Tumor Redox Heterogeneity-Responsive Prodrug Nanocapsules for Cancer Chemotherapy
Tumor Redox Heterogeneity-Responsive Prodrug Nanocapsules for Cancer Chemotherapy
复制标题
用于癌症化疗的肿瘤氧化还原异质性响应前药纳米胶囊
DOI：
10.1002/adma.201300929
复制
发表时间：
2013-07-19
影响因子：
29.4
通讯作者：
Gu, Zhongwei
中科院分区：
文献类型：
--
作者：
Wang, Jinqiang;Sun, Xuanrong;Gu, Zhongwei
Nanocarriers have been extensively explored for cancer drug delivery to increase the solubility of the drug in water [1] and tumor accumulation [2] by means of its enhanced permeation and retention effect.[3] Therapeutic advantages, including increased drug bioavailability and therapeutic superiority, have been demonstrated in many systems.[4] However, the clinical therapeutic efficacies of available systems are not as high as expected. While rational design of many aspects of nanocarriers is still needed,[5] their ability to respond to cancer heterogeneity was recently recognized as a critical doorway to a high therapeutic index.[6] One such characteristic is the nanocarrier’s ability to respond to the heterogeneous intracellular stimuli to release drugs quickly into cancer cells at various stages so as to efficiently induce death of various cancer cells.[7] Tumor cells are characteristically heterogeneous in many aspects.[8] For instance, cancer cells may exist in reducing conditions as a result of their elevated intracellular glutathione (GSH) levels, which may be several-fold higher than for normal cells and can be further enhanced upon treatments,[9] while many are reported to overproduce reactive oxygen species (ROS, eg, perhaps more than one order of magnitude higher than healthy cells [10]), and thus under increased oxidative stress.[11] Those cells may exist in different tumors, but may also coexist in different regions in one tumor, and even one tumor cell at different stages may have different GSH/ROS levels.[9, 11, 12] Nanocarriers are generally designed to respond to a single type of external stimuli to trigger the drug release,[13] mostly the characteristic lysosomal acidity,[14] the intracellular GSH,[15] or ROS.[16] These nanocarriers responding to only a single type of signal would release the drug only in the fraction of tumor cells overexpressing the signal, not in other tumor cells, causing low overall therapeutic efficacy.[17] Along this line, as a first step, we proposed a nanocarrier that could respond to both intracellular GSH and ROS to release the carried drug. Such a nanocarrier would be tumorspecific but also sensitive to the tumor GSH/ROS heterogeneity and capable of fast drug release in various tumor cells. We first designed such a nanocarrier for a potent camptothecin-based topoisomerase I inhibitor 7-ethyl-10-hydroxyl-camptothecin (SN38),[18] the parent drug of the widely used first-line clinical cancer chemotherapy drug irinotecan (or CPT-11). Irinotecan is converted to SN38 by carboxylesterase-catalyzed hydrolysis of the solubilizing group (the bispiperidine moiety) to exert its biological activity. Owing to its slow hydrolysis rate, irinotecan has an in vitro activity 100-to 1000-fold lower than SN38 and also very limited therapeutic efficacy in humans.[19] On the other hand, SN38 has extremely low solubility in water and pharmaceutically acceptable excipients, and thus cannot be used directly.[20]The key to a nanocarrier responsive to both GSH and ROS leading to fast release of SN38 is to identify a linker that can unite the two opposite stimuli. We found that the phenol ester of SN38, a highly potent anticancer drug, was very sensitive to its hydrophilicity/hydrophobicity environment and electronwithdrawing effect: this ester with a hydrophilic oligomer of ethylene oxide (oligo (ethylene glycol), OEG) chain hydrolyzed faster as the hydrophobic chain length between the OEG chain and SN38 moiety decreased (see Supporting Information, Figure S1). Thioethers are hydrophobic but can be easily oxidized to electron-withdrawing sulfone or sulfoxide and become hydrophilic.[16b] We thereby further proposed that an ester linker joining OEG to SN38 via a …
