Ao Hu,Xiaobing Chen,Qunjie Bi,Yang Xiang,Rongrong Jin,Hua Ai,Yu Nie
Polarization regulation of tumor-association macrophages (TAMs) is a promising treatment method for tumors, but aiming at TAMs alone shows unsatisfactory therapeutic efficiency. Therefore, we designed a parallel and cascade control system for both macrophage polarization and tumor cell inhibition. The system is composed of cationic lipopeptides with an arginine-rich periphery (RLS) and anionic magnetic nanoparticles (MNPs) for fleet transfection of miR-125b. Based on the highly efficient magnetofection, miR-125b successfully shows a parallel effect on both M1, promoting polarization by targeting interferon regulatory factor 4 (IRF4) in macrophages, and tumor cell inhibition, by targeting ETS proto-oncogene 1 and cyclin- J. The cascading effect on M1-associated genes is upregulated by up to two orders of magnitude, while M2-associated genes are downregulated. Meanwhile, MNPs also have an effect on the TAM polarization and 4T1 tumor cell inhibition via inflammatory related gene expression and Fenton reaction. Further mimicking the co-culture of RAW264.7 and 4T1 cells in vitro confirmed the synergistic therapy effect. In the treatment of orthotopic breast cancer in mice, considerable M1 macrophage polarization was observed in the RM125b treated group, showing distinct tumor-suppressive effects, with a tumor weight reduction of 60% and tumor metastasis suppression of 50%.
Su Meiling,Hu Heping,Zhao Xuan,Huang Chengyuan,Yang Bowen,Yin Zongning
This study evaluated the D-mannose modified polyethyleneimine-block-polycaprolactone biomacromolecule copolymer micelles (PCL-PEI-mannose) as a targeted delivery of the glucocorticoid dexamethasone (DXM) to lung inflammation tissues and enhances the vehicle for its anti-inflammatory effects. Dexamethasone was encapsulated in the hydrophobic core of cationic polymer micelles by solvent evaporation. The polymeric micelles exhibited sustained-release within 48 h, good blood compatibility, and colloidal stability in vitro. The cellular uptake of mannose-modified micelles was higher compared with the non-modified micelles. And drug-loaded targeted micelles could inhibit the production of inflammatory factors in activated RAW264.7 cells. The distribution results indicated that drug-loaded targeted micelles highly improved the lung targeting ability, reduced the wet/dry ratio of injured lung tissue, and relieved the lung inflammation, accompanied by the decrease of inflammatory cell infiltration, myeloperoxidase activity, and inflammatory mediator levels in bronchoalveolar lavage fluid. These findings suggested that PCL-PEI-mannose delivery system could facilitate the lung-specific delivery and inhibit the inflammatory response. Collectively, PCL-PEI-mannose polymer micelles could be used as a potential delivery system for the treatment of acute lung injury (ALI). Graphical abstract
Ziqing Wang,Wenwen Mu,Pengxiao Li,Guoyun Liu,Jie Yang
Curcumin was reported as an anti-inflammatory agent. However, curcumin's poor bioavailability limited its clinical utility. Here, thirty ortho -substituted mono-carbonyl curcumin derivatives, containing acetone, cyclopentanone, cyclohexanone or 4-piperidione ( N H, N -methyl or N -acrylyl) moieties replacing β-diketone moiety of curcumin, were investigated for anti-inflammatory activity. Two active ortho -trifluoromethoxy-substituted 4-piperidione-containing derivatives 22 and 24 owned good cell uptake ability, and displayed excellent anti-inflammatory activity in both lipopolysaccharide-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis . They inhibited the production of nitric oxide , reactive oxygen species , malonic dialdehyde and cyclooxygenase-2; and the expression of pro-inflammatory cytokines interleukin-1β, tumor necrosis factor-α and myeloperoxidase ; the phosphorylation of mitogen-activated protein kinases; and the nucleus translocation of p65. What's more, 22 or 24 oral administered reduced the severity of clinical symptoms of ulcerative colitis (body weight and disease activity index), and reduced obviously DSS-induced colonic pathological damage (the colon length and histopathology analysis). These results suggested that ortho -trifluoromethoxy-substituted 4-piperidione-containing mono-carbonyl curcumin derivatives 22 and 24 were potential anti-inflammatory agents; and offered the important information for design and discovery of more potent anti-inflammatory drug candidates.
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