Limmer Simone, Hahn Jasmin, Schmidt Rebecca, Wachholz Kirsten, Zengerle Anja, Lechner Katharina, Eibl Hansjörg, Issels Rolf D, Hossann Martin, Lindner Lars H
Department of Internal Medicine III, University Hospital Munich Ludwig-Maximilians University, Munich, Germany.
Pharm Res. 2014 Sep;31(9):2276-86. doi: 10.1007/s11095-014-1322-6. Epub 2014 Mar 6.
The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2-TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT).
DPPG2-TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure.
DPPG2-TSL were stable at 37°C in serum and showed a temperature dependent dFdC release >40°C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG2-TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT (p < 0.05), non-liposomal dFdC with HT (p < 0.01), and liposomal dFdC without HT (p < 0.05), respectively.
Gemcitabine encapsulated in DPPG2-TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation.
嘧啶类似物吉西他滨（dFdC）常用于实体瘤患者的治疗。然而，静脉注射后，dFdC会通过代谢迅速失活。在此，研究了基于1,2 - 二棕榈酰 - sn - 甘油 - 3 - 磷酸二甘油（DPPG2 - TSL）的热敏脂质体作为dFdC递送载体和靶向系统并结合局部热疗（HT）的潜力。
通过脂质膜水合和挤压法制备DPPG2 - TSL，并通过动态光散射、薄层色谱、磷酸盐测定和高效液相色谱进行表征。在患有同基因软组织肉瘤的棕色挪威大鼠中进行体内实验。通过光照进行局部热疗。
DPPG2 - TSL在37°C血清中稳定，在>40°C时表现出温度依赖性的dFdC释放。dFdC的血浆半衰期从0.07小时（非脂质体）显著增加到0.53小时（脂质体，囊泡大小105nm）或2.59小时（脂质体，129nm）。与未进行热疗的非脂质体dFdC（p < 0.05）、进行热疗的非脂质体dFdC（p < 0.01）以及未进行热疗的松脂质体dFdC（p < 0.05）相比分别，用封装在DPPG2 - TSL中的dFdC + HT治疗BN175肿瘤显示肿瘤生长延迟有显著改善。
封装在DPPG2 - TSL中的吉西他滨与局部热疗相结合是治疗实体瘤的一种有前景的工具。因此，这些令人鼓舞的结果需要进一步研究和评估。
