Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors.
Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors.
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DOI：
10.1016/j.jconrel.2014.01.012
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发表时间：
2014-03-28
期刊：
影响因子：
--
通讯作者：
Au JL
中科院分区：
文献类型：
--
作者：
Wang J;Lu Z;Yeung BZ;Wientjes MG;Cole DJ;Au JL
在美国，源自消化系统的癌症占每年所有新发癌症病例的290，000或~20%。我们先前开发了紫杉醇负载的肿瘤穿透微粒（TPM）用于腹膜内（IP）治疗腹膜肿瘤。TPM正在接受NIH支持的IND支持研究以进行临床评估。本研究评估了TPM通过诱导细胞凋亡和扩大间质间隙促进含siRNA的脂质载体的递送和转染的假设。体内模型是转移性人Hs 766 T胰腺肿瘤，IP注射后，在100%动物的腹腔中产生广泛分布的实体瘤和腹水。靶基因是survivin，一种由化疗诱导的抗凋亡蛋白，与胃癌和结直肠癌患者的转移和不良预后相关。siRNA载体是包含阳离子和中性脂质加上融合脂质（PCat）的聚乙二醇化脂质体。负载有存活素siRNA的PCat（PCat-siSurvivin）在培养的细胞中是有活性的（降低存活素mRNA和蛋白水平，降低细胞克隆形成，增强紫杉醇活性），但在体内失去其活性;这种差异与众所周知的体内siRNA递送和转染不足的问题一致。相比之下，单剂TPM延长了动物的生存期，正如预期的那样，诱导肿瘤中的生存素表达。加入PCat-siSurvivin逆转TPM诱导的Survivin表达，增强TPM的抗肿瘤活性。通过PCat-siSurvivin的体内生存素敲低仅在其与TPM组合给予时才成功的发现提供了肿瘤引发促进脂质体siRNA的递送和转染的概念验证。数据进一步表明TPM/PCat-siSurvivin组合作为腹膜癌的潜在有用的化学基因疗法。
Cancers originating from digestive system account for 290,000 or ~20% of all new cancer cases annually in the US. We previously developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal (IP) treatment of peritoneal tumors. TPM is undergoing NIH-supported IND-enabling studies for clinical evaluation. The present study evaluated the hypothesis that TPM, via inducing apoptosis and expanding the interstitial space, promotes the delivery and transfection of lipid vectors containing siRNA. The in vivo model was the metastatic human Hs766T pancreatic tumor that, upon IP injection, produced widely distributed solid tumors and ascites in the peritoneal cavity in 100% animals. The target gene was survivin, an anti-apoptotic protein induced by chemotherapy and associated with metastases and poor prognosis of patients with gastric and colorectal cancer. The siRNA carrier was pegylated liposomes comprising cationic and neutral lipids plus a fusogenic lipid (PCat). PCat-loaded with survivin siRNA (PCat-siSurvivin) was active in cultured cells (decreased survivin mRNA and protein levels, reduced cell clonogenicity, enhanced paclitaxel activity), but lost its activity in vivo; this difference is consistent with the well-known problem of inadequate delivery and transfection of siRNA in vivo. In comparison, single agent TPM prolonged animal survival and, as expected, induced survivin expression in tumors. Addition of PCat-siSurvivin reversed the TPM-induced survivin expression and enhanced the antitumor activity of TPM. The finding that in vivo survivin knockdown by PCat-siSurvivin was successful only when it was given in combination with TPM provides the proof-of-concept that tumor priming promotes the delivery and transfection of liposomal siRNA. The data further suggest the TPM/PCat-siSurvivin combination as a potentially useful chemo-gene therapy for peritoneal cancer.
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