Ling Qiu,Xi Li,Gaochao Lv,Yann Seimbille,Ke Li,Ying Peng,Qingzhu Liu,Minhao Xie,Jianguo Lin
Overexpression of legumain is closely associated with tumor proliferation, invasion, and metastasis. Because of its intrinsic properties, such as high sensitivity and resolution, positron emission tomography (PET) has become an effective imaging technique for early diagnosis, treatment response prediction, and monitoring. Herein, two legumain-targeting radiofluorinated smart probes (18F-2 and 18F-3) as well as a control probe (18F-1) were specifically designed for PET imaging of legumain activity in tumors. 18F-1, 18F-2, and 18F-3 were obtained with high radiochemical yield (RCY > 60%) and radiochemical purity (RCP > 99%) using a convenient “one-step” 18F-labeling method. The probes 18F-2 and 18F-3 exhibited high response to legumain activity and reductive environment and revealed comparable uptake in HCT116 cells (4.22% ± 0.14% and 4.64% ± 0.32% for 18F-2 and 18F-3, respectively; 8.46% ± 0.33% and 9.05% ± 0.24% for co-treatment of 18F-2 + 2 and 18F-3 + 3 at 1 h), while the control probe 18F-1 showed no response. PET imaging of tumor-bearing mice showed that the co-injection strategy (18F-2 + 2 and 18F-3 + 3) resulted in higher tumor uptake (3.57% ± 0.37% and 3.72% ± 0.19% ID/g at 10 min, respectively) than the single injection strategy (2.59% ± 0.19% and 2.60% ± 0.46% ID/g for 18F-2 and 18F-3, respectively). In addition, introduction of the trimeric histidine-glutamate (HEHEHE) tag to 18F-3 reduced the liver uptake by almost two-fold without any noticeable effect on the tumor uptake. All the results indicate that 18F-3 holds great potential applications in clinics for sensitive and specific PET imaging of legumain activity in tumors.
Various conventional treatment strategies for volumetric muscle loss (VML) are often hampered by the extreme donor site morbidity, the limited availability of quality muscle flaps, and complicated, as well as invasive surgical procedures. The conventional biomaterial-based scaffolding systems carrying myoblasts have been extensively investigated towards improving the regeneration of the injured muscle tissues, as well as their injectable forms. However, the applicability of such designed systems has been restricted due to the lack of available vascular networks. Considering these facts, here we present the development of a unique set of two minimally invasively injectable modular microtissues, consisting of mouse myoblast (C2C12)-laden poly(lactic- co -glycolic acid) porous microspheres (PLGA PMs), or the micro-muscles, and human umbilical vein endothelial cell (HUVEC)-laden poly(ethylene glycol) hollow microrods (PEG HMs), or the microvessels. Besides systematic in vitro investigations, the myogenic performance of these modular composite microtissues, when co-injected, was explored in vivo using a mouse VML model, which confirmed improved in situ muscle regeneration and remolding. Together, we believe that the construction of these injectable modular microtissues and their combination for minimally invasive therapy provides a promising method for in situ tissue healing.
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