Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis
| Autor: | Olga Yu. Zolotarskaya, Hongliang He, William J. Korzun, Ryan L. Wallace, Michael G. Lancina, Shobha Ghosh, Paul J. Yannie, Jing Wang, Hu Yang, Quan Yuan, Jinghua Bie |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Dendrimers Mannose 02 engineering and technology Article Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound Mice Physiology (medical) polycyclic compounds Macrophage Animals Liver X receptor Cells Cultured Liver X Receptors Liver cell Macrophages Biochemistry (medical) Public Health Environmental and Occupational Health General Medicine 021001 nanoscience & nanotechnology Atherosclerosis 030104 developmental biology chemistry Receptors LDL Immunology Cholesteryl ester Cancer research Nanoparticles lipids (amino acids peptides and proteins) Female 0210 nano-technology Cell activation Mannose receptor |
| Zdroj: | Translational research : the journal of laboratory and clinical medicine. 193 |
| ISSN: | 1878-1810 |
| Popis: | Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR-/- mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque burden. |
| Databáze: | OpenAIRE |
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