Department of Bioengineering, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Sci Transl Med. 2011 Jan 5;3(64):64ra2. doi: 10.1126/scitranslmed.3001385.
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.
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，用于卵巢癌的化疗药物。纳米载体由于其对大分子的增强通透性和保留而选择性地在肿瘤中积累，从而增强了与纳米载体相关的药物的抗肿瘤活性。我们通过荧光法评估其动力学稳定性，研究了包含（1,2-二氨基环己烷）铂（II）（DACHPt/m）的聚合物胶束的实时亚细胞命运，DACHPt/m 是奥沙利铂的母体复合物。这些观察结果表明，DACHPt/m 从血管渗出到肿瘤组织，并在每个细胞内解离。此外，DACHPt/m 选择性地在晚期内涵体中解离，与游离奥沙利铂相比，增加了对附近细胞核的药物递送，可能是通过绕过金属硫蛋白和蛋氨酸合酶等细胞质解毒系统。因此，这些载药胶束表现出比单独奥沙利铂更高的抗肿瘤活性，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在临床应用中可能具有相当大的益处。
