Strategies to maximize liposomal drug loading for a poorly water-soluble anticancer drug

Zhang, Wenli, Wang, Guangji, Falconer, James R., Baguley, Bruce C., Shaw, John P., Liu, Jianping, Xu, Hongtao, See, Esther, Sun, Jianguo, Aa, Jiye and Wu, Zimei (2015) Strategies to maximize liposomal drug loading for a poorly water-soluble anticancer drug. Pharmaceutical Research, 32 4: 1451-1461. doi:10.1007/s11095-014-1551-8

Author Zhang, Wenli
Wang, Guangji
Falconer, James R.
Baguley, Bruce C.
Shaw, John P.
Liu, Jianping
Xu, Hongtao
See, Esther
Sun, Jianguo
Aa, Jiye
Wu, Zimei
Title Strategies to maximize liposomal drug loading for a poorly water-soluble anticancer drug
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 1573-904X
Publication date 2015-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1007/s11095-014-1551-8
Open Access Status Not Open Access
Volume 32
Issue 4
Start page 1451
End page 1461
Total pages 11
Place of publication New York, NY, United States
Publisher Springer New York
Language eng
Formatted abstract
Purpose: To develop a liposomal system with high drug loading (DL) for intravenous (i.v.) delivery of a poorly water-soluble basic drug, asulacrine (ASL).

Methods: A thin-film hydration and extrusion method was used to fabricate the PEGylated liposomal membranes followed by a freeze and thaw process. A novel active drug loading method was developed using ammonium sulphate gradient as an influx driving force of ASL solubilized with sulfobutyl ether-β-cyclodextrin (SBE-β-CD). DL was maximized by optimizing liposomal preparation and loading conditions. Pharmacokinetics was evaluated following i.v. infusion in rabbits.

Results: Freeze-thaw resulted in unilamellar liposome formation (180 nm) free of micelles. Higher DL was obtained when dialysis was used to remove the untrapped ammonium sulphate compared to ultracentrifuge. The pH and SBE-β-CD level in the loading solution played key roles in enhancing DL. High DL ASL-liposomes (8.9%w/w, drug-to-lipid mole ratio 26%) were obtained with some drug “bundles” in the liposomal cores and were stable in a 5% glucose solution for >80 days with minimal leakage (<2%). Surprisingly, following administration of ASL-liposomes prepared with or without SBE-β-CD, the half-lives were similar to the drug solution despite an increased area under the curve, indicating drug leakage from the carriers.

Conclusions: High liposomal DL was achieved with multiple strategies for a poorly-water soluble weak base. However, the liposomal permeability needed to be tailored to improve drug retention.
Keyword Active loading
Q-Index Code CX
Q-Index Status Provisional Code
Grant ID UOAX1102
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 14 times in Scopus Article | Citations
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Created: Mon, 14 Dec 2015, 22:28:52 EST by Anthony Yeates on behalf of Scholarly Communication and Digitisation Service