ABSTRACT
Efficient therapy of idiopathic pulmonary fibrosis (IPF) is still a major challenge. The current studies with single-target drug therapy are the pessimistic approaches due to the complex characteristics of IPF. Here, a combination therapy of Tanshinone IIA and Puerarin for IPF was proposed to alleviate IPF due to their antiinflammatory and anti-fibrotic effects. In vivo, the combination therapy could significantly attenuate the area of ground glass opacification that was presented by 85% percentile density score of the micro-CT images when compared to single conditions. In addition, the combination therapy enormously improved the survival rate and alleviated pathological changes in bleomycin (BLM)-induced IPF mice. By using a wide spectrum of infiltration biomarkers in immunofluorescence assay in pathological sections, we demonstrate that fewer IL6 related macrophage infiltration and fibrosis area after this combination therapy, and further proved that IL6-JAK2-STAT3/STAT1 is the key mechanism of the combination therapy. In vitro, combination therapy markedly inhibited the fibroblasts activation and migration which was induced by TGF-ß1 or/and IL6 through JAK2-STAT3/STAT1 signaling pathway. This study demonstrated that combination therapeutic effect of TanIIA and Pue on IPF may be related to the reduced inflammatory response targeting IL6, which could be an optimistic and effective approach for IPF.
Subject(s)
Interleukin-6 , Pulmonary Fibrosis , Abietanes , Animals , Bleomycin , Fibroblasts/metabolism , Interleukin-6/metabolism , Isoflavones , Lung/metabolism , Mice , Pulmonary Fibrosis/drug therapy , STAT1 Transcription Factor , Signal TransductionABSTRACT
Molecular self-assembly has been widely used to develop nanocarriers for drug delivery. However, most of them have unsatisfactory drug loading capacity (DLC) and the dilemma between stimuli-responsiveness and stability, stagnating their translational process. Herein, we overcame these drawbacks using dynamic combinatorial chemistry. A carrier molecule was spontaneously and quantitatively synthesized, aided by co-self-assembly with a template molecule and an anti-cancer drug doxorubicin (DOX) from a dynamic combinatorial library that was operated by disulfide exchange under thermodynamic control. The highly selective synthesis guaranteed a stable yet pH- and redox- responsive nanocarrier with a maximized DLC of 40.1 % and an enhanced drug potency to fight DOX resistance in vitro and in vivo. Our findings suggested that harnessing the interplay between synthesis and self-assembly in complex chemical systems could yield functional nanomaterials for advanced applications.
