Pharmaco attributes of dioleoylphosphatidylethanolamine/cholesterylhemisuccinate liposomes containing different types of cleavable lipopolymers.
Pharmaco attributes of dioleoylphosphatidylethanolamine/cholesterylhemisuccinate liposomes containing different types of cleavable lipopolymers.
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DOI：
10.1016/j.phrs.2003.09.003
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发表时间：
2004-02
影响因子：
9.3
通讯作者：
Janny X Zhang;S. Zalipsky;N. Mullah;M. Pechar;T. Allen
中科院分区：
文献类型：
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作者：
Janny X Zhang;S. Zalipsky;N. Mullah;M. Pechar;T. Allen
将三种不同类型的可切割甲氧基聚乙二醇(mPEG)-磷脂或不可切割的对应物（mPEG- dspe）中的一种以6:4的摩尔比加入到含有二油基磷脂酰乙醇胺（DOPE）和半琥珀酸胆固醇（CHEMS）的ph敏感脂质体配方中，并测定其对血浆清除率和含量释放率的影响。这些可切割的脂质聚合物都是基于二硬脂酰磷脂酰脂质锚，通过二硫代二丙酸氨基乙醇（mPEG- dtp - dspe）、二硫代3-己醇（mPEG- dgh - dspa）或gli - phe - leu - gli -氨基乙醇（mPEG- gflg - dspe）连接到mPEG上。与第一代硫溶可切割的脂质聚合物mPEG-DTP-DSPE相比，第二代缀合物分别含有受阻二硫或酶溶可切割的四肽作为裂解点。在没有mpeg -脂质的情况下，DOPE/CHEMS脂质体具有快速的清除半衰期。随着脂质体中mpeg -脂的摩尔%的增加，小鼠对DOPE/CHEMS脂质体的清除率降低。zeta电位测量表明，清除率的降低与脂质体表面电荷的减少有关，当mpeg -脂质含量增加到15mol%以上时，脂质体表面电荷接近中性。在这些水平下，含有mPEG-DTP-DSPE的脂质体比含有其他不那么脆弱的脂聚合物的脂质体从血液循环中清除得更快。具有肽链脂聚合物的脂质体表现出最慢的清除率。在DOPE/CHEMS脂质体中存在浓度为5mol%或更高的可切割或不可切割的mpeg -脂质，可抑制这些脂质体对酸性pH的释放。
Various amounts of one of three different types of cleavable methoxy polyethylene glycol (mPEG)-phospholipids or of a non-cleavable counterpart (mPEG-DSPE) were included into pH-sensitive liposome formulations containing dioleoylphosphatidylethanolamine (DOPE) and cholesterylhemisuccinate (CHEMS) at a 6:4 molar ratio, and the effect on plasma clearance and contents release rates was determined. The cleavable lipopolymers were all based on a distearoylphosphatidyl lipid anchor, which was linked to mPEG via dithiodipropionateaminoethanol (mPEG-DTP-DSPE), dithio-3-hexanol (mPEG-DTH-DSPA), or Gly-Phe-Leu-Gly-aminoethanol (mPEG-GFLG-DSPE) linkers. In contrast to the first-generation thiolytically cleavable lipopolymer, mPEG-DTP-DSPE, the second generation conjugates contained a hindered disulfide or enzymatically cleavable tetrapeptide, respectively, as the points of scission. In the absence of mPEG-lipid, DOPE/CHEMS liposomes had rapid clearance half-lives. As the mol% of mPEG-lipid in the liposomes increased, the rate of clearance of DOPE/CHEMS liposomes in mice decreased. Zeta-potential measurements showed that decreased clearance was correlated with a decrease in the apparent surface charge of the liposomes, which approached neutrality as the content of mPEG-lipids increased to above 15mol%. At these levels, liposomes containing mPEG-DTP-DSPE were cleared from blood circulation faster than liposomes containing other, less vulnerable lipopolymers. Liposomes with the peptide-linked lipopolymer exhibited the slowest clearance. The presence of either cleavable or non-cleavable mPEG-lipids at concentrations of 5mol% or higher in the DOPE/CHEMS liposomes inhibited the release of doxorubicin from these liposomes in response to acid pH.