Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

Abstract

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. mDNPLXR-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.

Advanced nanomedicines for the treatment of inflammatory diseases

“…injections Significant inhibition of cartilage damage, synovial inflammation, and loss of type II collagen Down regulation of IL-1 β , MMP-3 and MMP-13 in synovial tissues [ 48 ] Mannose-functionalized dendrimeric NPs using polyamidoamine dendrimer Liver X receptor (LXR) ligand T0901317 12 weeks of Western Diet to induce atherosclerosis Ldlr -/- mice Once per week for 4 weeks after the 12 weeks of diet 200 μg of NPs by i.v. injection Specific uptake by macrophages and not hepatocytes in atherosclerotic plaques Increased expression of LXR target genes (ABCA1/ABCG1) Enhanced cholesterol efflux Significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation [ 108 ] Biodegradable diblock PLGA-b-PEG copolymer NPs Liver X receptor (LXR) ligand GW3965 Zymosan A-induced peritonitis Ldlr -/- mice 5h treatment (1) or over 2 weeks (2) 10 mg/kg of equivalent agonist 1h prior to Zymosan injection (1) or 6 injections of 10 mg/kg (2), i.v. injections Significantly more efficient than free drug for inducing LXR target gene expression and suppressing inflammatory factors Reduction of CD68-positive macrophage content of plaques (by 50%) [ 109 ] Phospholipid-reconstituted ApoA-I peptide-derived synthetic HDL Liver X receptor (LXR) ligand T0901317 Atherogenic diet for 14 weeks 8-week-old male ApoE-deficient mice 3 times a week for 6 weeks 30 mg/kg of NPs, which is equal to 1.5 mg/kg of ligands, i.v.…”

Mannose receptor 1 expression does not determine the uptake of high-density mannose dendrimers by activated macrophages populations

“…However, the results showed uptake of Mannose-dendrimer-Cy5 for RAW 264.7 treated with LPS and IL-4 and indicate that the compound was not specific uptake for MRC1. He et al [45] also developed PAMAM G5 dendrimer conjugated with mannose and LXR-LT091317. The objective was to develop an agent for specific delivery to atherosclerotic plaque-associated macrophages via MRC1.…”

Human serum albumin nanoparticles loaded with phthalocyanine dyes for potential use in photodynamic therapy for atherosclerotic plaques

“…35 Recently, different nanoparticle delivery systems for PDT in CVD were tested such as micellar preparations 36 or dendrimers. 37,38 While the micellar preparations were not stable enough to confirm the good in vitro data also in vivo experiments 36 the dendrimers were studied only in vitro in a very artificial system. 37…”