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- W2922083599 abstract "Imbalance between lipoprotein uptake and cholesterol efflux from macrophages underlies the formation of foam cells and development of fatty streaks, a process that starts early in life. While currently available lipid lowering interventions attenuate the progression of atherosclerotic plaques, no targeted therapy is presently available for reduction of existing plaques, a process dependent not only on limiting further accumulation of cholesterol but also on stimulation of cholesterol efflux. We earlier reported the development of a mannose functionalized dendrimeric nanoparticles (mDNP)-based platform for targeted delivery of therapeutics to arterial plaque associated macrophages. In this study, we used the optimized mDNP platform to simultaneously deliver SR-A siRNA (to knock down SR-A and limit modified LDL uptake) and LXR ligand (LXR-L, to stimulate macrophage cholesterol efflux by inducing expression of ABCA1/G1) - a “ Two Pronged ” approach. Compared to non-specific NS-siRNA, mDNP mediated delivery of SR-A siRNA led to significant reduction in expression of SR-A (A&B) with a corresponding decrease in uptake of DiI-labeled oxLDL (C). Delivery of LXR-L increased expression of ABCA1/G1 (D) as well as cholesterol efflux (E) and simultaneous delivery of SR-A siRNA did not alter these LXR-L effects. However, combined delivery of siRNA and LXR-L led to significantly higher decrease in macrophage cholesterol content compared to either treatment alone (F). Administration of this in vitro optimized formulation of mDNP complexed with SR-A siRNA and LXR-L to atherosclerotic LDLR-/- mice fed western diet (TD88137) led to a dramatic reduction in lesion area compared to single treatment alone (G). In conclusion, targeted delivery of multiple therapeutics using mDNP platform represents a novel strategy to not only reduce lesion size but it can also be used to simultaneously alter many lesion characteristics such as reducing inflammation or enhancing efferocytosis." @default.
- W2922083599 created "2019-03-22" @default.
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- W2922083599 date "2018-05-01" @default.
- W2922083599 modified "2023-09-25" @default.
- W2922083599 title "Abstract 036: Functionalized Nanoparticle Based “Two-pronged” Approach to Attenuate/regress Atherosclerosis by Simultaneous Knock Down OfSR-A and LXR-mediated Stimulation of Macrophage Cholesterol Efflux" @default.
- W2922083599 doi "https://doi.org/10.1161/atvb.38.suppl_1.036" @default.
- W2922083599 hasPublicationYear "2018" @default.
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