de Wolf Holger K, Luten Jordy, Snel Cor J, Storm Gert, Hennink Wim E
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences , Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Mol Pharm. 2008 Mar-Apr;5(2):349-57. doi: 10.1021/mp700108r. Epub 2008 Jan 9.
A series of cationic, methacrylamide polymers was tested for use as a biodegradable gene carrier in ovarian cancer. Tumor transfection activity of polyplexes consisting of a reporter gene and different methacrylamide polymers was assessed, after intraperitoneal injection in mice bearing an ovarian cancer xenograft. In this model, polyplexes based on poly(HPMA-DMAE) showed transfection activity similar to polyplexes based on the nondegradable and rather toxic polyethylenimine (PEI22). The tumor transfection activity of the pHPMA-DMAE polyplexes was remarkable considering their poor transfection activity in in vitro assays. Polyplexes based on pHPMA-DMAE were devoid of any cytotoxicity and mediated highest transfection activity at the highest N/P ratio investigated. Tumor cell gene expression after a single administration of these polyplexes rapidly declined within time, at a similar rate to that observed after injection with polyplexes based on PEI22. Incubation of the polyplexes with hyaluronic acid (HA), a polyanion accumulating in the ascitic fluid of ovarian cancer bearing mice, changed the physical characteristics of the pHPMA-DMAE and PEI22 polyplexes. The transfection activity of PEI22-based polyplexes, but not that of pHPMA-DMAE based polyplexes, was strongly impaired by HA. Differences in HA sensitivity might have contributed to the in vivo gene expression activities of pHPMA-DMAE- and PEI22-based polyplexes. pHPMA-DMAE-based polyplexes have potential for use in ovarian cancer therapy due to their considerable transfection activity, their low cytotoxicity, and their HA resistance.
测试了一系列阳离子甲基丙烯酰胺聚合物作为卵巢癌中可生物降解基因载体的用途。在对携带卵巢癌异种移植瘤的小鼠进行腹腔注射后，评估了由报告基因和不同甲基丙烯酰胺聚合物组成的多聚体的肿瘤转染活性。在该模型中，基于聚（HPMA-DMAE）的多聚体显示出与基于不可降解且毒性较大的聚乙烯亚胺（PEI22）的多聚体相似的转染活性。考虑到其在体外试验中转染活性较差，基于pHPMA-DMAE的多聚体的肿瘤转染活性非常显著。基于pHPMA-DMAE的多聚体没有任何细胞毒性，并且在研究的最高N/P比下介导了最高的转染活性。单次给予这些多聚体后肿瘤细胞基因表达随时间迅速下降，下降速率与注射基于PEI22的多聚体后观察到的相似。将多聚体与透明质酸（HA）孵育，HA是一种在携带卵巢癌的小鼠腹水中积累的聚阴离子，改变了pHPMA-DMAE和PEI22多聚体的物理特性。HA强烈损害基于PEI22的多聚体的转染活性，但不损害基于pHPMA-DMAE的多聚体的转染活性。HA敏感性的差异可能导致了基于pHPMA-DMAE和PEI22的多聚体在体内的基因表达活性。基于pHPMA-DMAE的多聚体因其相当高的转染活性、低细胞毒性和HA抗性而具有用于卵巢癌治疗的潜力。
