Formulation and Pharmacokinetics of Thermosensitive Stealth® Liposomes Encapsulating 5-Fluorouracil

• Published in: Pharmaceutical research Vol. 32; no. 5; pp. 1585 - 1603
• Main Authors: Al Sabbagh, Chantal, Tsapis, Nicolas, Novell, Anthony, Calleja-Gonzalez, Patricia, Escoffre, Jean-Michel, Bouakaz, Ayache, Chacun, Hélène, Denis, Stéphanie, Vergnaud, Juliette, Gueutin, Claire, Fattal, Elias
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-05-2015; American Association of Pharmaceutical Scientists
• Subjects: 1,2-Dipalmitoylphosphatidylcholine - analogs & derivatives; 1,2-Dipalmitoylphosphatidylcholine - chemistry; Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Biotechnology; Cancer; Cholesterol - chemistry; Drug Liberation; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Fluorouracil - pharmacology; HT29 Cells; Humans; Hyperthermia, Induced; Life Sciences; Liposomes - chemistry; Male; Medical Law; Mice; Mice, Inbred BALB C; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; Polyethyleneimine - chemistry; Research Paper; Tissue Distribution; pharmacokinetics; copper-polyethylenimine complex; thermosensitive stealth; 5-Fluorouracil; liposomes; focused ultrasound; thermosensitive stealth® liposomes
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1559-0

ABSTRACT
Purpose
We optimize the encapsulation and investigate the pharmacokinetics of 5-Fluorouracil (5-FU) delivered by thermosensitive stealth
®
liposomes (TSLs) designed to trigger drug release upon hyperthermia using focused ultrasound (FUS).
Methods
5-FU was encapsulated into liposomes made of 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/1,2-Distearoyl-
sn
-glycero-3-phosphoethanolamine-N-PEG
2000
either as a free molecule or complexed with copper-polyethylenimine. Heat-triggered drug release was evaluated using either a water bath or FUS. Formulation cytotoxicity was assessed on HT-29 cell line by MTS assay. Pharmacokinetics and biodistribution of 5-FU were evaluated in HT-29-tumor bearing mice.
Results
5-FU was easily encapsulated using the lipid hydration method (encapsulation efficacy of 13%) but poorly retained upon dilution. 5-FU complexation with copper-polyethylenimine improved 5-FU retention into liposomes and allowed to obtain an encapsulation efficacy of 37%. At 42°C, heat-triggered 5-FU release from TSLs was 63% using a water bath and 68% using FUS, within 10 min, whereas it remained below 20% for the non-thermosensitive formulation. The MTS assay revealed that formulation toxicity arose from 5-FU and not from the excipients. In addition, 5-FU complex encapsulation into TSLs induces a reduction of the IC
50
from 115 down to 49 μM. Pharmacokinetics reveals a longer circulation of encapsulated 5-FU and a more important body exposure, although tumor passive targeting is not significantly higher than free 5-FU.
Conclusions
Complexation of 5-FU with copper-polyethylenimine appears an interesting strategy to improve 5-FU retention into TSLs
in vitro
and
in vivo
. TSLs allow heat-triggered release of the drug within 10 min at 42°C, a reasonable time for future
in vivo
experiments.