Identification of a synovial fibroblast-specific protein transduction domain for delivery of apoptotic agents to hyperplastic synovium
Identification of a synovial fibroblast-specific protein transduction domain for delivery of apoptotic agents to hyperplastic synovium
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DOI：
10.1016/s1525-0016(03)00181-3
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发表时间：
2003-08-01
影响因子：
12.4
通讯作者：
Robbins, PD
中科院分区：
文献类型：
--
作者：
Mi, ZB;Lu, XL;Robbins, PD
滑膜增生导致软骨和骨的侵蚀，是类风湿性关节炎的主要病理之一。为了开发一种有效地将蛋白质或药物递送到滑膜以诱导增生性滑膜组织的靶向凋亡的方法，我们筛选了一个M13肽噬菌体展示文库，用于滑膜特异性转导肽。我们发现了一种新的滑膜靶向转导肽HAP-1，它能够促进蛋白质复合物特异性内化到培养的人和兔滑膜细胞以及兔体内滑膜衬里。HAP-1和非组织特异性阳离子蛋白转导结构域ppd -5与抗菌肽（KLAK）融合(2)，分别生成两种促凋亡肽，分别称为DP2和DP1。这些肽能够诱导兔和人培养的滑膜细胞凋亡，其中DP2诱导滑膜细胞特异性凋亡。关节内注射DP1和DP2诱导增生滑膜广泛凋亡，同时减少白细胞浸润和滑膜炎。这些结果表明，促凋亡肽，特别是DP2，在临床上可用于治疗滑膜增生和炎症。此外，这些结果证明了鉴定能够在体内介导有效转导的组织特异性转导肽的可行性。
Synovial hyperplasia, resulting in erosion of cartilage and bone, represents one of the major pathologies associated with rheumatoid arthritis. To develop an approach for efficient delivery of proteins or agents to synovium to induce targeted apoptosis of hyperplastic synovial tissue, we have screened an M13 peptide phage display library for synovial-specific transduction peptides. We identified a novel synovial-targeted transduction peptide, HAP-1, which is able to facilitate specific internalization of protein complexes into human and rabbit synovial cells in culture and rabbit synovial lining in vivo. HAP-1 and a non-tissue-specific cationic protein transduction domain, PTD-5, were fused to an antimicrobial peptide, (KLAK)(2), to generate two proapoptotic peptides termed DP2 and DP1, respectively. Administration of these peptides was able to induce apoptosis of rabbit and human synovial cells in culture, with DP2 inducing synovial cell-specific apoptosis. Intra-articular injection of DP1 and DP2 into arthritic rabbit joints with synovial hyperplasia induced extensive apoptosis of the hyperplastic synovium, while reducing the leukocytic infiltration and synovitis. These results suggest that proapoptotic peptides and, in particular, DP2 can be clinically useful for treatment of synovial hyperplasia, as well as inflammation. Moreover, the results demonstrate the feasibility of identifying tissue-specific transduction peptides capable of mediating efficient transduction in vivo.