Strategies to prevent the uptake of modified low density lipoproteins (LDLs) by immune cells, a major trigger of inflammation and atherogenesis, are challenged by complex interfacial factors governing LDL receptor-mediated uptake. We examine a new approach based on a family of "nanoblockers", which are designed to examine the role of size, charge presentation, and architecture on inhibition of highly oxidized LDL (hoxLDL) uptake in macrophages. The nanoblockers are macromolecules containing mucic acid, lauryl chloride, and poly(ethylene glycol) that self-assemble into 15-20 nm nanoparticles. We report that the micellar configuration of the macromolecules and the combined display of anionic (carboxylate) groups in the hydrophobic region of the nanoblockers caused the most effective inhibition in the uptake of hoxLDL by IC21 macrophages. The nanoblockers primarily targeted SR-A and CD36, the major scavenger receptors and modulated the "atherogenic" phenotype of cells in terms of the degree of cytokine secretion, accumulation of cholesterol, and "foam cell" formation. These studies highlight the promise of synthetically engineered nanoblockers against oxidized LDL uptake.
Nanoscale particles could be synthetically designed to potentially intervene in lipoprotein matrix retention and lipoprotein uptake in cells, processes central to atherosclerosis. We recently reported on lipoprotein interactions of nanoscale micelles self-assembled from amphiphilic scorpion-like macromolecules based on a lauryl chloride-mucic acid hydrophobic backbone and poly(ethylene glycol) shell. These micelles can be engineered to present varying levels of anionic chemistry, a key mechanism to induce differential retentivity of low-density lipoproteins (LDL) (Chnari, E.; Lari, H. B.; Tian, L.; Uhrich, K. E.; Moghe, P. V. Biomaterials 2005, 26, 3749). In this study, we examined the cellular interactions and the ability of carboxylate-terminated nanoparticles to modulate cellular uptake of differentially oxidized LDL. The nanoparticles were found to be highly biocompatible with cultured IC21 macrophages at all concentrations examined. When the nanoparticles as well as LDL were incubated with the cells over 24 h, a marked reduction in cellular uptake of LDL was observed in a nanoparticle concentration-dependent manner. Intermediate concentrations of nanoparticles (10(-6) M) elicited the most charge-specific reduction in uptake, as indicated by the difference in uptake due to anionic and uncharged nanoparticles. At these concentrations, anionic nanoparticles reduced LDL uptake for all degrees of oxidation (no oxidation, mild, high) of LDL, albeit with qualitative differences in the effects. The anionic nanoparticles were particularly effective at reducing the very high levels of uptake of the most oxidized level of LDL. Since complexation of LDL with anionic nanoparticles is reduced at higher degrees of LDL oxidation, our results suggest that anionic nanoparticles interfere in highly oxidized (hox) LDL uptake, likely by targeting cellular/receptor uptake mechanism, but control unoxidized LDL uptake by mechanisms related to direct LDL-nanoparticle complexation. Thus, anionically functionalized nanoparticles can modulate the otherwise unregulated internalization of differentially oxidized LDL.
Autologous adipose tissue grafting is a popular strategy for soft tissue reconstruction; yet its clinical outcomes are often suboptimal. Lack of metabolic and architectural support at recipient sites affects the capacity of cellularized autologous grafts to survive after transplantation. Allograft adipose matrices (AAMs) are composed of extracellular matrices of adipose tissue. They can provide critical biophysical cues and create a supportive microenvironment for autologous graft survival. Using murine models, we have optimized the in vivo use of an injectable AAM obtained from human cadaveric tissue and processed to remove lipid and cellular components. We hypothesized that the AAM could assist recipient site preparation before autologous adipose tissue grafting and-alone or combined with other treatments-improve surgical outcomes. The AAM scaffolds retained volume (measured as cross-sectional area at histology) over time and showed a higher local angiogenesis. Preconditioning of AAM recipient sites using intermittent external volume expansion further increased their vascularity and promoted adipogenesis. Low-density AAM combined with autologous adipose tissue grafts best assisted angiogenesis and tissue survival. These studies demonstrate that the AAM contributes to recipient site preparation before or in combination with autologous adipose tissue grafting by increasing vascularity and by creating an adipogenic microenvironment. This patient-ready scaffold could help improve outcomes in soft tissue reconstructive surgery.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.