VIP-grafted sterically stabilized phospholipid nanomicellar 17-allylamino-17-demethoxy geldanamycin: A novel targeted nanomedicine for breast cancer
VIP-grafted sterically stabilized phospholipid nanomicellar 17-allylamino-17-demethoxy geldanamycin: A novel targeted nanomedicine for breast cancer
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DOI：
10.1016/j.ijpharm.2008.08.024
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发表时间：
2009-01-05
影响因子：
5.8
通讯作者：
Rubinstein, Israel
中科院分区：
文献类型：
--
作者：
Oenyueksel, Hayat;Mohanty, Prem S.;Rubinstein, Israel
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAC）是一种热休克蛋白90（Hsp 90）功能抑制剂，目前正在开发用于乳腺癌患者的抗肿瘤药物。然而，水不溶性和肝毒性限制了其使用。本研究的目的是开始通过确定17-AAC是否可以配制在长循环（PEG化）、生物相容性和生物可降解的空间稳定磷脂纳米胶束（SSM）中来解决这些问题，其中血管活性肠肽（VIP）作为活性靶向部分移植到SSM中，并且如果是这样，这些纳米胶束是否对MCF-7人乳腺癌细胞具有细胞毒性。我们发现，在VIP表面接枝的SSIVI中负载的17-AAG的粒径为16 +/- 1 nm，药物含量为97 +/- 2%（300 μ g/ml）。加载在VIP表面接枝的SSIVI中的17-AAG对MCF-7细胞的细胞毒性显著高于加载在非靶向SSIVI中的17-AAG（p < 0.05），并且与溶解在二甲基亚砜中的17-AAG相似。总的来说，这些数据表明，17-AAG以治疗相关浓度溶解在活性靶向VIP表面接枝的SSIVI中。这些纳米胶束对MCF-7细胞的细胞毒性被保留，这意味着在这些细胞上过表达的高亲和力VIP受体部分介导它们的细胞内摄取，从而放大药物效力。我们建议，17-AAG加载在VIP表面接枝SSIVI应进一步发展为积极的靶向纳米药物乳腺癌。由爱思唯尔公司出版
17-Allylamino-17-demethoxy geldanamycin (17-AAC), an inhibitor of heat shock protein 90 (Hsp90) function, is being developed as antitumor drug in patients with breast cancer. However, water-insolubility and hepatotoxicity limit its use. The purpose of this study was to begin to address these issues by determining whether 17-AAC can be formulated in long-circulating (PEGylated), biocompatible and biodegradable sterically stabilized phospholipid nanomicelles (SSM) to which vasoactive intestinal peptide (VIP) was grafted as an active targeting moiety and, if so, whether these nanomicelles are cytotoxic to MCF-7 human breast cancer cells. We found that particle size of 17-AAG loaded in VIP surface-grafted SSIVI was 16 +/- 1 nm and drug content was 97 +/- 2% (300 mu g/ml). Cytotoxicity of 17-AAG loaded in VIP surface-grafted SSIVI to MCF-7 cells was significantly higher than that of 17-AAG loaded in non-targeted SSIVI (p < 0.05) and similar to that of 17-AAG dissolved in dimethylsulfoxide. Collectively, these data demonstrate that 17-AAG is solubilized at therapeutically relevant concentrations in actively targeted VIP surface-grafted SSIVI. Cytotoxicity of these nanomicelles to MCF-7 cells is retained implying high affinity VIP receptors overexpressed on these cells mediate, in part, their intracellular uptake thereby amplifying drug potency. We propose that 17-AAG loaded in VIP surface-grafted SSIVI should be further developed as actively targeted nanomedicine for breast cancer. Published by Elsevier B.V.