Furin targeted drug delivery for treatment of rhabdomyosarcoma in a mouse model.
Furin targeted drug delivery for treatment of rhabdomyosarcoma in a mouse model.
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DOI：
10.1371/journal.pone.0010445
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发表时间：
2010-05-03
期刊：
影响因子：
3.7
通讯作者：
Bernasconi M
中科院分区：
文献类型：
--
作者：
Hajdin K;D'Alessandro V;Niggli FK;Schäfer BW;Bernasconi M
横纹肌肉瘤(RMS)是儿童最常见的软组织肉瘤。通过肿瘤靶向给药来提高治疗效果和减少副作用将是可取的。通过噬菌体展示的环状随机多肽文库的筛选，我们在体内外筛选出与RMS有较强亲和力的多肽。经丙氨酸扫描鉴定，其最小结合基序为Arg-X-(Arg/Lys)(Arg/Lys)，提示靶向受体为原蛋白转换酶(PC)。所有PC在RMS活检和细胞系中的表达谱显示，膜结合的Furin和PC7的表达水平一致高。亲和层析证实了RMS-P3多肽与呋喃的直接结合，并得到活性和共定位研究的支持。与阿霉素单独治疗相比，阿霉素与靶向多肽联合治疗小鼠RMS的疗效提高了两倍。我们的发现表明，表面-呋喃结合是治疗细胞渗透的新机制，需要进一步研究。此外，这项工作证明了在肿瘤中特异性靶向膜结合的Furin是可能的，并提示RMS和其他肿瘤可能受益于原蛋白转换酶靶向药物输送。
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Improvement of treatment efficacy and decreased side effects through tumor-targeted drug delivery would be desirable. By panning with a phage-displayed cyclic random peptide library we selected a peptide with strong affinity for RMS in vitro and in vivo. The peptide minimal binding motif Arg-X-(Arg/Lys)(Arg/Lys) identified by alanine-scan, suggested the target receptor to be a proprotein convertase (PC). Expression profiling of all PCs in RMS biopsies and cell lines revealed consistent high expression levels for the membrane-bound furin and PC7. Direct binding of RMS-P3 peptide to furin was demonstrated by affinity chromatography and supported by activity and colocalization studies. Treatment of RMS in mice with doxorubicin coupled to the targeting peptide resulted in a two-fold increase in therapeutic efficacy compared to doxorubicin treatment alone. Our findings indicate surface-furin binding as novel mechanism for therapeutic cell penetration which needs to be further investigated. Furthermore, this work demonstrates that specific targeting of membrane-bound furin in tumors is possible for and suggests that RMS and other tumors might benefit from proprotein convertases targeted drug delivery.
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