1. Cyclo-RGD Truncated Polymeric Nanoconstruct with Dendrimeric Templates for Targeted HDAC4 Gene Silencing in a Diabetic Nephropathy Mouse Model
Nidhi Raval, Hardi Jogi, Piyush Gondaliya, Kiran Kalia, Rakesh K Tekade Mol Pharm. 2021 Feb 1;18(2):641-666. doi: 10.1021/acs.molpharmaceut.0c00094. Epub 2020 May 26.
Diabetic nephropathy (DN), a chronic progressive kidney disease, is a significant complication of diabetes mellitus. Dysregulation of the histone deacetylases (HDACs) gene has been implicated in the pathogenesis of DN. Hence, the HDAC-inhibitors have emerged as a critical class of therapeutic agents in DN; however, the currently available HDAC4-inhibitors are mostly nonselective in nature as well as inhibit multiple HDACs. RNA interference of HDAC4 (HDAC4 siRNA) has shown immense promise, but the clinical translation has been impeded due to lack of a targeted, specific, and in vivo applicable delivery modality. In the present investigation, we examined Cyclo(RGDfC) (cRGD) truncated polymeric nanoplex with dendrimeric templates for targeted HDAC4 Gene Silencing. The developed nanoplex exhibited enhanced encapsulation of siRNA and offered superior protection against serum RNase nucleases degradation. The nanoplex was tested on podocytes (in vitro), wherein it showed selective binding to the αvβ3 integrin receptor, active cellular uptake, and significant in vitro gene silencing. The in vivo experiments showed remarkable suppression of the HDAC4 and inhibition in the progression of renal fibrosis in the Streptozotocin (STZ) induced DN C57BL/6 mice model. Histopathological and toxicological studies revealed nonsignificant abnormality/toxicity with the nanoplex. Conclusively, nanoplex was found as a promising tactic for targeted therapy of podocytes and could be extended for other kidney-related ailments.
2. Neural Stem Cell Spreading on Lipid Based Artificial Cell Surfaces, Characterized by Combined X-ray and Neutron Reflectometry
Martin Huth, Samira Hertrich, Gabor Mezo, Emilia Madarasz, Bert Nickel Materials (Basel). 2010 Nov 22;3(11):4994-5006. doi: 10.3390/ma3114994.
We developed a bioadhesive coating based on a synthetic peptide-conjugate (AK-cyclo[RGDfC]) which contains multiples of the arginyl-glycyl-aspartic acid (RGD) amino acid sequence. Biotinylated AK-cyclo[RGDfC] is bound to a supported lipid bilayer via a streptavidin interlayer. Layering, hydration and packing of the coating is quantified by X-ray and neutron reflectometry experiments. AK-cyclo[RGDfC] binds to the streptavidin interlayer in a stretched-out on edge configuration. The highly packed configuration with only 12% water content maximizes the number of accessible adhesion sites. Enhanced cell spreading of neural stem cells was observed for AK-cyclo[RGDfC] functionalized bilayers. Due to the large variety of surfaces which can be coated by physisorption of lipid bilayers, this approach is of general interest for the fabrication of biocompatible surfaces.
3. Kidney podocytes as specific targets for cyclo(RGDfC)-modified nanoparticles
Klaus Pollinger, Robert Hennig, Miriam Breunig, Joerg Tessmar, Andreas Ohlmann, Ernst R Tamm, Ralph Witzgall, Achim Goepferich Small. 2012 Nov 5;8(21):3368-75. doi: 10.1002/smll.201200733. Epub 2012 Aug 8.
Renal nanoparticle passage opens the door for targeting new cells like podocytes, which constitute the exterior part of the renal filter. When cyclo(RGDfC)-modified Qdots are tested on isolated primary podocytes for selective binding to the αvβ3 integrin receptor a highly cell- and receptor-specific binding can be observed. In displacement experiments with free cyclo(RGDfC) IC(50) values of 150 nM for αvβ3 integrin over-expressing U87-MG cells and 60 nM for podocytes are measured. Confocal microscopy shows a cellular Qdot uptake into vesicle-like structures. Our ex vivo study gives clear evidence that, after renal filtration, nanoparticles can be targeted to podocyte integrin receptors in the future. This could be a highly promising approach for future therapy and diagnostics of podocyte-associated diseases.
