Transferrin receptor-targeted lipid nanoparticles for delivery of an antisense oligodeoxyribonucleotide against Bcl-2.
Transferrin receptor-targeted lipid nanoparticles for delivery of an antisense oligodeoxyribonucleotide against Bcl-2.
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DOI：
10.1021/mp800149s
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发表时间：
2009-01
影响因子：
4.9
通讯作者：
Lee RJ
中科院分区：
文献类型：
--
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
反义寡核苷酸G3139介导的Bcl-2下调是克服白血病化疗耐药的潜在策略。然而，在最近的临床试验中显示的有限的功效引起了人们对进一步开发新的和更有效的递送系统的需要的关注。为了解决这个问题，转铁蛋白受体（TfR）靶向的，含鱼精蛋白的脂质纳米颗粒（Tf-LN）的合成作为G3139的传递媒介物。通过乙醇稀释法制备LN，然后通过后插入法掺入脂质缀合的Tf配体。所得Tf-LN的平均粒径为约90 nm，G3139负载效率为90.4%。在K562、MV 4 -11和Raji白血病细胞系中评估Tf-LN的反义递送效率。结果显示，Tf-LN在降低Bcl-2表达（在K562细胞中在mRNA水平上高达62%）和诱导caspase依赖性凋亡方面比非靶向LN和游离G3139更有效（p <0.05）。此外，Bcl-2下调和凋亡诱导的Tf-LN G3139被证明是由过量的游离Tf阻断，因此是TfR依赖性的。具有较高TfR表达的细胞系也表现出较大的Bcl-2下调。此外，铁螯合剂去铁胺上调白血病细胞中TfR表达导致Tf-LN进一步增加反义效应（在mRNA水平上K562中Bcl-2减少高达79%）和caspase依赖性凋亡（约3倍）。Tf-LN介导的递送结合由去铁胺上调的TfR似乎是用于增强反义寡核苷酸的递送效率和治疗功效的潜在有前途的策略。
Antisense oligonucleotide G3139-mediated down-regulation of Bcl-2 is a potential strategy for overcoming chemoresistance in leukemia. However, the limited efficacy shown in recent clinical trials calls attention to the need for further development of novel and more efficient delivery systems. In order to address this issue, transferrin receptor (TfR)-targeted, protamine-containing lipid nanoparticles (Tf-LNs) were synthesized as delivery vehicles for G3139. The LNs were produced by an ethanol dilution method and lipid-conjugated Tf ligand was then incorporated by a post-insertion method. The resulting Tf-LNs had a mean particle diameter of ~ 90 nm and G3139 loading efficiency of 90.4%. Antisense delivery efficiency of Tf-LNs was evaluated in K562, MV4-11 and Raji leukemia cell lines. The results showed that Tf-LNs were more effective than non-targeted LNs and free G3139 (p <0.05) in decreasing Bcl-2 expression (by up to 62% at the mRNA level in K562 cells) and in inducing caspase-dependent apoptosis. In addition, Bcl-2 down-regulation and apoptosis induced by Tf-LN G3139 were shown to be blocked by excess free Tf and thus were TfR-dependent. Cell lines with higher TfR expression also showed greater Bcl-2 down-regulation. Furthermore, upregulation of TfR expression in leukemia cells by iron chelator deferoxamine resulted in a further increase in antisense effect (up to 79% Bcl-2 reduction in K562 at the mRNA level) and in caspase-dependent apoptosis (by ~ 3-fold) by Tf-LN. Tf-LN mediated delivery combined with TfR up-regulation by deferoxamine appears to be a potentially promising strategy for enhancing the delivery efficiency and therapeutic efficacy of antisense oligonucleotides.
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影响因子：
11.4
作者：
Marcucci, G;Livak, KJ;Caligiuri, MA
通讯作者：
Caligiuri, MA
影响因子：
46.9
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影响因子：
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Huang, L
影响因子：
5.1
作者：
Li, S;Huang, L
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Huang, L