cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells
cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells
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DOI：
10.1016/j.jconrel.2017.06.021
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发表时间：
2017-09-10
影响因子：
10.8
通讯作者：
Yamasoba, Tatsuya
中科院分区：
文献类型：
--
作者：
Miyano, Kazuki;Cabral, Horacio;Yamasoba, Tatsuya
由于耐药性癌症干细胞样细胞（CSC）的富集，顽固性头颈鳞状细胞癌（HNSCC）通常在治疗后复发。纳米药物已显示出通过有效的瘤内导航到达特定细胞群并控制药物输送来消灭癌细胞和癌症干细胞的潜力。尽管CSC选择性配体-受体系统的开发一直具有挑战性，但在纳米药物上安装配体是改善肿瘤内CSC递送的一种有吸引力的方法。在此，我们发现HNSCC细胞中的CSC亚群过度表达α(v)β(5)整合素，该整合素优先在肿瘤新生血管和癌细胞中表达，并且可以通过使用环Arg-Gly-Asp (cRGD)肽有效地靶向。因此，在本研究中，我们建议将 cRGD 肽安装在掺有顺铂的胶束纳米药物上，以提高其对抗 CSC 的活性并提高存活率。负载顺铂的胶束 (CDDP/m) 和安装 cRGD 的 CDDP/m (cRGD-CDDP/m) 在体外均能有效对抗 HNSCC SAS-L1-Luc 细胞，但安装 cRGD 的 CDDP/m 比 CDDP/m 对抗 CSC 部分更有效。在体内，cRGD-CDDP/m 还对 HNSCC 原位肿瘤（即 SAS-L1 和 HSC-2）表现出显着的抗肿瘤活性。此外，cRGD-CDDP/m迅速积累到SAS-L1肿瘤的淋巴结转移中，有效抑制其生长，延长小鼠的生存期。这些发现表明，cRGD 安装的纳米药物是针对 HNSCC 中 CSC 的有利策略，特别是 cRGD-CDDP/m 作为针对区域晚期 HNSCC 的重要治疗策略。
Recalcitrant head and neck squamous cell carcinoma (HNSCC) usually relapses after therapy due to the enrichment of drug resistant cancer stem-like cells (CSCs). Nanomedicines have shown potential for eradicating both cancer cells and CSCs by effective intratumoral navigation for reaching particular cell populations and controlling drug delivery. The installation of ligands on nanomedicines is an attractive approach for improving the delivery to CSCs within tumors, though the development of CSC-selective ligand-receptor systems has been challenging. Herein, we found that the CSC subpopulation in HNSCC cells overexpresses alpha(v)beta(5) integrins, which is preferentially expressed in tumor neovasculature and cancer cells, and can be effectively targeted by using cyclic Arg-Gly-Asp (cRGD) peptide. Thus, in this study, we propose installing cRGD peptide on micellar nanomedicines incorporating cisplatin for improving their activity against CSCs and enhancing survival. Both cisplatin-loaded micelles (CDDP/m) and cRGD-installed CDDP/m (cRGD-CDDP/m) were effective against HNSCC SAS-L1-Luc cells in vitro, though cRGD-installed CDDP/m was more potent than CDDP/m against the CSC fraction. In vivo, the cRGD-CDDP/m also showed significant antitumor activity against HNSCC orthotopic tumors, i.e. SAS-L1 and HSC-2. Moreover, cRGD-CDDP/m rapidly accumulated into the lymph node metastasis of SAS-L1 tumors, effectively inhibiting their growth, and prolonging mice survival. These findings indicate cRGD-installed nanomedicines as an advantageous strategy for targeting CSCs in HNSCC, and particularly, cRGD-CDDP/m as a significant therapeutic strategy against regionally advanced HNSCC.