iTEP nanoparticle-delivered salinomycin displays an enhanced toxicity to cancer stem cells in orthotopic breast tumors.
iTEP nanoparticle-delivered salinomycin displays an enhanced toxicity to cancer stem cells in orthotopic breast tumors.
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DOI：
10.1021/mp5002312
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发表时间：
2014-08-04
影响因子：
4.9
通讯作者：
Chen M
中科院分区：
文献类型：
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作者：
Zhao P;Dong S;Bhattacharyya J;Chen M
盐霉素（Salinomycin，Sali）对肿瘤干细胞（cancer stem cells，CSCs）具有选择性毒性，CSCs是最近发现的与肿瘤多药耐药（multidrug resistance，MDR）有关的癌细胞亚群。为了利用其对癌症治疗的选择性毒性，我们试图设计一种纳米颗粒（NP）载体，通过增强的渗透性和保留效应将Sali递送至实体瘤，从而增加其对CSC的暴露。首先，将疏水性Sali缀合至亲水性、免疫耐受性、弹性蛋白样多肽（iTEP）;两亲性iTEP-Sali缀合物自组装成NP。接下来，将游离Sali单独或与两种添加剂N，N-二甲基己胺（DMHA）和α-生育酚一起包封到NP中。共包封显著改善了Sali的装载效率和释放曲线。共包封的所得NP（称为iTEP-Sali NP 3）具有4.1小时的体外释放半衰期，比仅包封Sali的NP iTEP-Sali NP 2长四倍。此外，NP 3制剂使Sali的血浆曲线下面积和肿瘤累积分别增加10倍和2.4倍。最后，这些改善的药代动力学和肿瘤蓄积特征与Sali体内CSC消除作用的增强一致。在NP 3处理的4 T1原位肿瘤中，平均CSC频率为55.62%，与未处理的肿瘤的平均频率75.00%或游离Sali处理的肿瘤的平均频率64.32%相比显著降低。NP 3的CSC消除作用可以进一步转化为肿瘤生长的延迟。鉴于CSC在驱动肿瘤MDR和复发中的作用，将NP 3添加到常规癌症化疗中以预防或逆转MDR可能是一种有前途的策略。
Salinomycin (Sali) has selective toxicity to cancer stem cells (CSCs), a subpopulation of cancer cells that have been recently linked with tumor multidrug resistance (MDR). To utilize its selective toxicity for cancer therapy, we sought to devise a nanoparticle (NP) carrier to deliver Sali to solid tumors through the enhanced permeability and retention effect and, hence, to increase its exposure to CSCs. First, hydrophobic Sali was conjugated to a hydrophilic, immune-tolerant, elastin-like polypeptide (iTEP); the amphiphilic iTEP–Sali conjugates self-assemble into NPs. Next, free Sali was encapsulated into the NPs alone or with two additives, N,N-dimethylhexylamine (DMHA) and α-tocopherol. The coencapsulation significantly improved the loading efficiency and release profile of Sali. The resulting NPs of the coencapsulation, termed as iTEP–Sali NP3s, have an in vitro release half-life of 4.1 h, four times longer than iTEP–Sali NP2s, the NPs that have encapsulated Sali only. Further, the NP3 formulation increases the plasma area under curve and the tumor accumulation of Sali by 10 and 2.4 times, respectively. Lastly, these improved pharmacokinetic and tumor accumulation profiles are consistent with a boost of CSC-elimination effect of Sali in vivo. In NP3-treated 4T1 orthotopic tumors, the mean CSC frequency is 55.62%, a significant reduction from the mean frequencies of untreated tumors, 75.00%, or free Sali-treated tumors, 64.32%. The CSC-elimination effect of the NP3 can further translate to a delay of tumor growth. Given the role of CSCs in driving tumor MDR and recurrence, it could be a promising strategy to add the NP3 to conventional cancer chemotherapies to prevent or reverse the MDR.
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