Physicochemical properties of epidermal growth factor receptor inhibitors and development of a nanoliposomal formulation of gefitinib.
Physicochemical properties of epidermal growth factor receptor inhibitors and development of a nanoliposomal formulation of gefitinib.
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DOI：
10.1002/jps.23180
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发表时间：
2012-08
影响因子：
3.8
通讯作者：
Straubinger, Robert M.
中科院分区：
文献类型：
--
作者：
Trummer, Brian J.;Iyer, Vandana;Balu-Iyer, Sathy V.;O'Connor, Robert;Straubinger, Robert M.
关键词：
Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinases show efficacy in cancers that are highly addicted to non-mutated EGF signaling, but off-target effects limit therapy. Carrier-based formulations could reduce drug deposition in normal tissues, enhance tumor deposition, and reduce free drug concentrations, thereby reducing side effects. Therefore, the feasibility of developing nano-liposomal formulations of EGF receptor inhibitors was investigated. Gefitinib and erlotinib fluorescence was characterized as a tool for formulation development. Peak excitation was 345 nm and peak emission was 385–465 nm, depending upon environment polarity. Emission was negligible in water but intense in non-polar solvents, membranes, or bound to serum proteins. Cellular uptake and distribution also could be imaged by fluorescence in drug-resistant tumor spheroids. Gefitinib fluorescence characteristics enabled facile optimization of formulations. Whereas 4–6 mol% gefitinib could be incorporated in the liposome bilayer, 40–60 mol% could be encapsulated in stable, remote-loaded liposomes consisting of distearoylphosphatidylcholine:polyethylene glycol-distereoylphosphatidylethanolamine:cholesterol (9:1:5 mol:mol:mol). Drug leakage in serum, monitored by fluorescence, was minimal over 24 h at 37°C. The results provide both promising lead formulations as well as novel tools for evaluating new formulations of structurally-similar receptor tyrosine kinase inhibitors and their cellular uptake and tissue biodistribution.
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