The targeted intracellular delivery of cytochrome C protein to tumors using lipid-apolipoprotein nanoparticles.
The targeted intracellular delivery of cytochrome C protein to tumors using lipid-apolipoprotein nanoparticles.
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DOI：
10.1016/j.biomaterials.2012.02.010
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发表时间：
2012-05
期刊：
影响因子：
14
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Kim, Sang Kyoon;Foote, Michael B.;Huang, Leaf
细胞内作用的治疗蛋白提供了一种很有前途的细胞外作用药物的临床替代方案，但由于其对细胞质的低渗透性，其疗效受到限制。我们开发了一种由脂质(DOTAP/DOPE)和载脂蛋白(APO A-I)组成的纳米颗粒(NP)，以介导细胞内作用蛋白药物的靶向递送到非小细胞肺癌。NPS是用荧光模型蛋白GFP或细胞色素C(CytC)产生的，细胞色素C是癌细胞中的凋亡诱导剂。GFP和CytC分别与膜可渗透序列(MPS)多肽偶联，并与DOPE/DOTAP纳米制剂(NPs)混合，以实现成功的蛋白质负载。在异种移植模型中，用DSPE-PEG-苯甲酰胺修饰蛋白质负载的NPs，以实现特定的NP靶向肿瘤部位。制得的纳米粒子尺寸为20-30 nm，载药率为-75%。经聚乙二醇化的MPS-cytC-NPs处理的H460细胞出现大量的细胞凋亡。H460荷瘤小鼠静脉注射MPS-GFP-NPs或MPS-cytC-NPs后，肿瘤靶向性明显增强，肝脏内NP积聚较少。此外，MPS-cytC-NP治疗对H460异种移植小鼠的肿瘤生长有抑制作用。我们的结论是，我们的NP使靶向、有效的治疗性蛋白输送用于肺癌的治疗。
Intracellular-acting therapeutic proteins offer a promising clinical alternative to extracellular-acting agents, but are limited in efficacy by their low permeability into the cell cytoplasm. We have developed a nanoparticle (NP) composed of lipid (DOTAP/DOPE) and apolipoprotein (APO A-I) to mediate the targeted delivery of intracellular-acting protein drugs to non-small cell lung tumors. NPs were produced with either GFP, a fluorescent model protein, or cytochrome C (cytC), an inducer of apoptosis in cancer cells. GFP and cytC were separately conjugated with a membrane permeable sequence (MPS) peptide and were admixed with DOPE/DOTAP nanoparticle formulations (NPs) to enable successful protein loading. Protein-loaded NPs were modified with DSPE-PEG-Anisamide to enable specific NP targeting to the tumor site in a xenograft model. The resulting particle was 20–30 nm in size and exhibited a 64–75% loading efficiency. H460 cells treated with the PEGylated MPS-cytC-NPs exhibited massive apoptosis. When MPS-GFP-NPs or MPS-cytC-NPs were intravenously administered in H460 tumor bearing mice, a specific tumor targeting effect with low NP accumulation in the liver was observed. In addition, MPS-cytC-NP treatment provoked a tumor growth retardation effect in H460 xenograft mice. We conclude that our NP enables targeted, efficacious therapeutic protein delivery for the treatment of lung cancer.
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影响因子：
4.9
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