The targeted intracellular delivery of cytochrome聽C protein to tumors using lipid-apolipoprotein nanoparticles
- 作者：Sang Kyoon Kim ; Michael B. Foote ; Leaf Huang ; leafh@email.unc.edu ; leafh@unc.edu
- 关键词：Nanoparticle ; Liposome ; Apolipoprotein ; PEGylation ; Protein delivery ; Anisamide
- 刊名：Biomaterials
- 出版年：2012
- 期刊代码：7_01429612
- 类别：ms
- 出版时间：May, 2012
- 卷：33
- 期：15
- 页码：3959-3966
- 文件大小：2119 K
摘要
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 (APOA-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 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聽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.