Biology subjects

Maiocchi, S. L.

Publications and source records attributed to Maiocchi, S. L..

2 recordsLinked to original sources

bioRxiv2021

Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the Nrf2 pathway

Atherosclerotic disease is the leading cause of death world-wide with few novel therapies available despite the ongoing health burden. Redox dysfunction is a well-established driver of atherosclerotic progression; however, the clinical translation of redox-based therapies is lacking. One of the challenges facing redox-based therapies is their targeted delivery to cellular domains of redox dysregulation. In the current study, we sought to develop Antioxidant Response Activating nanoParticles (ARAPas), encapsulating redox-based interventions, that exploit macrophage biology and the dysfunctional endothelium in order to selectively accumulate in atherosclerotic plaque. We employed flash nanoprecipitation (FNP) to synthesize bio-compatible polymeric nanoparticles encapsulating the hydrophobic Nrf2 activator drug, CDDO-Methyl (CDDOMe-ARAPas). Nuclear factor erythroid 2-related factor 2 (Nrf2)-activators are a promising class of redox-active drug molecules whereby activation of Nrf2 results in the expression of several antioxidant and cyto-protective enzymes that can be athero-protective. In this study, we characterize the physiochemical properties of CDDOMe-ARAPas as well as confirm their in vitro internalization by murine macrophages. Drug release of CDDOMe was determined by Nrf2-driven GFP fluorescence. Moreover, we show that these CDDOMe-ARAPas exert anti-inflammatory effects in classically activated macrophages. Finally, we show that CDDOMe-ARAPas selectively accumulate in atherosclerotic plaque of two widely-used murine models of atherosclerosis: ApoE-/- and LDLr-/- mice, and are capable of increasing gene expression of Nrf2-transcriptional targets in the atherosclerotic aortic arch. Future work will assess the therapeutic efficacy of intra-plaque Nrf2 activation with CDDOMe-ARAPas to inhibit atherosclerotic plaque progression. Overall, our present studies underline that targeting of atherosclerotic plaque is an effective means to enhance delivery of redox-based interventions.

bioengineering↗

bioRxiv2020

Targeting of atherosclerotic plaque is achieved with polymeric nanoparticles encapsulating Nrf2 activator and LDL-like nanoparticles

Atherosclerotic vascular disease is the leading cause of death world-wide with few novel therapies available in spite of the ongoing health burden. Oxidative stress is a well-established driver of atherosclerotic progression; however the clinical translation of redox-based therapies is lacking. One of the challenges facing redox-based therapies is their targeted delivery to cellular domains of redox dysregulation. In the current study we sought to develop NPs encapsulating redox-based interventions that exploit passive means of targeting to selectively accumulate in atherosclerotic plaque with the aim of enhancing the intra-plaque bioavailability of interventions. Herein we present two types of nanoparticles (NPs): (i) We have employed flash nanoprecipitation to synthesize polymeric NPs encapsulating the hydrophobic Nrf2 activator drug, CDDO-Methyl, (ii) we have generated LDL-like NPs encapsulating the anti-inflammatory compound, oleic acid (OA). Nrf2-activators are a promising class of redox-active drug molecules whereby activation of Nrf2 results in the expression of several antioxidant and cyto-protective enzymes. Moreover, local activation of Nrf2 within the atherosclerotic plaque can be athero-protective. In this study we characterize the physiochemical properties of these NPs as well as confirm in vitro association of NPs with murine macrophages. In vitro drug release of CDDO-Me from polymeric NPs was determined by Nrf2-ARE-driven GFP fluorescence. In vivo localization was assessed through immunofluorescence of histological sections as well as whole-tissue light sheet fluorescence microscopy. We show that CDDO-Me-NPs and LDL-OA-NPs selectively accumulate in atherosclerotic plaque of two widely-used murine models of atherosclerosis: ApoE-/- and LDLr-/- mice. Overall, these studies underline that targeting of atherosclerotic plaque is an effective means to enhance delivery of redox-based interventions. Future work will assess the therapeutic efficacy of intra-plaque Nrf2 activation or anti-inflammatory actions with CDDO-Me-NPs or LDL-OA-NPs, respectively.

bioengineering↗