Tumor efficacy and biodistribution of linear polyethylenimin-cholesterol/DNA complexes
Tumor efficacy and biodistribution of linear polyethylenimin-cholesterol/DNA complexes
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DOI：
10.1016/j.ymthe.2004.02.014
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发表时间：
2004-06-01
影响因子：
12.4
通讯作者：
Kim, SW
中科院分区：
文献类型：
--
作者：
Furgeson, DY;Yockman, JW;Kim, SW
使用线性聚乙烯亚胺（LPEI）Mw 25 k以T形几何形状（LPC-T）缀合至胆固醇和编码鼠白细胞介素-12（pmIL-12 e）的pDNA形成非病毒聚合物/pDNA复合物。随后每周将这些复合物静脉内和局部注射到BALB/c小鼠中，分别用于治疗鼠肾细胞腺癌（Renca）诱导的肺转移和皮下（SC）Renca肿瘤。在肺转移研究停止时，全身注射LPC-T/pmIL-12 e制剂的肺转移数目显著少于（p < 0.001）单独的pmIL-12 e或pmIL-12 e与LPEI、支链聚乙烯亚胺（BPEI）Mw 25 k或LPEI/pEGFP对照的复合物。此外，生物分布研究显示，在将LPC-T/pmIL-12 e复合物全身注射到携带肺转移的小鼠中后，LPC-T载体和pmIL-12 e载体的肺水平增加达3小时。此外，用LPC-T/pmIL-12 e全身治疗的小鼠在肺转移研究过程中显示出体重增加的近线性曲线，这表明生物相容性增加。最后，由于LPC-T在体外具有良好的特性，因此也可用于SC Renca肿瘤的局部（瘤周）注射。与BPEI/pmIL-12 e、LPEI/pmIL-12 e和裸pmIL-12 e对照相比，仅在LPC-T/pmIL-12 e处理的小鼠中观察到肿瘤停滞和轻微肿瘤消退。因此，可以得出结论，LPC-T是被动靶向肺组织、治疗Renca诱导的肺转移和局部施用Renca细胞SC肿瘤的有效载体。
Non-viral polymer/pDNA complexes were formed using linear polyethylenimine (LPEI) Mw 25 k conjugated to cholesterol in a T-shaped geometry (LPC-T) and pDNA encoding murine interleukin-12 (pmIL-12e). These complexes were subsequently injected weekly into BALB/c mice intravenously and locally for the treatment of murine renal cell adenocarcinoma (Renca) induced pulmonary metastases and subcutaneous (SC) Renca tumors, respectively. At the cessation of the pulmonary metastases study, the number of pulmonary metastases was significantly less (p < 0.001) with systemic injections of LPC-T/pmIL-12e formulations than with pmIL-12e alone or pmIL-12e complexed with LPEI, branched polyethylenimine (BPEI) Mw 25 k, or an LPEI/pEGFP control. In addition, biodistribution studies showed increased pulmonary levels of both the LPC-T carrier and pmIL-12e vector up to 3 hr after systemic injection of the LPC-T/pmIL-12e complexes into mice carrying pulmonary metastases. Furthermore, mice systemically treated with LPC-T/pmIL-12e showed a near linear profile in weight gain in the course of the pulmonary metastases study that suggests increased biocompatibility. Finally, due to favorable characteristics in vitro, LPC-T was also used for local (peritumoral) injection of SC Renca tumors. Tumor stasis and slight tumor regression were seen only with the LPC-T/pmIL-12e treated mice compared to BPEI/pmIL-12e, LPEI/pmIL-12e, and naked pmIL-12e controls. Thus, it was concluded that LPC-T is an effective carrier for passive targeting of the pulmonary tissue, treatment of Renca-induced pulmonary metastases, and local administration of Renca cell SC tumors.