration & dosage*; D051379:Mice; D008815:Mice, Inbred Strains; D053758:Nanoparticles; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D007155:Immunologic Factors; D008055:Lipids; D009838:Oligodeoxyribonucleotides