Novel temperature-sensitive liposomes with prolonged circulation time
Novel temperature-sensitive liposomes with prolonged circulation time
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DOI：
10.1158/1078-0432.ccr-03-0035
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发表时间：
2004-03-15
影响因子：
11.5
通讯作者：
Dellian, M
中科院分区：
文献类型：
--
作者：
Lindner, LH;Eichhorn, ME;Dellian, M
热疗增加了各种化疗药物的效率，并作为化疗的辅助手段用于治疗癌症患者。温度依赖性效应可以通过使用温度敏感性脂质体与区域热疗组合来强烈增加，其在加热的肿瘤组织中特异性地释放截留的药物。与天然存在的1.2-二棕榈酰-sn-甘油-3-磷酸甘油密切相关的新型脂质1.2-二棕榈酰-sn-甘油-3-磷酸甘油（DPPG 0 G）与1.2-二棕榈酰-sn-甘油-3-磷酸胆碱和1.2-二硬脂酰-sn-甘油-3-磷酸胆碱组合提供了在轻度过热条件（41- 42 ℃）下具有有利性质的长循环温度敏感性脂质体。DPPGOG促进温度触发的药物从这些脂质体（直径，175 nm）释放，并导致包封药物的血浆半衰期显著延长，在仓鼠中t（1/2）= 9.6 h，在大鼠中t（1/2）= 5.0 h。在仓鼠透明背部皮肤褶皱室中生长的无黑色素性黑素瘤的定量荧光显微镜检查证明，静脉内应用这些脂质体（42 ℃，1小时）后，在加热组织中有良好的药物蓄积。与非脂质体药物递送相比，通过应用新脂质体，组织药物浓度的曲线下平均面积增加了六倍以上。总之，我们提出了一种新的基于DPPGOG的脂质体制剂，其能够在轻度高温下实现长循环时间与快速有效的药物释放相结合。这积极地增加了迄今为止在温度敏感性脂质体中使用的脂质接枝聚乙二醇的结果，并拓宽了临床应用的可能性。
Hyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipaimitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is closely related to the naturally occurring 1.2-dipalmitoyi-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyi-sn-glycero-3-phosphocholine provides long-circulating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41-42degreesC). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t(1/2) = 9.6 h in hamsters and t(1/2) = 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42degreesC for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOG-based liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipid-grafted polyethylenglycol used thus far in temperature-sensitive liposomes and widens the possibilities for clinical applications.