Folate-linked lipoplexes for short hairpin RNA targeting claudin-3 delivery in ovarian cancer xenografts
Folate-linked lipoplexes for short hairpin RNA targeting claudin-3 delivery in ovarian cancer xenografts
复制标题
叶酸连接的脂质复合物用于卵巢癌异种移植物中靶向claudin-3的短发夹RNA递送
DOI：
10.1016/j.jconrel.2013.10.015
复制
发表时间：
2013-12-28
影响因子：
10.8
通讯作者：
Wei, Yu-Quan
中科院分区：
文献类型：
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作者：
He, Zhi-Yao;Wei, Xia-Wei;Wei, Yu-Quan
卵巢癌高表达叶酸受体α(FRα)和Claudin3(CLDN3)，二者均与肿瘤进展和患者预后不良有关。卵巢癌组织中FRα和CLDN3的表达下调可能抑制肿瘤生长，促进肿瘤的良性分化。本研究制备了以短发夹状RNA(ShRNA)为靶向的FRα靶向脂质体F-P-LP/CLDN3，并对其药学性质进行了表征。然后，在进展期卵巢癌的体内模型上，研究了F-P-LP/CLDN3的抗肿瘤作用。与对照组相比，F-P-LP/CLDN3促进了肿瘤的良性分化，达到了约90%的肿瘤生长抑制率。同时，恶性腹水的产生被完全抑制，肿瘤结节数和肿瘤重量显著减少(p<；0.001)。F-P-LP/CLDN3处理的肿瘤组织中FRα和CLDN3共同下调。其抗肿瘤机制是通过促进肿瘤细胞凋亡、抑制肿瘤细胞增殖、降低微血管密度来实现的。最后，安全性评价表明，F-P-LP/CLDN3是一种安全的腹腔给药治疗癌症的制剂。我们得出结论：F-P-LP/CLDN3是一种潜在的卵巢癌基因治疗靶向制剂。爱思唯尔出版公司(Elsevier B.V.)
Ovarian cancers highly overexpress folate receptor alpha (FR alpha) and claudin3 (CLDN3), both of which are associated with tumor progression and poor prognosis of patients. Downregulation of FR alpha and CLDN3 in ovarian cancer may suppress tumor growth and promote benign differentiation of tumor. In this study, F-P-LP/CLDN3, a FR alpha targeted liposome loading with short hairpin RNA (shRNA) targeting CLDN3 was prepared and the pharmaceutical properties were characterized. Then, the antitumor effect of F-P-LP/CLDN3 was studied in an in vivo model of advanced ovarian cancer. Compared with Control, F-P-LP/CLDN3 promoted benign differentiation of tumor and achieved about 90% tumor growth inhibition. In the meantime, malignant ascites production was completely inhibited, and tumor nodule number and tumor weight were significantly reduced (p < 0.001). FR alpha and CLDN3 were downregulated together in tumor tissues treated by F-P-LP/CLDN3. The antitumor mechanisms were achieved by promoting tumor cell apoptosis, inhibiting tumor cell proliferation and reducing microvessel density. Finally, safety evaluation indicated that F-P-LP/CLDN3 was a safe formulation in intraperitoneally administered cancer therapy. We come to a conclusion that F-P-LP/CLDN3 is a potential targeting formulation for ovarian cancer gene therapy. Published by Elsevier B.V.