Tumor-penetrating peptide for systemic targeting of Tenascin-C
Tumor-penetrating peptide for systemic targeting of Tenascin-C
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DOI：
10.1038/s41598-020-62760-y
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发表时间：
2020-04-02
影响因子：
4.6
通讯作者：
Teesalu, Tambet
中科院分区：
文献类型：
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作者：
Lingasamy, Prakash;Tobi, Allan;Teesalu, Tambet
实体瘤中的细胞外基质已成为亲和导向抗癌药物递送的特异性、稳定性和丰富性靶点。在这里，我们描述了归巢肽，相互作用的C-异构体的腱生蛋白-C（TNC-C）在恶性组织中上调。通过对重组TNC-C进行体外生物淘选来鉴定TNC-C结合PL 3肽（氨基酸序列：AGRGRLVR）。除了TNC-C，PL 3通过其C-末端规则（CendR）基序与细胞和组织穿透受体神经纤毛蛋白-1（NRP-1）相互作用。用PL 3肽官能化氧化铁纳米颗粒（NW）和金属银纳米颗粒（AgNP）增加了系统性纳米颗粒对裸鼠中胶质母细胞瘤（GBM）和前列腺癌异种移植病变的趋向性（分别为8倍和5倍）。用促凋亡PL 3引导的NW治疗荷胶质瘤小鼠改善了小鼠的存活率，而用非靶向颗粒治疗则没有效果。发现PL 3包被的纳米颗粒在临床肿瘤样品中的TNC-C和NRP-1阳性区域中积累，表明了翻译相关性。PL 3-NP的全身肿瘤靶向特性和与临床肿瘤切片的结合表明PL 3肽可能可用作将成像剂和治疗剂选择性递送至实体瘤的靶向部分。
Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinity-guided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated in malignant tissues. TNC-C binding PL3 peptide (amino acid sequence: AGRGRLVR) was identified by in vitro biopanning on recombinant TNC-C. Besides TNC-C, PL3 interacts via its C-end Rule (CendR) motif with cell-and tissue penetration receptor neuropilin-1 (NRP-1). Functionalization of iron oxide nanoworms (NWs) and metallic silver nanoparticles (AgNPs) with PL3 peptide increased tropism of systemic nanoparticles towards glioblastoma (GBM) and prostate carcinoma xenograft lesions in nude mice (eight and five-fold respectively). Treatment of glioma-bearing mice with proapoptotic PL3-guided NWs improved the survival of the mice, whereas treatment with untargeted particles had no effect. PL3-coated nanoparticles were found to accumulate in TNC-C and NRP-1-positive areas in clinical tumor samples, suggesting a translational relevance. The systemic tumor-targeting properties and binding of PL3-NPs to the clinical tumor sections, suggest that the PL3 peptide may have applications as a targeting moiety for the selective delivery of imaging and therapeutic agents to solid tumors.