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Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing.

ABSTRACT: Gene silencing mediated by small interfering RNA (siRNA) is a novel approach in the development of new cancer therapeutics. Polycations used for nucleic acid delivery still remain heterogeneous compounds, despite continuous progress in polymer synthetic technologies. Here we report the development of a structural defined folic acid polyethylene glycol (PEG) siRNA conjugate accessible via click chemistry yielding a monodisperse ligand-PEG-siRNA conjugate. The folic acid targeting ligand was synthesized by solid phase supported peptide chemistry. The conjugate was shown to be specifically internalized into folic acid receptor expressing cells. When combined with a structurally defined polycation, again synthesized with the precision of solid phase chemistry, efficient receptor specific gene silencing is achieved.

SUBMITTER: Dohmen C

PROVIDER: S-EPMC3381594 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing.

Dohmen Christian C Fröhlich Thomas T Lächelt Ulrich U Röhl Ingo I Vornlocher Hans-Peter HP Hadwiger Philipp P Wagner Ernst E

Molecular therapy. Nucleic acids 20120131

Gene silencing mediated by small interfering RNA (siRNA) is a novel approach in the development of new cancer therapeutics. Polycations used for nucleic acid delivery still remain heterogeneous compounds, despite continuous progress in polymer synthetic technologies. Here we report the development of a structural defined folic acid polyethylene glycol (PEG) siRNA conjugate accessible via click chemistry yielding a monodisperse ligand-PEG-siRNA conjugate. The folic acid targeting ligand was synth ...[more]

PMID: 23344624

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Project description:We recently demonstrated the far-red light-activatable prodrug of paclitaxel (PTX), Pc-(L-PTX)2. Upon illumination with a 690 nm laser, Pc-(L-PTX)2 showed combinational cell killing from rapid photodynamic therapy damage by singlet oxygen, followed by sustained chemotherapy effects from locally released PTX. However, its high lipophilicity (log D7.4 > 3.1) caused aggregation in aqueous solutions and has nonselectivity toward cancer cells. To solve these important problems, we prepared folic acid (FA)-conjugated and photoactivatable prodrugs of PTX with a polyethylene glycol (PEG) spacer of various chain lengths: FA-PEG n -Pc-L-PTX [n = 0 (0k, 5), ?23 (1k, 7a), ?45 (2k, 7b), ?80 (3.5k, 7c), or ?114 (5k, 7d)]. The PEGylated prodrugs 7a-d had a much improved hydrophilicity compared with the non-PEGylated prodrug, Pc-(L-PTX)2. As the PEG length increased, the hydrophilicity of the prodrug increased (log D7.4 values: 1.28, 0.09, -0.24, and -0.59 for 1k, 2k, 3.5k, and 5k PEG prodrugs, respectively). Fluorescence spectral data suggested that the PEGylated prodrugs had good solubility in the culture medium at lower concentrations (<1-2 ?M), but showed fluorescence quenching due to limited solubility at higher concentrations (>2 ?M). Dynamic light scattering indicated that all of the prodrugs formed nanosized particles in both phosphate-buffered saline and culture medium at a concentration of 5 ?M. The PEG length affected both nonspecific and folate receptor (FR)-mediated uptake of the prodrugs. The enhanced cellular uptake was observed for the prodrugs with medium-sized PEGs (1k, 2k, or 3.5k) in FR-positive SKOV-3 cells, but not for the prodrugs with no PEG or with the longest PEG (5k), which suggests the optimal range of PEG length around 1k-3.5k for effective uptake of our prodrug system. Consistent with the cellular uptake pattern, medium-sized PEGylated prodrugs showed more potent phototoxic activity (IC50s, ?130 nM) than prodrugs with no PEG or the longest PEG (IC50, ?400 nM). In conclusion, we have developed far-red light-activatable prodrugs with improved water solubility and FR-targeting properties compared with the nontargeted prodrug.

Dataset Information

Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing.

Publications

Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing.

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