Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide.
Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide.
复制标题
DOI：
10.1158/1535-7163.mct-09-0045
复制
发表时间：
2009-07
影响因子：
5.7
通讯作者：
O'Halloran TV
中科院分区：
文献类型：
--
作者：
Chen H;Ahn R;Van den Bossche J;Thompson DH;O'Halloran TV
三氧化二砷（As 2 O3）是治疗急性早幼粒细胞白血病的一线药物，目前正在进行治疗其他恶性肿瘤（包括多发性骨髓瘤）的临床试验;然而，将临床效用扩展到实体瘤的努力受到毒性的限制。纳米颗粒形式的As 2 O3封装在100纳米尺度，叶酸靶向脂质体已被开发，以降低系统毒性，并提供一个平台，针对这种代理。所得到的砷“纳米仓”在生理条件下是稳定的，但当pH降低至内体/溶酶体水平时经历触发的药物释放。通过共聚焦显微镜、电感耦合等离子体质谱和细胞毒性研究，在叶酸受体（FR）阳性的人鼻咽（KB）和宫颈（HeLa）细胞以及FR阴性的人乳腺（MCF-7）肿瘤细胞中评价了这些砷脂质体的细胞摄取和抗肿瘤功效。叶酸靶向脂质体砷KB细胞的摄取是三至六倍高于游离As 2 O3或非靶向脂质体砷;增强的摄取发生通过叶酸介导的内吞作用，导致细胞毒性增加28倍。相比之下，表面FR密度较低的肿瘤细胞（HeLa和MCF-7）对叶酸靶向药物的摄取要少得多，疗效也较低。在KB和MCF-7细胞的共培养物中，叶酸靶向的砷脂质体仅被KB细胞内化，显示出高靶向特异性。我们的研究进一步表明，叶酸靶向递送的As 2 O3与coencapsulated镍（II）离子（作为一种无毒的佐剂）增强As 2 O3在相对不敏感的实体瘤衍生细胞的疗效，并持有改善药物治疗指数的承诺。
Arsenic trioxide (As2O3) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As2O3 encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic “nanobins” are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)–positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As2O3 or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As2O3 with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As2O3 efficacy in relatively insensitive solid tumor–derived cells and holds the promise of improving drug therapeutic index.