title: Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides.
abstract: Pharmacokinetic properties of oligonucleotides are largely driven by chemistry of the backbone and thus are sequence independent within a chemical class. Tissue bioavailability (% of administered dose) is assisted by plasma protein binding that limits glomerular filtration and ultimate urinary excretion of oligonucleotides. The substitution of one non-bridging oxygen with the more hydrophobic sulfur atom (phosphorothioate) increases both plasma stability and plasma protein binding and thus, ultimately, tissue bioavailability. Additional modifications of the sugar at the 2' position, increase RNA binding affinity and significantly increase potency, tissue half-life and prolong RNA inhibitory activity. Oligonucleotides modified in this manner consistently exhibit the highest tissue bioavailability (>90%). Systemic biodistribution is broad, and organs typically with highest concentrations are liver and kidney followed by bone marrow, adipocytes, and lymph nodes. Cell uptake is predominantly mediated by endocytosis. Both size and charge for most oligonucleotides prevents distribution across the blood brain barrier. However, modified single-strand oligonucleotides administered by intrathecal injection into the CSF distribute broadly in the CNS. The majority of intracellular oligonucleotide distribution following systemic or local administration occurs rapidly in just a few hours following administration and is facilitated by rapid endocytotic uptake mechanisms. Further understanding of the intracellular trafficking of oligonucleotides may provide further enhancements in design and ultimate potency of antisense oligonucleotides in the future.
authors: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA. Electronic address: rgeary@isisph.com.
authors: Richard S
authors: RS
authors: Geary
authors: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: Daniel
authors: D
authors: Norris
authors: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: Rosie
authors: R
authors: Yu
authors: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: C Frank
authors: CF
authors: Bennett
mesh_terms: D000818:Animals; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D015195:Drug Design; D004705:Endocytosis; D006801:Humans; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009928:Organ Specificity; D011485:Protein Binding; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D001798:Blood Proteins; D016376:Oligonucleotides, Antisense
keywords: Biodistribution; Cell uptake; Oligonucleotide; Pharmacokinetics