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Comparison of pharmacokinetics and biodistribution of doxorubicin loaded in PEGylated liposomes and a phospholipid-free small unilamilar vesicle

University of British Columbia

The thesis focuses on the development and characterization of an innovative phospholipid-free small unilamellar vesicle (PFSUV) for drug delivery. The optimal PFSUVs composed of Tween80/cholesterol (1/5 molar ratio) were fabricated by microfluidics, exhibiting a mean diameter of 60-80 nm. The PFSUVs displayed a single bilayer spherical structure, similar to that of a standard liposomal formulation. Doxorubicin could be actively loaded into the aqueous core of PFSUVs at a drug-to-lipid ratio of 1/20 (w/w) via an ammonium sulfate gradient, and was stably retained for 6 days when incubated in 50% serum. In the presence of serum, DOX loaded PFSUVs were internalized by EMT6 murine breast tumor cells 2-fold more efficiently compared to the serum-free conditions due to LDL endocytosis pathway, while PEGylated liposomal doxorubicin (PLD, DSPC/Chol/DSPE-PEG2000) displayed little cellular uptake in both conditions. The results suggest that serum component(s) triggered cellular internalization of the PFSUVs. As a result, the in vitro potency of PFSUVs-DOX against EMT6 cells was comparable as free DOX and was significantly increased compared to the PLD. In mice, PFSUVs-DOX displayed rapid clearance from the blood (<5 µg/mL at 2 h post injection), while the PLD showed significantly prolonged blood circulation with a blood level of 34 µg/ml in 2 days. After i.v. delivery, the PLD selectively accumulated in the liver (4-5 µg/g tissue), spleen (3-5 µg/g) and tumor (0.5-1.3 µg/g) with minimal uptake in other tissues. The PFSUVs-DOX displayed a distinct biodistribution pattern with a high liver uptake at 2 h (~15 µg/g). Relatively low but significant uptake of the PFSUVs-DOX in the spleen (3~4 µg/g) and tumor (1 µg/g) was measured from 2-48 h post injection. DOX delivered by the PFSUVs was mainly detected in the hepatocytes and Kupffer cells evidenced by confocal microscopy. To the best of our knowledge, this is the first report showing SUVs containing a phospholipid-free bilayer could be formed using microfluidics, and a drug could be actively loaded into the aqueous core for liver-targeted delivery.

Text

2019-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/67217

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/