Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines
Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines
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通过负载顺铂的纳米药物的受控细胞内导航根除头颈肿瘤中的 CD44 变异阳性群体
DOI：
10.1016/j.jconrel.2016.03.038
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发表时间：
2016
影响因子：
10.8
通讯作者：
Kazunori Kataoka
中科院分区：
文献类型：
--
作者：
Ming Wang;Yutaka Miura;Kenji Tsuchihashi;Kazuki Miyano;Osamu Nagano;Momoko Yoshikawa;Ami Tanabe;Jun Makino;Yuki Mochida;Nobuhiro Nishiyama;Hideyuki Saya;Horacio Cabral;Kazunori Kataoka
在头颈癌患者中，在接受铂类化疗治疗后，肿瘤生长最终复发是很常见的。这种情况被认为与无法根除耐药的癌症干细胞（CSC）壁龛有关，从而在治疗后使其在肿瘤中的种群丰富。在这项研究中，我们发现与游离顺铂（CDDP）相比，含有顺铂（CDDP/m）的聚合物胶束纳米药物可以根除头颈部肿瘤模型中的未分化细胞和分化癌细胞群。治疗后肿瘤的免疫组化结果显示，与CDDP治疗相反，CDDP/m可以抑制肿瘤生长，而不会使csc样细胞聚集。我们进一步发现，CDDP/m，而不是CDDP，可以定位到肿瘤中的缺氧区域，可能是富含csc的区域，并且可以克服基于谷胱甘肽的高细胞表达的解毒机制，成功地将Pt传递到核DNA。我们的数据表明，CDDP/m可以替代目前的铂类疗法，因为它能够根除大部分和csc样人群，进而防止肿瘤复发。
Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.