Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.
Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.
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DOI：
10.1016/j.jconrel.2015.08.012
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发表时间：
2015-10-28
期刊：
影响因子：
--
通讯作者：
Au JL
中科院分区：
文献类型：
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作者：
Wang J;Lu Z;Wang J;Cui M;Yeung BZ;Cole DJ;Wientjes MG;Au JL
使用小干扰RNA （siRNA）作为癌症治疗的主要障碍是实体瘤中的递送和转染不足。我们之前的研究表明，紫杉醇肿瘤启动通过诱导细胞凋亡，扩大肿瘤间质空间，提高纳米颗粒和sirna -脂丛在三维肿瘤组织培养中的渗透和分散，促进sirna -脂丛在体内局部环境下的传递和转染效率（即腹腔内治疗腹膜内肿瘤）。目前的研究评估了肿瘤启动是否对通过静脉注射全身递送siRNA起作用，这将使siRNA受到几个额外的递送障碍和消除过程。我们使用与腹腔研究中相同的聚乙二醇化阳离子(PCat)-siRNA脂丛来治疗皮下人胰腺Hs766T异种移植肿瘤的小鼠。靶基因为可诱导耐药基因survivin。结果显示，单药紫杉醇可延缓肿瘤生长，但可显著诱导残余肿瘤的survivin蛋白水平，而添加PCat-siSurvivin可完全逆转紫杉醇诱导的survivin蛋白水平，增强紫杉醇活性（p<0.05）。相比之下，单独使用PCat-siSurvivin不能产生survivin敲低或抗肿瘤活性，这表明静脉sirna介导的基因沉默在体内的有效性需要紫杉醇联合治疗。另外的体外研究表明紫杉醇促进了siGLO的细胞质释放，siGLO是一种22个核苷酸的双链RNA，没有mRNA靶标，从其PCat脂质体和/或内体/溶酶体中释放出来。综上所述，我们早期和当前的数据表明，紫杉醇肿瘤启动通过促进间质转运和细胞质释放，对促进siRNA在体内的传递和转染至关重要。此外，由于紫杉醇具有广谱活性，可用于治疗多种类型的实体肿瘤，包括难以治疗的胰腺癌，因此紫杉醇+siSurvivin的协同组合代表了一种潜在有用的化学基因治疗。
The major barrier for using small interfering RNA (siRNA) as cancer therapeutics is the inadequate delivery and transfection in solid tumors. We have previously shown that paclitaxel tumor priming, by inducing apoptosis, expands the tumor interstitial space, improves the penetration and dispersion of nanoparticles and siRNA-lipoplexes in 3-dimensional tumor histocultures, and promotes the delivery and transfection efficiency of siRNA-lipoplexes under the locoregional setting in vivo (i.e., intraperitoneal treatment of intraperitoneal tumors). The current study evaluated whether tumor priming is functional for systemically delivered siRNA via intravenous injection, which would subject siRNA to several additional delivery barriers and elimination processes. We used the same pegylated cationic (PCat)-siRNA lipoplexes as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic Hs766T xenograft tumors. The target gene was survivin, an inducible chemoresistance gene. The results show single agent paclitaxel delayed tumor growth but also significantly induced the survivin protein level in residual tumors, whereas addition of PCat-siSurvivin completely reversed the paclitaxel-induced survivin and enhanced the paclitaxel activity (p<0.05). In comparison, PCat-siSurvivin alone did not yield survivin knockdown or antitumor activity, indicating the in vivo effectiveness of intravenous siRNA-mediated gene silencing requires paclitaxel cotreatment. Additional in vitro studies showed that paclitaxel promoted the cytoplasmic release of siGLO, a 22 nucleotide double-stranded RNA that has no mRNA targets, from its PCat lipoplex and/or endosomes/lysosomes. Taken together, our earlier and current data show paclitaxel tumor priming, by promoting the interstitial transport and cytoplasmic release, is critical to promote the delivery and transfection of siRNA in vivo. In addition, because paclitaxel has broad spectrum activity and is used to treat multiple types of solid tumors including the hard-to-treat pancreatic cancer, the synergistic paclitaxel+siSurvivin combination represents a potentially useful chemo-gene therapy.