CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia.
CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia.
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CD33 靶向脂质纳米颗粒 (aCD33LN) 用于治疗性递送 GTI-2040 治疗急性髓性白血病。
DOI：
10.1021/mp5008212
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发表时间：
2015
影响因子：
4.9
通讯作者：
Lee,RobertJ
中科院分区：
文献类型：
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作者：
Li,Hong;Xu,Songlin;Quan,Jishan;Yung,BryantC;Pang,Jiuxia;Zhou,Chenguang;Cho,Young-Ah;Zhang,Mengzi;Liu,Shujun;Muthusamy,Natarajan;Chan,KennethK;Byrd,JohnC;Lee,LJames;Marcucci,Guido;Lee,RobertJ
合成了 CD33 靶向脂质纳米颗粒 (aCD33LN)，用于将 GTI-2040（一种针对核糖核苷酸还原酶 R2 亚基的反义寡核苷酸 (ASO)）递送至急性髓性白血病 (AML)。这些 LN 结合了脱氧胆酸盐-聚乙烯亚胺 (DOC-PEI) 缀合物，该缀合物显示出促进寡核苷酸递送的显着活性。添加抗 CD33 scFv (aCD33) 作为靶向配体。在体外和体内研究了该系统的递送效率。当用 aCD33LN/GTI-2040 处理细胞时，在 CD33 阳性 Kasumi-1 细胞中观察到显着的摄取。负载 GTI-2040 的 aCD33LN 诱导 AML 细胞中 R2 mRNA 和蛋白质水平显着下调。此外，aCD33LN/GTI-2040 显示抗白血病药物 Ara-C 在 Kasumi-1 细胞中的 IC50 降低了 15 倍。在 Kasumi-1 异种移植模型中，与 LN/GTI-2040 相比，aCD33LN/GTI-2040 显示 R2 显着下调。此外，aCD33LN/GTI-2040 与 Ara-C 联合给药可高度有效地抑制肿瘤生长，并大大延长携带 Kasumi-1 异种移植肿瘤的小鼠的存活时间。缀合物 DOC-PEI 显示出包含脂质纳米颗粒释放钙黄绿素的能力，这表明有助于 DOC-PEI2K 有效释放内体的潜在机制。这些结果表明，aCD33LN 是治疗性递送反义药物治疗 AML 的高效载体。
CD33-targeted lipid nanoparticles (aCD33LNs) were synthesized for delivery of GTI-2040, an antisense oligonucleotide (ASO) against the R2 subunit of ribonucleotide reductase, to acute myelogenous leukemia (AML). These LNs incorporated a deoxycholate-polyethylenimine (DOC-PEI) conjugate, which has shown significant activity to facilitate oligonucleotide delivery. Anti-CD33 scFv (aCD33) was added as a targeting ligand. The delivery efficiency of this system was investigated bothin vitroandin vivo. When cells were treated with aCD33LN/GTI-2040, significant uptake was observed in CD33 positive Kasumi-1 cells. aCD33LNs loaded with GTI-2040 induced significant down-regulation of R2 mRNA and protein levels in AML cells. Moreover, aCD33LN/GTI-2040 showed a 15-fold reduction in the IC50of antileukemic drug Ara-C in Kasumi-1 cells. In Kasumi-1 xenograft model, aCD33LN/GTI-2040 showed significant R2 downregulation compared to LN/GTI-2040. Furthermore, aCD33LN/GTI-2040 coadministered with Ara-C was shown to be highly effective in tumor growth inhibition and to greatly increase survival time of mice bearing Kasumi-1 xenograft tumors. The conjugate DOC-PEI has shown an ability to include calcein release from lipid nanoparticles, suggesting a potential mechanism contributing to efficient endosome release by DOC-PEI2K. These results indicate that aCD33LNs are a highly effective vehicle for the therapeutic delivery of antisense agents to AML.
影响因子：
4.9
作者：
Yang X;Koh CG;Liu S;Pan X;Santhanam R;Yu B;Peng Y;Pang J;Golan S;Talmon Y;Jin Y;Muthusamy N;Byrd JC;Chan KK;Lee LJ;Marcucci G;Lee RJ
通讯作者：
Lee RJ
用于反义寡核苷酸递送的共价稳定脂质聚阳离子 DNA (sLPD) 载体。
影响因子：
4.9
作者：
Yang,Xiaojuan;Peng,Yong;Yu,Bo;Yu,Jianhua;Zhou,Chenguang;Mao,Yicheng;Lee,LJames;Lee,RobertJ
通讯作者：
Lee,RobertJ