A preliminary study on the interaction between Asn-Gly-Arg (NGR)-modified multifunctional nanoparticles and vascular epithelial cells

Liu, Chunxi; Liu, Tingxian; Yu, Xiaoyue; Gu, Yizhu

In recent years, gene therapy and drug targeting studies have revealed the importance of identifying intracellular mechanisms of efficient delivery 1 . Understanding the potential uptake mechanisms involved in the cellular entry of test nanoparticles could be helpful to provide feedback for the rational design of improved vectors 2, 3 . Accordingly, scientists have been aware of the characteristics of typical trafficking pathways for many targeted therapeutics. Endocytosis pathways other than classical clathrin-mediated endocytosis (CME) have been recently characterized in some details. Such pathways may offer alternative uptake and trafficking pathways for gene delivery vectors 4 . Caveolae-mediated endocytosis (CvME) has been generally considered to be a non-acidic and nondigestive uptake route, which indicates that it does not sense a drop in pH but travels through pH-neutral caveosomes directly to the Golgi and/or endoplasmic reticulum (ER), from which nuclear entry can take place, thereby avoiding lysosomal degradation [5] [6] [7] [8] . CvME is characterized by the evolution of caveolae, which are small, flask-shaped non-clathrin coated invaginations of the hydrophobic membrane subdomains enriched in cholesterol, glycosphingolipids and caveolin protein 9 . The caveolin protein family has three members: caveolin 1 (CAV1), caveolin 2 (CAV2) and caveolin 3 (CAV 3). Among them, CAV1 is the major structural protein in caveolae possessing the ability to interact with numerous proteins [10] [11] [12] . Caveolae in vascular endothelial cells were first identified by Paladern 13 in 1968. Caveolae exist alone or in a cluster on many types of mammalian cells, particularly on epithelial cells, endothelial cells, fibroblasts, adipocytes and smooth muscle cells 14 . Caveolae can transport bioactive molecules into cells and participate in the reception and transduction of multiple signals 11 . In recent years, the cell physiological function of caveolae has drawn increasing attention, especially in signal transduction, cholesterol transport, cell internalization, tumor suppression and muscle cell synthesis 15 . Additionally, increasing numbers of studies have shown caveolae to be closely related to many diseases, including cancer, arteriosclerosis, muscular dystrophy, early Alzheimer's and diabetes 16 . Because of these characteristics, CvME has attracted tremendous attention in the field of gene delivery research. Among of them, attaching specific ligands to the polymer-based carriers to target CvME has been become a promising approach in gene therapy 5, [17] [18] .