Stable and potent polyvalent anthrax toxin inhibitors: raft-inspired domain formation in liposomes that contain PEGylated lipids.
Stable and potent polyvalent anthrax toxin inhibitors: raft-inspired domain formation in liposomes that contain PEGylated lipids.
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稳定有效的多价炭疽毒素抑制剂：含有聚乙二醇化脂质的脂质体中筏启发的结构域形成。
DOI：
10.1002/chem.200801097
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Kane,RaviS
中科院分区：
文献类型：
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作者：
Rai,Prakash;Vance,David;Poon,Vincent;Mogridge,Jeremy;Kane,RaviS
The design of polyvalent molecules [1–5], consisting of multiple copies of a ligand attached to a suitable scaffold, represents a promising approach for designing potent inhibitors of pathogens and microbial toxins [1, 6–11]. Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9, 10, 12–15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16, 17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes). Furthermore, drawing from the concept of lipid rafts [15, 18, 19]–domains that are believed to exist in cellular membranes–we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17, 20–22]. We first tested whether the use of PEGylated liposomes (Scheme 1b) would enable the design of stable and active polyvalent anthrax lethal toxin (LeTx) inhibitors.
