An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors.
An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors.
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DOI：
10.1016/j.biomaterials.2016.03.032
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发表时间：
2016-07
期刊：
影响因子：
14
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Zhao P;Xia G;Dong S;Jiang ZX;Chen M
肿瘤干细胞抑制剂是一种新型的肿瘤转移治疗药物。盐霉素（Salinomycin，Sali）是研究最多的CSC抑制剂之一，并已进入临床试验阶段。已经开发了几种药物载体来提高Sali的功效。然而，Sali尚未显示出抑制原位肿瘤的转移，这是转移的金标准。为了填补这一空白，我们开发了一种免疫耐受的弹性蛋白样多肽（iTEP）基纳米颗粒（iTEP-Sali-阿坝NP），其在酸性条件下释放4-（氨甲基）苯偶姻修饰的Sali（Sali-ABA）。我们发现，NP使Sali-ABA的曲线下面积（AUC）增加30倍，肿瘤积累增加3.4倍。此外，在给予NP的任何小鼠中均未检测到转移。然而，所有小鼠都死于原发性肿瘤负担。为了克服原发性肿瘤生长并提高总体存活率，我们应用了由iTEP-Sali-阿坝NP和iTEP NP递送的紫杉醇组成的组合疗法。这种疗法有效地延缓了原发性肿瘤的生长，最重要的是，提高了总生存率。总之，通过NP单独或与紫杉醇组合递送Sali-ABA在减少转移和增加存活方面比游离Sali-ABA更有效。这种iTEP-Sali-阿坝NP代表了一种新的和临床上有前途的治疗转移。
Cancer stem cell (CSC) inhibitors are a new category of investigational drugs to treat metastasis. Salinomycin (Sali) is one of most studied CSC inhibitors and has reached clinical tests. Several drug carriers have been developed to improve efficacy of Sali. However, Sali has not been shown to inhibit metastasis from orthotopic tumors, the gold standard for metastasis. To fill this gap, we developed an immune-tolerant, elastin-like polypeptide (iTEP)-based nanoparticle (iTEP-Sali-ABA NP) that released 4-(aminomethyl)benzaldehyde-modified Sali (Sali-ABA) under acidic conditions. We found that the NP increased the area under the curve (AUC) of Sali-ABA by 30-fold and the tumor accumulation by 3.4-fold. Furthermore, no metastasis was detected in any of the mice given the NP. However, all the mice died of primary tumor burdens. To overcome primary tumor growth and improve the overall survival, we applied a combination therapy consisting of the iTEP-Sali-ABA NP and iTEP NP-delivered paclitaxel. This therapy effectively retarded primary tumor growth, and most importantly, improved the overall survival. In conclusion, delivery of Sali-ABA by the NP, alone or in combination with paclitaxel, was more effective than free Sali-ABA in decreasing metastasis and increasing survival. This iTEP-Sali-ABA NP represents a novel and clinically promising therapy to combat metastasis.