A covalently stabilized lipid-polycation-DNA (sLPD) vector for antisense oligonucleotide delivery.
A covalently stabilized lipid-polycation-DNA (sLPD) vector for antisense oligonucleotide delivery.
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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。
DOI：
10.1021/mp100272k
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发表时间：
2011
影响因子：
4.9
通讯作者：
Lee,RobertJ
中科院分区：
文献类型：
--
作者：
Yang,Xiaojuan;Peng,Yong;Yu,Bo;Yu,Jianhua;Zhou,Chenguang;Mao,Yicheng;Lee,LJames;Lee,RobertJ
反义寡核苷酸 G3139 专为 Bcl-2 下调而设计，已知可诱导 Toll 样受体激活。构建了新型稳定的脂质-聚阳离子-DNA (sLPD) 纳米粒子，并评估了 G3139 向人癌 KB 细胞的递送以及体内生物活性。聚乙烯亚胺 (PEI) 被掺入作为 DNA 缩合剂。使用的脂质组合物是摩尔比为30/30/34/1/5/0.2的DOTAP/DDAB/Chol/TPGS/亚油酸/十六碳烯醛。通过在顺式11-十六碳烯醛上的醛基和PEI上的胺之间形成可逆共价键来稳定纳米颗粒。当使用 sLPD 转染 KB 细胞时，观察到 90.4% 的 Bcl-2 下调，相比之下，游离 G3139 没有显着下调，不稳定 LPD-G3139 下调 54.6%。随后评估了 sLPD 对携带 KB 皮下肿瘤的小鼠的治疗效果，结果发现其可引发强烈的抗肿瘤反应，抑制肿瘤生长并延长生存期，使寿命 (ILS) 延长 72%。与之前关于其他 G3139 纳米粒子的报道一致，发现 sLPD 体内抗肿瘤活性的增加与细胞因子诱导的增加有关，而不是与 Bcl-2 的下调有关，这表明了一种免疫学机制。
Antisense oligonucleotide G3139 is designed for Bcl-2 downregulation and is known to induce toll-like receptor activation. Novel stabilized lipid−polycation−DNA (sLPD) nanoparticles were constructed and evaluated for the delivery of G3139 to human carcinoma KB cells and for bioactivityin vivo. Polyethylenimine (PEI) was incorporated as a DNA condensing agent. The lipid composition used was DOTAP/DDAB/Chol/TPGS/linoleic acid/hexadecenal at molar ratios of 30/30/34/1/5/0.2. The nanoparticles were stabilized by the formation of a reversible covalent bond between the aldehyde group on thecis-11-hexadecenal and amines on the PEI. When sLPDs were used to transfect KB cells, 90.4% Bcl-2 downregulation was observed, compared to no significant downregulation by free G3139 and 54.6% downregulation by nonstabilized LPD-G3139. The sLPDs were then evaluated for therapeutic efficacy in mice bearing KB subcutaneous tumors and were found to trigger a strong antitumor response, inhibiting tumor growth and prolonging survival with 72% increase in lifespan (ILS). Consistent with previous reports on other G3139 nanoparticles, the increased antitumor activities of sLPDs in vivo were found to be associated with increased cytokine induction rather than Bcl-2 downregulation, suggesting an immunological mechanism.