Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting
Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting
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DOI：
10.1126/scitranslmed.3001385
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发表时间：
2011-01-05
影响因子：
17.1
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Murakami, Mami;Cabral, Horacio;Kataoka, Kazunori
纳米载体介导的药物靶向是一种新兴的癌症治疗策略，例如正在与卵巢癌的化疗药物一起使用。纳米载体增强了大分子的渗透性和滞留性，在肿瘤中选择性积累，从而增强了纳米载体相关药物的抗肿瘤活性。我们通过基于荧光的动力学稳定性评估，研究了含有（1,2-二氨基环己烷）铂（II） （DACHPt/m）（奥沙利铂的母体复合物）的聚合物胶束在肿瘤组织中的实时亚细胞命运。这些观察结果表明，DACHPt/m从血管外渗到肿瘤组织，并在每个细胞内解离。此外，DACHPt/m选择性地在晚期核内体内解离，相对于游离奥沙利铂，增强药物向附近核的递送，可能是通过绕过细胞质解毒系统，如金属硫蛋白和蛋氨酸合成酶。因此，这些载药胶束比单独使用奥沙利铂表现出更高的抗肿瘤活性，甚至对奥沙利铂耐药的肿瘤也是如此。这些发现表明，靶向亚细胞区室的纳米载体可能在临床应用中具有相当大的益处。
Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.