A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging
A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging
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DOI：
10.1007/s00280-007-0482-z
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发表时间：
2008-03-01
影响因子：
3
通讯作者：
Von Dobschuetz, E.
中科院分区：
文献类型：
--
作者：
Bornmann, C.;Graeser, R.;Von Dobschuetz, E.
尽管吉西他滨的酶失活速度很快，因此体内活性有限，但它仍然是治疗胰腺癌的标准药物。为了保护药物，实现被动肿瘤靶向，我们开发了吉西他滨的脂质体GemLip(PHI：36 nm：47%包封率)。在裸鼠原位生长的MIA-Paca-2细胞上检测其抗肿瘤活性。利用荧光素酶基因稳定整合介导的生物发光测量，将小鼠随机分组，监测肿瘤生长情况。GemLip(4 mg/kg和8 mg/kg)、吉西他滨(240 mg/kg)和空脂质体(相当于8 mg/kg GemLip)每周静脉注射1次，共5周。通过体内生物发光测量，GemLip(8 mg/kg)阻止了肿瘤的生长，使原发肿瘤大小减少了68%(SD+/-8%；p<；0.02)，而吉西他滨对肿瘤大小几乎没有影响(-7%；+/-1.5%)。在80%的动物中，肝脏中的荧光素酶活性表明存在转移。所有的治疗，包括空的脂质体，都减少了转移负担。因此，GemLip在该模型中显示出良好的抗肿瘤活性。令人惊讶的是，与吉西他滨和GemLip类似，空脂质体可以抑制转移瘤的扩散。此外，荧光素酶标记的肿瘤细胞是观察肿瘤体内生长以及检测和量化转移的有力工具。
Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (phi: 36 nm: 47% entrapment). Its anti-tumoral activity was tested on MIA PaCa-2 cells growing orthotopically in nude mice. Bioluminescence measurement mediated by the stable integration of the luciferase gene was employed to randomize the mice, and monitor tumor growth. GemLip (4 and 8 mg/kg), Gemcitabine (240 mg/kg), and empty liposomes (equivalent to 8 mg/kg GemLip) were injected intravenously once weekly for 5 weeks. GemLip (8 mg/kg) stopped tumor growth, as measured via in vivo bioluminescence, reducing the primary tumor size by 68% (SD +/- 8%; p < 0.02), whereas Gemcitabine hardly affected tumor size (-7%; +/- 1.5%). In 80% of animals, luciferase activity in the liver indicated the presence of metastases. All treatments, including the empty liposomes, reduced the metastatic burden. Thus, GemLip shows promising antitumoral activity in this model. Surprisingly, empty liposomes attenuate the spread of metastases similar to Gemcitabine and GemLip. Further, luciferase marked tumor cells are a powerful tool to observe tumor growth in vivo, and to detect and quantify metastases.