In vitro and in vivo antitumor activity of a novel pH-activated polymeric drug delivery system for doxorubicin.
In vitro and in vivo antitumor activity of a novel pH-activated polymeric drug delivery system for doxorubicin.
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DOI：
10.1371/journal.pone.0044116
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mei Q
中科院分区：
文献类型：
--
作者：
Huan M;Zhang B;Teng Z;Cui H;Wang J;Liu X;Xia H;Zhou S;Mei Q
传统的化疗药物如阿霉素(DOX)因其固有的低选择性而限制了其临床应用，这可能会导致正常健康组织的全身毒性。以多柔比星为靶向载体，制备了一种以聚乙二醇(PEG)为载体的pH刺激敏感的肿瘤靶向给药系统。以合成的聚乙二醇单甲氧基异氰酸酯(PEGAMI-DOX)为对照。合成的偶联物经质子核磁共振波谱分析证实，聚乙二醇化羟基多柔比星的释药曲线是DOX与聚乙二醇肼键合的酸性产物，导致了不同的细胞内摄取途径；由于pH触发，聚乙二醇化羟基多糖在细胞内的蓄积量高于聚乙二醇一阿米多糖，从而对MCF-7、MDA-MB-231(乳腺癌模型)和HepG2(肝癌模型)细胞具有更强的细胞毒作用。根据体外实验结果，我们将MDA-MB-231细胞异种移植到SCID小鼠身上，显示出比游离DOX更强的抗肿瘤作用，并且具有肿瘤靶向性。这些体内实验结果与我们的体外实验结果一致，表明这种pH触发的聚乙二醇羟乙二胺-DOX结合物可以靶向肿瘤组织，并在酸性肿瘤环境中释放游离药物，在抗肿瘤药物传递方面具有很大的潜力。
Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue. A pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control. The synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG-hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting. Results from these in vivo experiments were consistent with our in vitro results; suggested this pH-triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery.
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