Pharmacokinetics and Biodistribution of LCP Nanoparticles Public Deposited

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  • March 22, 2019
  • Liu, Yang
    • Affiliation: Eshelman School of Pharmacy
  • Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a well-defined lipid bilayer-core structure are effective in encapsulating nucleic acids for the purpose of silencing target genes in tumor cells following their systemic injection. The pharmacokinetics and biodistribution of LCP NPs was investigated using nanoparticles containing a tritium-labeled oligonucleotide administered to an H460 human lung cancer cell line in a xenograft mouse model. LCP NPs displayed a biphasic clearance profile. Approximately 5% and 25% of the injected dose was observed in the tumor and liver, respectively. Confocal microscopy showed that LCP NPs localized within hepatocytes while Kupffer cell uptake was avoided. Small angle neutron scattering (SANS) and fluorescent polyethylene glycol (PEG) quantification data suggested that 20% (mol ratio of outer lipids) PEG was grafted on the surface of LCP NPs with an entangled and collapsed conformation. We also demonstrated that the delivery to hepatocytes was PEG concentration and surface lipid dependent. LCP NPs could be redirected to the reticuloendothelial system (RES) from hepatocytes by decreasing PEG concentration on the particle surface. LCP NPs with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) exhibited higher accumulation in the liver than LCP NPs with Dioleoylphosphatidylcholine (DOPC). Analysis of NP-bound proteins revealed that apolipoprotein E (apoE) might serve as an endogenous targeting ligand for LCP-DOTAP NPs, but not LCP-DOPC NPs. The enhanced liver accumulation of LCP-DOTAP NPs was reduced in apoE deficient mice. In all, characteristics of surface chemistry played important roles in influencing the PK and biodistribution of LCP NPs. The significant uptake by hepatocytes is of great interest to formulation design for oncologic and hepatic applications.
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  • In Copyright
  • Huang, Leaf
  • Doctor of Philosophy
Graduation year
  • 2012

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