Pancreatic cancer therapy by systemic administration of VEGF siRNA contained in calcium phosphate/charge-conversional polymer hybrid nanoparticles
Pancreatic cancer therapy by systemic administration of VEGF siRNA contained in calcium phosphate/charge-conversional polymer hybrid nanoparticles
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DOI：
10.1016/j.jconrel.2012.05.005
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发表时间：
2012-08-10
影响因子：
10.8
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Pittella, Frederico;Miyata, Kanjiro;Kataoka, Kazunori
开发一种高效的小干扰RNA （siRNA）体内递送载体是siRNA治疗成功的关键挑战。在本研究中，为了将siRNA系统地递送到实体肿瘤中，利用pH敏感的聚乙二醇嵌段共聚物和电荷转换聚合物（PEG-CCP）制备了一种智能聚合物/磷酸钙(CaP)/siRNA杂交纳米颗粒，该纳米颗粒具有生物相容性、可逆稳定性和内体逃逸功能，其中阴离子官能团可以在内体酸性条件下转化为阳离子官能团，促进内体逃逸。纳米颗粒的尺寸约为100 nm，分布狭窄，呈球形。此外，纳米颗粒在含有血清的培养基中具有高度耐受性，同时在模拟细胞质的离子条件下释放被捕获的siRNA，可能是基于CaP复合物和钙离子之间的平衡。此外，纳米颗粒在培养的胰腺癌细胞（BxPC3）中显示出高的基因沉默效率，而没有相关的细胞毒性。最终，全身给药携带血管内皮生长因子（VEGF） siRNA的纳米颗粒导致皮下BxPC3肿瘤生长显著减少，这与肿瘤中siRNA积累增强和VEGF基因沉默（类似68%）完全一致。因此，混合纳米颗粒被证明是一种有希望的基于sirna的癌症治疗配方。(c) 2012 Elsevier B.V.版权所有
Development of an efficient in vivo delivery vehicle of small interfering RNA (siRNA) is the key challenge for successful siRNA-based therapies. In this study, toward systemic delivery of siRNA to solid tumors, a smart polymer/calcium phosphate (CaP)/siRNA hybrid nanoparticle was prepared to feature biocompatibility, reversible stability and endosomal escape functionality using a pH sensitive block copolymer of poly(ethylene glycol) and charge-conversional polymer (PEG-CCP), of which anionic functional groups could be converted to cationic groups in an endosomal acidic condition for facilitated endosomal escape. Nanoparticles were confirmed to be approximately 100 nm in size, narrowly dispersed and spherical. Also, the nanoparticle was highly tolerable in medium containing serum, while releasing the entrapped siRNA in a cytoplasm-mimicking ionic condition, presumably based on the equilibrium between CaP complexes and calcium ions. Further, the nanoparticle showed high gene silencing efficiency in cultured pancreatic cancer cells (BxPC3) without associated cytotoxicity. Ultimately, systemic administration of the nanoparticles carrying vascular endothelium growth factor (VEGF) siRNA led to the significant reduction in the subcutaneous BxPC3 tumor growth, well consistent with the enhanced accumulation of siRNA and the significant VEGF gene silencing (similar to 68%) in the tumor. Thus, the hybrid nanoparticle was demonstrated to be a promising formulation toward siRNA-based cancer therapies. (c) 2012 Elsevier B.V. All rights reserved.