Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system
Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system
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DOI：
10.1038/nature03794
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发表时间：
2005-07-28
期刊：
影响因子：
64.8
通讯作者：
Sasisekharan, R
中科院分区：
文献类型：
--
作者：
Sengupta, S;Eavarone, D;Sasisekharan, R
在继续寻找有效的癌症治疗方法的过程中，新兴的模式是将传统的化疗与抑制血管生长的抗血管生成药物(1)相结合。然而，这一战略的执行面临两大障碍。首先，抗血管生成药物对肿瘤血管的长期关闭可以阻止肿瘤接受治疗浓度的化疗药物。其次，抑制血液供应驱动肿瘤内缺氧诱导因子-1 α (hif1 - α)的积累；hif1 - α的过表达与肿瘤侵袭性增加和化疗耐药相关（2-5）。在这里，我们报道了一种疾病驱动的药物输送系统的工程，一种“纳米细胞”，它克服了实体肿瘤所特有的这些障碍。纳米细胞包括核外聚乙二醇脂质包膜内的核纳米颗粒，并优先被肿瘤吸收。纳米细胞可以暂时释放两种药物：外层包膜首先释放一种抗血管生成剂，导致血管关闭；内部的纳米粒子被困在肿瘤内部，然后释放一种化疗药物。肿瘤内的病灶释放可提高治疗指数，降低毒性。该技术可以扩展到其他药物，从而针对多种信号通路或不同的肿瘤区室，从而实现癌症治疗的“综合”方法模型。
In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents(1) that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1 alpha (HIF1-alpha); overexpression of HIF1-alpha is correlated with increased tumour invasiveness and resistance to chemotherapy(2-5). Here we report the disease-driven engineering of a drug delivery system, a 'nanocell', which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an 'integrative' approach in cancer therapy.