Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox‐Sensitive Nanogels

Abstract

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.

Translating Therapeutic Microgels into Clinical Applications

“…DOX was used as model drug. The microgels entered the tumor via the EPR effect, [ 172 ] where DOX was quickly released mediated by the high concentration of intracellular glutathione (GSH) (≈10.0 m m ). [ 171 ]…”

“…DOX was used as model drug. The microgels entered the tumor via the EPR effect, [172] where DOX was quickly released mediated by the high concentration of intracellular glutathione (GSH) (≈10.0 mm). [171] In addition to pH and redox, enzyme-responsive microgels have great potential as drug delivery systems as enzymes like lipases, proteases, and glycosidases can recognize specific domains and induce highly selective bond scission.…”

PLGA-Based Nanoparticles in Cancer Treatment

“…Those changes in biodistribution and pharmacokinetics are the “hidden” faces of the cube, which can only be manipulated to a certain (rather low) extent via co-medication or interventions, e.g., sonoporation ( Dasgupta et al, 2016 ; Dimcevski et al, 2016 ; Koczera et al, 2017 ) or in vivo modulation of oxidative stress via administration of buthionine sulfoximine (BSO), an inhibitor of the antioxidant glutathione (GSH). GSH neutralizes reactive oxygen species (ROS) and its depletion cannot only prevent premature degradation of a redox-sensitive nanoformulation but can also serve as a hypoxic cell sensitizer in combination with radiation and some chemotherapeutic drugs ( Drude et al, 2018 ; Miran et al, 2018 ).…”

Dandelion flower-like micelles

“…To mimic the release of seeds from dandelion owers by wind, we introduced redox-sensitive disuldes between SCMs and PCL chains, which were cleaved in a reductive environment, releasing the SCMs from the DFMs. [47][48][49][50] To verify this hypothesis, we incubated the DFMs (1 mg mL À1 ) in the presence of 20 mM GSH to study the structural changes of DFMs and the release of SCMs under the stimuli. As expected, the Tyndall phenomenon rapidly became very weak, accompanied by a small amount of precipitation aer the addition of 20 mM GSH (Fig.…”