Schwerdt Alenka, Zintchenko Arkadi, Concia Massimo, Roesen Nick, Fisher Kerry, Lindner Lars H, Issels Rolf, Wagner Ernst, Ogris Manfred
Pharmaceutical Biology-Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, Munich, Germany.
Hum Gene Ther. 2008 Nov;19(11):1283-92. doi: 10.1089/hum.2008.064.
Locoregional hyperthermia (HT) can be used for site-directed activation of macromolecular drug delivery systems. We have developed a gene delivery system based on thermosensitive block copolymers (TSCs) with a phase transition temperature of 42 degrees C [Zintchenko, A., Ogris, M., and Wagner, E. (2006). Bioconjug. Chem. 17, 766-772], in which the statistical copolymer of vinylpyrrolidinone and N-isopropylacryamide is grafted on polyethylenimine (PEI). Here we applied polyplexes consisting of plasmid DNA and TSCs systemically in A/J mice bearing a syngeneic Neuro2A neuroblastoma tumor subcutaneously in each hind limb. One limb was selectively treated by HT at 42 degrees C, at the same time that polyplexes were injected via the tail vein. Hyperthermia led to increased accumulation of thermosensitive polymer and aggregation of thermosensitive polyplexes in HT-treated tumors, resulting in up to 10-fold increased DNA deposition compared with non-HT-treated tumor. The level of transgene expression induced by TSC polyplexes in HT-treated tumors was significantly higher and selective for tumor tissue. With nonthermosensitive PEI polyplexes HT did not influence transgene deposition or expression in tumor.
局部区域热疗（HT）可用于大分子药物递送系统的定点激活。我们基于相变温度为42℃的热敏嵌段共聚物（TSCs）开发了一种基因递送系统[津琴科，A.，奥格里斯，M.，和瓦格纳，E.（2006年）。生物共轭化学杂志。17，766 - 772]）,其中乙烯基吡咯烷酮和N - 异丙基丙烯酰胺的统计共聚物接枝在聚乙烯亚胺（PEI）上。在此，我们将由质粒DNA和TSCs组成的多聚体经尾静脉全身注射到每只后肢皮下接种同基因Neuro2A神经母细胞瘤肿瘤的A/J小鼠体内。在经尾静脉注射多聚体的同时，对其中一条后肢进行42℃的选择性热疗。热疗导致热敏聚合物在热疗处理的肿瘤中积累增加，热敏多聚体聚集，与未进行热疗的肿瘤相比，DNA沉积增加了10倍。TSC多聚体在热疗处理的肿瘤中诱导的转基因表达水平显著更高，且对肿瘤组织具有选择性。对于非热敏的PEI多聚体，热疗不影响肿瘤中的转基因沉积或表达。
