Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
J Control Release. 2021 Apr 10;332:434-447. doi: 10.1016/j.jconrel.2021.02.028. Epub 2021 Mar 1.
Osteosarcoma (OS) is the most common malignancy of the skeletal system, with a poor prognosis and high rate of recurrence. Adequate surgical margin and adjuvant chemotherapy improve the overall survival and limb salvage rate of osteosarcoma patients. Previous studies have showed that OS exhibits an increase in the expression of proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinase, and high levels of PIM1 are also associated with poor OS prognosis and metastasis. We exploited the overexpression of proto-oncogenic PIM1 in OS towards the development of a novel near-infrared imaging and targeted therapeutic agent, namely QCAi-Cy7d by conjugating a PIM1 small molecule inhibitor and heptamethine cyanine dye, for simultaneous guiding surgery and chemotherapy. QCAi-Cy7d showed targeted imaging and anticancer activities against OS in vitro and vivo without any obvious toxicity, and its antitumoral activity was much greater than the parent PIMI inhibitor. These results demonstrated the potential of new conjugate of PIM1 inhibitor and near-infrared imaging, supporting structure-based design and development of theranostic agents for precise tumor imaging and targeted treatment.
骨肉瘤（OS）是最常见的骨骼系统恶性肿瘤，预后不良，复发率高。充分的手术切缘和辅助化疗可提高骨肉瘤患者的总体生存率和保肢率。先前的研究表明，骨肉瘤中存在 Moloney 鼠白血病病毒 1 前病毒整合位点激酶（PIM1）激酶表达增加，高水平的 PIM1 也与骨肉瘤预后不良和转移有关。我们利用原癌基因 PIM1 在骨肉瘤中的过表达，开发了一种新型近红外成像和靶向治疗剂 QCAi-Cy7d，该试剂通过连接 PIM1 小分子抑制剂和七甲川花菁染料，实现了同时指导手术和化疗的目的。QCAi-Cy7d 在体外和体内对骨肉瘤具有靶向成像和抗癌活性，且没有明显的毒性，其抗肿瘤活性明显大于母体 PIM1 抑制剂。这些结果表明，PIM1 抑制剂和近红外成像的新结合物具有潜力，为精确的肿瘤成像和靶向治疗的治疗药物研发提供了结构基础。
