The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents.
The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents.
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DOI：
10.1016/j.biomaterials.2009.09.101
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发表时间：
2010-02
期刊：
影响因子：
14
通讯作者：
Bronich TK
中科院分区：
文献类型：
--
作者：
Sahay G;Kim JO;Kabanov AV;Bronich TK
具有交联的聚（甲基丙烯酸）的离子核和聚（环氧乙烷）的非离子壳的聚合物胶束（cl-胶束）在此显示容易在上皮癌细胞中内化，但在形成紧密连接（TJ）的正常上皮细胞中不内化。癌细胞内的这种氯胶束的内化主要通过小窝介导的内吞作用进行。在融合的正常上皮细胞中，这种内吞途径在顶端侧不存在，并且Cl-胶束在细胞膜的TJ区域中被隔离而不进入细胞至少24小时。中断TJ的钙剥夺导致重新分配的Cl-胶束内的细胞。在癌细胞中，在最初进入细胞后，cl-胶束绕过早期内体并在30分钟内到达溶酶体。这允许设计具有细胞毒性药物多柔比星的Cl-胶束，其通过pH敏感性腙键连接，其在溶酶体的酸性环境中裂解，导致5小时后药物在细胞核中积累。这种pH敏感的氯离子胶束对癌细胞具有选择性毒性，但对正常上皮细胞无毒。总之，我们描述了氯胶束与癌细胞和正常细胞相互作用的主要差异，这可以导致开发新的药物递送系统，减少副作用，提高癌症化疗的疗效。
Polymeric micelles with cross-linked ionic cores of poly(methacrylic acid) and nonionic shell of poly(ethylene oxide) (cl-micelles) are shown here to readily internalize in epithelial cancer cells but not in normal epithelial cells that form tight junctions (TJ). The internalization of such cl-micelles in the cancer cells proceeded mainly through caveolae-mediated endocytosis. In confluent normal epithelial cells this endocytosis route was absent at the apical side and the cl-micelles sequestered in TJ regions of the cell membrane without entering the cells for at least 24 hours. Disruption of the TJ by calcium deprivation resulted in redistribution of cl-micelles inside the cells. In cancer cells following initial cellular entry the cl-micelles bypassed the early endosomes and reached the lysosomes within 30 minutes. This allowed designing cl-micelles with cytotoxic drug, doxorubicin, linked via pH-sensitive hydrazone bonds, which were cleaved in the acidic environment of lysosomes resulting in accumulation of the drug in the nucleus after 5 hours. Such pH-sensitive cl-micelles displayed selective toxicity to cancer cells but were nontoxic to normal epithelial cells. In conclusion, we describe major difference in interactions of cl-micelles with cancer and normal cells that can lead to development of novel drug delivery system with reduced side effects and higher efficacy in cancer chemotherapy.
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影响因子：
3.7
作者：
Foerg, Christina;Ziegler, Urs;Merkle, Hans P.
通讯作者：
Merkle, Hans P.
I阶段剂量升级和药代动力学研究对晚期癌症患者的pluronic聚合物结合的阿霉素（SP1049C）。
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.7
作者：
Sahay, Gaurav;Batrakova, Elena V.;Kabanov, Alexander V.
通讯作者：
Kabanov, Alexander V.
影响因子：
10.8
作者：
Bontha, Satya;Kabanov, Alexander V.;Bronich, Tatiana K.
通讯作者：
Bronich, Tatiana K.
DOI：
10.1073/pnas.0801763105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Gratton, Stephanie E. A.;Ropp, Patricia A.;DeSimone, Joseph M.
通讯作者：
DeSimone, Joseph M.