Abstract
Polyethyleneimine, poly-L-lysine, chitosan and some others cationic polymers have been thoroughly studied as nucleic acid delivery systems in gene therapy. However, the drug release from these systems proceeds at a very low rate due to extremely high binding between a carrier and gene material. To reduce these interactions and to enhance drug release, we developed a set of amphiphilic polypeptides containing positively and negatively charged amino acids as well as a hydrophobic one. The copolymers obtained were characterized by size-exclusion chromatography, static light scattering, HPLC amino acid analysis and 1HNMR spectroscopy. All copolymers formed particles due to a self-assembly in aqueous media. Depending on polypeptide composition, the formation of particles with hydrodynamic diameters from 180 to 900 nm was observed. Stability of polymer particles, loading and release efficiency were carefully studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. The application of polymer carriers, containing siRNA, to vascular endothelial growth factor (VEGF-A165) silencing of ARPE-19 cells was successful. The gene silencing was confirmed by suppression of both messenger RNA and protein expression.
Highlights
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are among the most common ocular diseases that lead to the impairment or loss of vision [1,2]
To reduce these interactions and to enhance drug release, we developed a set of amphiphilic polypeptides containing positively and negatively charged amino acids as well as a hydrophobic one
Proliferative neovascular forms of DR and AMD are characterized by the formation of new vessels from the existing ones, because the proliferation and migration of endothelial cells are stimulated by over-expression of vascular endothelial growth factor (VEGF) [3]
Summary
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are among the most common ocular diseases that lead to the impairment or loss of vision [1,2]. Inhibition of VEGF via intraocular injections of anti-VEGF drugs are the corner-stone approach in the treatment of AMD and diabetic macular edema that is associated with DR. A common clinical therapy is based on application of the monoclonal antibodies (mABs) that bind to VEGF, and neutralize its function. Such recombinant monoclonal antibodies as bevacizumab and its Fab-fragment ranibizumab bind with high affinity to the site present in all VEGF isoforms [4,5]. The intravitreal injections may lead to some complications, such as retinal detachment, intraocular pressure increase, ocular infection, and hyperemia
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