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  • Title: A novel tumor-targeted delivery system with hydrophobized hyaluronic acid-spermine conjugates (HHSCs) for efficient receptor-mediated siRNA delivery.
    Author: Shen Y, Wang B, Lu Y, Ouahab A, Li Q, Tu J.
    Journal: Int J Pharm; 2011 Jul 29; 414(1-2):233-43. PubMed ID: 21545832.
    Abstract:
    A novel target specific small interfering RNA (siRNA) delivery system was successfully developed using hydrophobized hyaluronic acid-spermine conjugates (HHSCs), which were previously synthesized and their properties were also characterized in our published papers. Fluorescein isothiocyanate (FITC) labeled specific Silencer Select siRNAs were used as a model system suppressing the cyclooxygenase-2 (COX-2) gene expression. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. The cytotoxicity of siRNA/HHSCs complex to SGC-7901 cells was lower than that of siRNA/PEI 25k and Lipofectamine 2000 complex according to the MTT assay. When SGC-7901 and GES-1 cells were treated with FITC labeled siRNA/HHSCs complexes, SGC-7901 cells, with a cluster determinant 44 receptor (CD(44)), showed higher green fluorescent intensity than GES-1 cells because of the HA receptor mediated endocytosis of the complex. In addition, the inhibitory effect on the uptake in the presence of free HA in the transfection medium revealed that siRNA/HHSC-1 complex was selectively taken up to SGC-7901 cells via HA-receptor mediated endocytosis. Based on flow cytometry and microscopy, observation revealed that siRNA/HHSC complex was taken up preferentially through caveolae-mediated endocytosis, which may be a desirable pathway for avoiding the lysosomal degradation of delivered genes. All these results demonstrated that the intracellular delivery of siRNA/HHSC complex could be facilitated by the HA-receptor mediated endocytosis.
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