Targeted Nanoassembly Loaded with Docetaxel Improves Intracellular Drug Delivery and Efficacy in Murine Breast Cancer Model
Targeted Nanoassembly Loaded with Docetaxel Improves Intracellular Drug Delivery and Efficacy in Murine Breast Cancer Model
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DOI：
10.1021/mp800072e
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发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Li, Yaping
中科院分区：
文献类型：
--
作者：
Gao, Yu;Chen, Lingli;Li, Yaping
多西紫杉醇是治疗转移性乳腺癌最有前途的化疗药物之一，但其副作用却令人泪目。我们假设一种新型靶向纳米组件（TNA）可以在过度表达表皮生长因子（EGF）受体的乳腺肿瘤细胞中提供有效的细胞内药物递送，从而提高多西紫杉醇的疗效并减少副作用。我们制备了由聚乙二醇-二硬脂酰磷脂酰乙醇胺（PEG-DSPE）形成并用EGF修饰的新型负载多西紫杉醇的TNA。与非靶向纳米组件（NNAs）相比，TNA 表现出细胞特异性摄取和内化的明显改善，并且与 NNA 或泰索帝相比，通过在低药物浓度下诱导更多的晚期凋亡和 subG1 细胞，或在高药物浓度下诱导更多的 G2/M 停滞，对 MDA-MB-468 细胞具有更强的细胞毒性。在携带乳腺肿瘤异种移植物的 BALB/c 小鼠中，与 NNA（用 5 mg/kg TNA 治疗的小鼠的相对肿瘤体积 = 0.99 和 10 mg/kg NNA = 1.71，p < 0.05）或泰索帝（用 5 mg/kg TNA 治疗的小鼠的相对肿瘤体积 = 0.99 和 10 mg/kg 泰索帝 = ）相比，TNA 对肿瘤生长表现出更强的抑制作用。 4.20，p < 0.01）。特别是，在剂量为10mg/kg的TNA组中，肿瘤完全消失。 TNA 的最大耐受剂量（MTD）大约是泰索帝的四倍。在小鼠乳腺癌模型中，TNA 还表现出比泰索帝更长的体内循环时间和更多的药物积累。 TNA 治疗还延长了小鼠的存活时间。这些结果表明 TNA 作为乳腺癌化疗的递送系统具有更大的潜力。
Docetaxel is one of the most promising chemotherapeutic agents for the treatment of metastatic breast cancer, but it shows tearful side effects. We hypothesized that a novel targeted nanoassembly (TNA) could provide efficient intracellular drug delivery in breast tumor cells overexpressing epidermal growth factor (EGF) receptor and thus improve the efficacy and reduce the side effects of docetaxel. We prepared the novel docetaxel loaded TNAs formed by polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) and modified with EGF. Compared with nontargeted nanoassemblies (NNAs), TNAs showed obvious improvement of cell-specific uptake and internalization, and revealed more cytotoxicity against MDA-MB-468 cells by inducing more late apoptosis and subG1 cells at low drug concentration, or more G2/M arrest at high drug concentration than NNAs or Taxotere. In BALB/c mice bearing breast tumor xenografts, TNAs showed stronger inhibition of tumor growth compared with NNAs (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg NNAs = 1.71, p < 0.05) or Taxotere (relative tumor volume in mice treated with 5 mg/kg TNAs = 0.99 and 10 mg/kg Taxotere = 4.20, p < 0.01). In particular, tumor disappeared completely in the TNA group at a dose of 10 mg/kg. The maximum tolerated dose (MTD) of TNAs was about four times higher than that of Taxotere. TNAs also demonstrated a much longer circulation time in vivo and more drug accumulation in tumor in a murine breast cancer model than Taxotere. TNA treatment also prolonged survival of mice. These results suggested that TNAs could have more potential as a delivery system for breast cancer chemotherapy.