Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma.
Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma.
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亚 50 nm tenfibgen 纳米胶囊用于癌细胞定向递送抗 CK2 RNAi 至原发性和转移性鳞状细胞癌的机制和功效。
DOI：
10.1158/1535-7163.mct-14-0166
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发表时间：
2014
影响因子：
5.7
通讯作者：
Ahmed,Khalil
中科院分区：
文献类型：
--
作者：
Unger,GretchenM;Kren,BetsyT;Korman,VicciL;Kimbrough,TylerG;Vogel,RachelI;Ondrey,FrankG;Trembley,JaneenH;Ahmed,Khalil
头颈癌（HNC）复发性和转移性患者生存率的提高证明了癌症治疗是特异性的，治疗药物被保护地递送到原发性和转移性癌细胞。进一步的目标应该是下调细胞内治疗靶点导致细胞死亡而不通过替代途径补偿。为了实现这些目标，我们报道了一种低于50纳米的tenfigen （s50-TBG）纳米胶囊的使用，该胶囊以癌细胞特异性的方式递送针对必需生存信号蛋白激酶CK2 （RNAi-CK2）的RNAi寡核苷酸。我们已经评估了使用s50-TBG-RNAi-CK2纳米胶囊治疗原发性和转移性头颈部鳞状细胞癌（HNSCC）的机制和疗效。s50-TBG纳米胶囊通过脂质筏/腔泡途径进入癌细胞，并优先将其货物（RNAi-CK2）递送到恶性组织，而不是正常组织。我们的数据表明，RNAi-CK2是一种独特的单链寡核苷酸，可通过argonaute 2/ rna诱导的沉默复合物途径靶向CK2αα ' mrna。s50-TBG-RNAi-CK2抑制肿瘤细胞生长，相应降低肿瘤细胞的CK2表达。对三种异种移植HNSCC模型的治疗表明，原发肿瘤和转移瘤对s50-TBG-RNAi-CK2治疗有反应，在小鼠的正常组织中，相对低剂量的治疗药物可以实现肿瘤缩小和6个月的宿主生存，而没有任何不良毒性作用。我们建议我们的纳米胶囊技术和抗ck2靶向结合成一种具有重大转化潜力的治疗方式。巨蟹座；13 (8);2018 - 29。AACR©2014。
Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub–50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell–specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα′ mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise.Mol Cancer Ther; 13(8); 2018–29. ©2014 AACR.