scholarly journals Characterization of LXR-activating nanoparticle formulations in primary mouse macrophages

2019 ◽  
Author(s):  
Tyler KT Smith ◽  
Zaina Kahiel ◽  
Nicholas D LeBlond ◽  
Peyman Ghorbani ◽  
Eliya Farah ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cholesterol Efflux ◽  
Specific Drug ◽  
Redox Active ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Nanoparticle Formulation ◽  
Abca1 Protein ◽  
Disease Specific

AbstractActivation of the transcription factor liver X receptor (LXR), has shown to be efficient at curbing aberrant lipid metabolism and inflammation. While small molecule delivery via nanomedicine has promising applications for a number of chronic diseases, there remain questions as to how nanoparticle formulation might be tailored to suit different tissue microenvironments and aid in drug delivery. In the current study, we compared the drug delivery capability of three nanoparticle (NP) formulations encapsulating the LXR activator, GW-3956. We observed little difference in the base characteristics of standard PLGA-PEG NP when compared to two redox-active polymeric NP formulations (DD and DB). Moreover, we also observed similar uptake of these NP into primary mouse macrophages. After an initial acute uptake period and using the transcript and protein expression of the cholesterol efflux protein ATP binding cassette A1 (ABCA1) as a readout, we determined that while the induction of transcript expression was similar between NPs, treatment with the redox-sensitive DB formulation resulted in a higher level of ABCA1 protein 24 h after the removal of the drug-containing NPs. Our results suggest that NP formulations responsive to cellular cues may be an effective tool for targeted and disease-specific drug release.

scholarly journals Characterization of Redox-Responsive LXR-Activating Nanoparticle Formulations in Primary Mouse Macrophages

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3751 ◽  
Author(s):  
Tyler K. T. Smith ◽  
Zaina Kahiel ◽  
Nicholas D. LeBlond ◽  
Peyman Ghorbani ◽  
Eliya Farah ◽  
...  
Keyword(s):  
Potential Candidate ◽  
Beneficial Effects ◽  
Redox Active ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Redox Responsive ◽  
Exposure In Vivo ◽  
Abca1 Protein

Activation of the transcription factor liver X receptor (LXR) has beneficial effects on macrophage lipid metabolism and inflammation, making it a potential candidate for therapeutic targeting in cardiometabolic disease. While small molecule delivery via nanomedicine has promising applications for a number of chronic diseases, questions remain as to how nanoparticle formulation might be tailored to suit different tissue microenvironments and aid in drug delivery. In the current study, we aimed to compare the in vitro drug delivering capability of three nanoparticle (NP) formulations encapsulating the LXR activator, GW-3965. We observed little difference in the base characteristics of standard PLGA-PEG NP when compared to two redox-active polymeric NP formulations, which we called redox-responsive (RR)1 and RR2. Moreover, we also observed similar uptake of these NP into primary mouse macrophages. We used the transcript and protein expression of the cholesterol efflux protein and LXR target ATP-binding cassette A1 (ABCA1) as a readout of GW-3956-induced LXR activation. Following an initial acute uptake period that was meant to mimic circulating exposure in vivo, we determined that although the induction of transcript expression was similar between NPs, treatment with the redox-sensitive RR1 NPs resulted in a higher level of ABCA1 protein. Our results suggest that NP formulations responsive to cellular cues may be an effective tool for targeted and disease-specific drug release.

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