Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox-Sensitive Nanogels
| Autor: | Felix M. Mottaghy, Martin Möller, Smriti Singh, Hiltrud Königs, Agnieszka Morgenroth, Natascha Drude, Oliver Winz, Marion Roller |
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| Přispěvatelé: | RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Beeldvorming, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Biodistribution
RADIOLABELED NANOGELS Metabolite Nanogels redox-sensitive nanogels 02 engineering and technology 010402 general chemistry 01 natural sciences Redox Polyethylene Glycols Biomaterials chemistry.chemical_compound In vivo SYSTEMS NANOPARTICLES Polyethyleneimine General Materials Science CELL glutathione DRUG-DELIVERY DISULFIDE BONDS Buthionine Sulfoximine INTRACELLULAR DRUG Chemistry buthioninsulfoximin small animal positron emission tomography General Chemistry Glutathione CHEMOTHERAPY 021001 nanoscience & nanotechnology 0104 chemical sciences REDUCTION Positron-Emission Tomography Drug delivery Biophysics POLYMERS 0210 nano-technology Oxidation-Reduction pharmacokinetics Intracellular Biotechnology Nanogel |
| Zdroj: | Small, 14(14):1704093. Wiley-VCH Verlag |
| ISSN: | 1613-6810 |
| DOI: | 10.1002/smll.201704093 |
| Popis: | Nanoparticles degradable upon external stimuli combine pharmacokinetic features of both small molecules as well as large nanoparticles. However, despite promising preclinical results, several redox responsive disulphide-linked nanoparticles failed in clinical translation, mainly due to their unexpected in vivo behavior. Glutathione (GSH) is one of the most evaluated antioxidants responsible for disulfide degradation. Herein, the impact of GSH on the in vivo behavior of redox-sensitive nanogels under physiological and modulated conditions is investigated. Labelling of nanogels with a DNA-intercalating dye and a radioisotope allows visualization of the redox responsiveness at the cellular and the systemic levels, respectively. In vitro, efficient cleavage of disulphide bonds of nanogels is achieved by manipulation of intracellular GSH concentration. While in vivo, the redox-sensitive nanogels undergo, to a certain extent, premature degradation in circulation leading to rapid renal elimination. This instability is modulated by transient inhibition of GSH synthesis with buthioninsulfoximin. Altered GSH concentration significantly changes the in vivo pharmacokinetics. Lower GSH results in higher elimination half-life and altered biodistribution of the nanogels with a different metabolite profile. These data provide strong evidence that decreased nanogel degradation in blood circulation can limit the risk of premature drug release and enhance circulation half-life of the nanogel. |
| Databáze: | OpenAIRE |
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