National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , 210093 Nanjing , China.
The Center of Diagnosis and Treatment for Joint Disease , Drum Tower Hospital Affiliated to Medical School of Nanjing University , Nanjing , China.
Mol Pharm. 2019 Sep 3;16(9):3977-3984. doi: 10.1021/acs.molpharmaceut.9b00602. Epub 2019 Jul 29.
Integrin αvβ3 is a cell adhesion molecule involved in the progression and invasion of glioblastoma, making it an attractive target for the diagnosis of glioblastoma. Although some integrin αvβ3 specific ligands, such as RGD and its mimetic peptides (Cilengitide), have been devoted in detecting glioblastoma, their clinical practices have been limited due to low specificity and affinity. Herein, we have identified a linear peptide RWrNK, containing an unnatural d-arginine (r), as the integrin αvβ3-specific ligand. RWrNK shows high binding affinity to integrin αvβ3 with a value of 1.6 nM, which is 2-fold higher than Cilengitide (3.2 nM), a well-established integrin αvβ3 ligand. In addition, RWrNK can not only rapidly transport in human glioblastoma U87MG cells but effectively label U87MG tumor spheroids, compared to Cilengitide, indicating that it possesses an ability to sensitively detect glioblastoma. Importantly, RWrNK can pass through blood-brain tumor barrier (BBTB) and selectively accumulate in orthotopic U87MG tumor within 2 h, allowing for imaging glioblastoma with high sensitivity and specificity. Overall, RWrNK has the great potential in theranostic applications for glioblastoma, in consideration of its high specificity and affinity for integrin αvβ3.
整合素αvβ3 是一种参与神经胶质瘤进展和侵袭的细胞黏附分子，使其成为神经胶质瘤诊断的一个有吸引力的靶点。虽然一些整合素αvβ3 特异性配体，如 RGD 及其模拟肽（西仑吉肽），已被用于检测神经胶质瘤，但由于特异性和亲和力低，其临床应用受到限制。在此，我们鉴定了一种线性肽 RWrNK，其中含有非天然的 d-精氨酸（r），作为整合素αvβ3 的特异性配体。RWrNK 与整合素αvβ3 的结合亲和力很高，Ki 值为 1.6 nM，比已确立的整合素αvβ3 配体西仑吉肽（3.2 nM）高 2 倍。此外，与西仑吉肽相比，RWrNK 不仅能快速转运到人类神经胶质瘤 U87MG 细胞中，而且能有效地标记 U87MG 肿瘤球体，表明它具有敏感检测神经胶质瘤的能力。重要的是，RWrNK 能在 2 h 内穿过血脑肿瘤屏障（BBTB）并选择性地在原位 U87MG 肿瘤中积聚，从而能够高灵敏度和特异性地对神经胶质瘤进行成像。总的来说，鉴于其对整合素αvβ3 的高特异性和亲和力，RWrNK 在神经胶质瘤的治疗应用中具有很大的潜力。
