Effect of cationic carriers on the pharmacokinetics and tumor localization of nucleic acids after intravenous administration.
Nucleic acid based therapeutics are currently being studied for their application in cancer therapy. In this study, the effect of different cationic delivery systems on the circulation kinetics, tumor localization, and tissue distribution of short interfering RNA (siRNA) and plasmid DNA (pDNA) was examined, after intravenous administration in mice bearing a s.c. Neuro 2A tumor. Nanosized particles were formed upon complexation of siRNA with the cationic liposome formulation DOTAP/DOPE and the targeted, cationic polymer RGD-PEG-PEI. Both the circulation kinetics and the overall tumor localization of the siRNA complexes were similar to non-complexed siRNA. Importantly, the different carriers changed the intratumoral distribution of siRNA within the tumor. pDNA was effectively condensed with linear polyethylenimine (PEI), PEGylated linear PEI (PEG-PEI) or poly(2-dimethylamino ethylamino)phosphazene. Only PEG-PEI was able to improve the pDNA circulation kinetics. All pDNA complexes yielded similar pDNA tumor localization (1% of the injected dose, 60 min after administration). We conclude that the level of nucleic acid tumor localization is independent on the type of formulation used in this study. Therefore, the value of carrier systems for the intravenous delivery of nucleic acids cannot be solely attributed to benefits relevant during the transport towards the tumor. Rather, the benefits are arising from carrier-induced changes in the intratumoral fate of the nucleic acids.
de Wolf
Holger K
HK
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
Snel
Cor J
CJ
Verbaan
Ferry J
FJ
Schiffelers
Raymond M
RM
Hennink
Wim E
WE
Storm
Gert
G
D000818:Animals; D002412:Cations; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009696:Nucleic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds; D010599:Pharmacokinetics; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D011108:Polymers / Q000493:pharmacokinetics* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D002412:Cations; D004337:Drug Carriers; D009696:Nucleic Acids; D009943:Organophosphorus Compounds; D011108:Polymers; D034741:RNA, Small Interfering; C508109:poly(2-dimethylamino ethylamino)phosphazene; D011092:Polyethylene Glycols; D011094:Polyethyleneimine