Characterizing Time Course of Contrast Enhancement, Biodistribution, Elimination Pathway and Hepatocyte Selectivity of Fenestra Nanoemulsions

Characterizing Time Course of Contrast Enhancement, Biodistribution, Elimination Pathway and Hepatocyte Selectivity of Fenestra Nanoemulsions

Work on characterizing Fenestra emulsions started in early 90s’ and was first presented at 1994 Controlled Release Society Annual Meeting in Nice France. This preliminary work confirmed the almost exclusive hepatobiliary route for the elimination of these lipid emulsions in bile.

Similar studies using radio-labelled (I-125) fenestra like nano-emulsions in normal and bile duct ligated rat model compared relative clearance of agent in urine and fecal matter and confirmed that 95% of dose was excreted through bile in normal animals as opposed to animals with ligated bile-duct which preferentially use the urinary pathway.

Subsequent trials by scientists at the University of Michigan using radio-labelled Fenestra® LC emulsions sought to confirm the hepatocyte selective uptake of Fenestra – these studies demonstrated that over 70% of the total dose is localized to the liver 30 minutes post-injection and the tissue distribution of I-125 for the remaining dose is in the spleen (15%), blood (4-8%), muscle (5%), and adipose (2-3%) with detectable levels under 1% in other tissues.

The time course of liver contrast enhancement for Fenestra LC was examined for different IV doses in FVB mice and displayed peak liver enhancement in mice at at 6 hours followed by a steady decline in contrast enhancement due to hepatobiliary elimination. At later time points the vessels usually become hypodense relative to the liver, which will usually remain enhanced up to 6 hours post‐injection. Hepatic tumors normally display very little or no contrast enhancement. Hepatobiliary elimination of Fenestra causes liver contrast values to return to baseline levels within 18 to 24 hours after administration.

With Fenestra VC, vascular contrast rapidly increases after injection to a level that is sustained for up to 4 hours. During this time, the liver will show a slight increase in CT density due to its significant vascular supply. After the 4 hour time point, vascular contrast enhancement declines gradually as Fenestra™ VC undergoes hepatobiliary elimination. Peak liver enhancement with IV injections of Fenestra VC injections in C57 Bl/6 mice occurs at 24 hours after injection followed by a decline in liver signal intensity due to hepatobiliary elimination.

Other studies have confirmed the hepatocyte selective nature of Fenestra emulsions depends on ApoE receptors on surface of hepatocytes. In these studies performed at the University of Wisconsin, female ApoE knockout mice displayed different liver sequestration of Fenestra LC than normal B6 control mice injected at 15mL/Kg. Liver uptake was significantly delayed as indicated by decreased liver densities in the ApoE knowckout mice relative to wild-type controls at 1, 2 and 8 hour time points.

APOE Dependant Mechanism for Uptake
Courtesy of Dr. Jamey Weichert, University of Wisconsin

The capacity for retention of Fenestra emulsions is up to several days and varies with the dose used. Doses of 7.5, 10, and 15 mL/Kg in C57 mice had significant liver/GI (1.17-1.28) and spleen/GI (1.3-1.62) contrast one day post-injection. Similar elevations were seen in Nude and Scid mice injected at 10 mL/Kg with spleen to GI ratios peaking on day 2 post-injection and liver to GI ratios peaking on day 1 post-injection. At doses of 7.5 mL/Kg and 10 mL/Kg, Fenestra is completely eliminated by the hepatobiliary system in all three mouse strains. Fenestra® LC at 15 mL/Kg provides sufficient contrast for imaging a week possibly due to partial uptake by kupffer cells of reticulo-endothelial system at higher doses.

 

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