Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Cancer Res. 2019 Aug 15;79(16):4271-4282. doi: 10.1158/0008-5472.CAN-18-3089. Epub 2019 Jun 26.
The lack of molecular targets and targeting probes remains a major drawback for targeted imaging and drug delivery in lung cancer. In this study, we exploited phage display to identify a novel targeting probe that homes to the tumor in a mutant mouse lung cancer model. Compared with other candidate peptides selected from 5 rounds of phage display, the CRQTKN peptide homed to tumor nodules in the lung of mutant mice at higher levels. Photoacoustic tomography of mutant mice detected lung tumors via tumor homing of the near-infrared fluorescence dye-labeled CRQTKN peptide. photoacoustic images of isolated organs further demonstrated tumor homing of the CRQTKN peptide, whereas minimal accumulation was observed in control organs, such as the liver. Compared with untargeted liposomes and doxorubicin, doxorubicin-loaded liposomes whose surface was modified with the CRQTKN peptide more efficiently delivered doxorubicin and reduced the number or size of tumor lesions in mutant mice. Analysis of hematologic parameters and liver and kidney function showed no significant systemic side effects by the treatments. Affinity-based identification was used to detect TNF receptor superfamily member 19L (TNFRSF19L), which was upregulated in lung tumors of mutant mice, as the receptor for the CRQTKN peptide. In conclusion, these results suggest that the CRQTKN peptide is a promising targeting probe for photoacoustic-guided detection and drug delivery to lung cancer, and acts by binding to TNFRSF19L. SIGNIFICANCE: These findings present a new tumor-targeting probe for photoacoustic-guided detection and drug delivery.
缺乏分子靶点和靶向探针仍然是肺癌靶向成像和药物输送的主要障碍。在这项研究中，我们利用噬菌体展示技术来鉴定一种新型的靶向探针，该探针可在突变型小鼠肺癌模型中靶向肿瘤。与从 5 轮噬菌体展示中筛选出的其他候选肽相比，CRQTKN 肽在突变型小鼠的肺肿瘤结节中具有更高的靶向性。近红外荧光染料标记的 CRQTKN 肽靶向肿瘤后，可通过光声断层扫描检测突变型小鼠的肺肿瘤。对分离器官的光声图像进一步证明了 CRQTKN 肽的肿瘤靶向性，而在对照器官（如肝脏）中则很少观察到其聚集。与非靶向脂质体和阿霉素相比，表面经 CRQTKN 肽修饰的载阿霉素脂质体更有效地递送至肿瘤部位，并减少了突变型小鼠的肿瘤病变数量或大小。分析血液学参数以及肝肾功能显示，这些治疗方法未引起明显的全身副作用。基于亲和力的鉴定表明，TNF 受体超家族成员 19L（TNFRSF19L）是突变型小鼠肺癌中上调的受体，是 CRQTKN 肽的受体。总之，这些结果表明，CRQTKN 肽是一种很有前途的靶向探针，可用于光声引导的肺癌检测和药物输送，并通过与 TNFRSF19L 结合发挥作用。意义：这些发现为光声引导的检测和药物输送提供了一种新的肿瘤靶向探针。
