Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Int J Pharm. 2010 Apr 15;389(1-2):10-7. doi: 10.1016/j.ijpharm.2009.12.061. Epub 2010 Jan 7.
The clinical application of cisplatin to treat solid tumours is often limited by the development of tumour cell resistance against this cytostatic agent. Although liposomal carriers of cisplatin are currently in clinical development, approaches to functionally overcome cisplatin resistance by liposomes have hardly been reported. We prepared PEGylated cisplatin-containing liposomes with diameters of about 110 nm and targetability to transferrin receptors (TfR) to correlate cisplatin cell uptake with cytotoxicity in sensitive and cisplatin resistant ovarian cancer cells A2780 compared to the free drug. Whereas the cell entry of free cisplatin was reduced by factor 4 after 24h in resistant cells, liposomal uptake was similar in both cell lines and not affected by resistance. Cytotoxicity was clearly related to intracellular platinum levels, which were even higher for liposomal vs. free cisplatin in the resistant cells after 24, 48, and 72 h and slightly lower in the sensitive cells. However, TfR targeting was of less impact on activity in comparison to non-targeted liposomes. Detection of cellular ATP levels within 24h allowed postulations on the intracellular fate of the liposomes. Altogether, this study strongly supports approaches to overcome cisplatin resistance by a liposomal application of the drug.
顺铂治疗实体瘤的临床应用常受到肿瘤细胞对该细胞抑制剂产生耐药性的限制。虽然顺铂的脂质体载体目前正在临床开发中，但通过脂质体在功能上克服顺铂耐药性的方法几乎没有报道。我们制备了聚乙二醇化的顺铂脂质体，其直径约为 110nm，并具有转铁蛋白受体（TfR）的靶向性，以将顺铂细胞摄取与在敏感和对顺铂耐药的卵巢癌细胞 A2780 中的细胞毒性相关联，与游离药物相比。尽管游离顺铂在耐药细胞中的细胞内进入在 24 小时后减少了 4 倍，但脂质体摄取在两种细胞系中相似，不受耐药性影响。细胞毒性与细胞内铂水平明显相关，在耐药细胞中，与游离顺铂相比，脂质体的铂水平在 24、48 和 72 小时后更高，在敏感细胞中略低。然而，与非靶向脂质体相比，TfR 靶向对活性的影响较小。在 24 小时内检测细胞内 ATP 水平可以推测脂质体的细胞内命运。总的来说，这项研究强烈支持通过脂质体应用药物来克服顺铂耐药性的方法。
