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T7 Peptide-Conjugated Lipid Nanoparticles for Dual Modulation of Bcl-2 and Akt-1 in Lung and Cervical Carcinomas
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-23 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00696 Xinwei Cheng , Daorui Yu 1 , Guang Cheng 2, 3 , Bryant C. Yung 4 , Yang Liu , Hewen Li , Chen Kang 5 , Xingyue Fang 1 , Shuhong Tian 1 , Xiaoju Zhou 6 , Qibing Liu 1 , Robert J. Lee
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-08-23 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00696 Xinwei Cheng , Daorui Yu 1 , Guang Cheng 2, 3 , Bryant C. Yung 4 , Yang Liu , Hewen Li , Chen Kang 5 , Xingyue Fang 1 , Shuhong Tian 1 , Xiaoju Zhou 6 , Qibing Liu 1 , Robert J. Lee
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Expression of Bcl-2 and Akt-1 has been associated with human cancer. G3139 and RX-0201, targeting Bcl-2 and Akt-1, respectively, are antisense oligonucleotides (ASOs) that have shown limited efficacy in clinical trials. Herein, we report a combination of newly designed ASOs based on these agents and was delivered by tumor cell-targeting lipid nanoparticles (LNPs). A “Gapmer” design strategy was applied to these ASOs with the addition of 2′-O-methyl modifications on the nucleotides at 5′ and 3′ ends. A dual-channel syringe pump-based system was developed for the synthesis of the LNPs. ASO-LNPs composed of DODMA, egg PC, cholesterol, T7-PEG-DSPE, and PEG-DMG at a molar ratio of 35:39.5:20:0.5:5 and carrying either individual ASOs or co-loaded ASO combinations (Co-ASOs) were synthesized and evaluated in both KB and A549 cancer cells and in an A549 murine xenograft model to determine their antitumor effects and biological activities. The ASO-LNPs exhibited excellent colloidal stability and high ASO encapsulation efficiency with relatively small mean particle sizes and moderately positive zeta potentials. Transferrin receptor-targeting T7-conjugated LNPs showed enhanced cellular uptake compared to nontargeted LNPs. In addition, both T7-conjugated Co-ASOs-LNPs and non-T7-conjugated Co-ASOs-LNPs at a molar ratio of (G3139-GAP to RX-0201-GAP at 1:2) showed efficient downregulation of both Bcl-2 and Akt-1 in both A549 and KB cells. Furthermore, T7-conjugated Co-ASOs-LNPs (Co-ASOs-LNPs) produced superior antitumor activity, prolonged the overall survival time, and demonstrated tumor targeting activity in an A549 xenograft model.
中文翻译：
T7肽缀合的脂质纳米颗粒对肺癌和宫颈癌中Bcl-2和Akt-1的双重调节
Bcl-2和Akt-1的表达与人类癌症有关。分别靶向Bcl-2和Akt-1的G3139和RX-0201是反义寡核苷酸（ASO），在临床试验中显示出有限的功效。在本文中，我们报告了基于这些药物的新设计ASO的组合，并由靶向肿瘤细胞的脂质纳米颗粒（LNPs）传递。一个“将Gapmer的设计策略应用于这些ASO，并在5'和3'末端的核苷酸上添加了2'-O-甲基修饰。开发了基于双通道注射泵的系统来合成LNP。由DODMA，卵PC，胆固醇，T7-PEG-DSPE和PEG-DMG组成的ASO-LNP，摩尔比为35：39.5：20：0.5：5，并带有单独的ASO或共同装载的ASO组合（Co-在KB和A549癌细胞以及A549鼠异种移植模型中合成和评估ASO），以确定它们的抗肿瘤作用和生物学活性。ASO-LNPs具有出色的胶体稳定性和高的ASO包封效率，具有相对较小的平均粒径和适度的正Zeta电位。与未靶向的LNP相比，靶向转铁蛋白受体的T7偶联LNP表现出增强的细胞摄取。此外，摩尔比为（G3139-GAP与RX-0201-GAP的摩尔比为1：2的T7共轭Co-ASOs-LNP和非T7共轭Co-ASOs-LNP）均有效下调了Bcl- A549和KB单元中的2和Akt-1。此外，在A549异种移植模型中，缀合T7的Co-ASOs-LNP（Co-ASOs-LNP）产生了优异的抗肿瘤活性，延长了总生存时间，并证明了肿瘤靶向活性。
更新日期：2018-08-23
中文翻译：
T7肽缀合的脂质纳米颗粒对肺癌和宫颈癌中Bcl-2和Akt-1的双重调节
Bcl-2和Akt-1的表达与人类癌症有关。分别靶向Bcl-2和Akt-1的G3139和RX-0201是反义寡核苷酸（ASO），在临床试验中显示出有限的功效。在本文中，我们报告了基于这些药物的新设计ASO的组合，并由靶向肿瘤细胞的脂质纳米颗粒（LNPs）传递。一个“将Gapmer的设计策略应用于这些ASO，并在5'和3'末端的核苷酸上添加了2'-O-甲基修饰。开发了基于双通道注射泵的系统来合成LNP。由DODMA，卵PC，胆固醇，T7-PEG-DSPE和PEG-DMG组成的ASO-LNP，摩尔比为35：39.5：20：0.5：5，并带有单独的ASO或共同装载的ASO组合（Co-在KB和A549癌细胞以及A549鼠异种移植模型中合成和评估ASO），以确定它们的抗肿瘤作用和生物学活性。ASO-LNPs具有出色的胶体稳定性和高的ASO包封效率，具有相对较小的平均粒径和适度的正Zeta电位。与未靶向的LNP相比，靶向转铁蛋白受体的T7偶联LNP表现出增强的细胞摄取。此外，摩尔比为（G3139-GAP与RX-0201-GAP的摩尔比为1：2的T7共轭Co-ASOs-LNP和非T7共轭Co-ASOs-LNP）均有效下调了Bcl- A549和KB单元中的2和Akt-1。此外，在A549异种移植模型中，缀合T7的Co-ASOs-LNP（Co-ASOs-LNP）产生了优异的抗肿瘤活性，延长了总生存时间，并证明了肿瘤靶向活性。
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