Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice
Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice
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DOI：
10.1073/pnas.1016233107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Ruoslahti, Erkki
中科院分区：
文献类型：
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作者：
Jaervinen, Tero A. H.;Ruoslahti, Erkki
永久性疤痕是在组织损伤愈合后形成的，如由缺血（心肌梗死、中风）、创伤、手术和炎症引起的组织损伤。目前减少疤痕形成的选择仅限于局部干预。我们设计了一种系统管理的、靶向性的疤痕预防生物疗法。它由一种血管靶向肽组成，该肽能特异性识别血管生成血管并外溢到损伤部位，与一种治疗性分子decorin融合。Decorin通过抑制tgf - β活性和其他调节活性来防止组织纤维化并促进组织再生。与未靶向的decorin相比，靶向decorin的肽融合蛋白在体外对tgf - β 1的中和活性显著增加。在体内，融合蛋白选择性地在伤口中积累，并在非靶向decorin失活的剂量下促进伤口愈合和抑制疤痕形成。这些结果表明，选择性靶向产生具有增强特异性和效力的组织愈合和疤痕减少化合物。这种方法可能有助于通过全身给药来减少疤痕形成，这对于外科手术和疤痕形成问题的病理过程的治疗来说是一种可行的选择。
Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-beta activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-beta 1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.