Shu Zhang,Yuewu Li,Rui Dong,Weitao Li,Zhiyu Qian,Yamin Yang
Photodynamic therapy (PDT) elicits cell death , vascular damage , or/and anti-tumor host immune response upon activating the administered photosensitive drug by an appropriate light source. Because PDT is heavily dependent on tissue oxygen (O 2 ) in essence, the concentration-dependent impact of O 2 on tailoring cellular response to PDT remains an in-depth investigation. As a multifaceted modality, optimal combinations of photosensitizer (PS) concentration, light dose, and O 2 delivery are critical to achieve ideal therapeutic outcomes. We herein present a fully integrated all-in-one device for the in vitro assessment of PDT efficacy synchronizing the quantitative control of three PDT disciplines simultaneously, aiming at 1) identifying the influence of varying gaseous microenvironments on PDT; and 2) determining the contribution of each PDT factor and estimating the strength of their synergic effect. The gas-gradient-generating unit for contactless headspace O 2 delivery and spatial light control filtering layer in our device could either work as a stand-alone module or combine to screen a range of experimental PDT parameters. By sweeping a total of 128 conditions over four 5-aminolevulinic acid (5-ALA) concentrations, four light dosages, and eight O 2 levels in one single experiment, we determined the main effects of the three key PDT agents and highlighted the interactive effect between 5-ALA and light after full-factorial statistical analysis. Our device is not only a versatile tool for predicting PDT efficacy during the translational study but also provides valuable multidimensional information for the interrelation between key PDT factors, which may expedite clinical PDT dosimetry and furnish new insights for the fundamental understanding of photobiological processes.
Lymphocyte activation gene 3 (LAG-3) has attracted much attention as a potentially valuable immune checkpoint. Individual identification of LAG-3 expression at screening and during treatment could improve the successful implementation of anti-LAG-3 therapies. HuL13 is a human IgG1 monoclonal antibody that binds to the LAG-3 receptor in T cells. Here, we used [89Zr]Zr-labeled HuL13 to delineate LAG-3+ T-cell infiltration into tumors via positron emission tomography (PET) imaging. A549/LAG-3 cells, which stably express LAG-3, were generated by infection with lentivirus. The uptake of [89Zr]Zr-DFO-HuL13 in A549/LAG-3 cells was greater than that in the negative control (A549/NC) cells at each time point. The equilibrium dissociation constant (Kd) of [89Zr]Zr-DFO-HuL13 for the LAG-3 receptor was 8.22 nM. PET imaging revealed significant uptake in the tumor areas of A549/LAG-3 tumor-bearing mice from 24 h after injection (SUVmax = 2.43 ± 0.06 at 24 h). As a proof of concept, PET imaging of the [89Zr]Zr-DFO-HuL13 tracer was further investigated in an MC38 tumor-bearing humanized LAG-3 mouse model. PET imaging revealed that the [89Zr]Zr-DFO-HuL13 tracer specifically targets human LAG-3 expressed on tumor-infiltrating lymphocytes (TILs). In addition to the tumors, the spleen was also noticeably visible. Tumor uptake of the [89Zr]Zr-DFO-HuL13 tracer was lower than its uptake in the spleen, but high uptake in the spleen could be reduced by coinjection of unlabeled antibodies. Coinjection of unlabeled antibodies increases tracer activity in the blood pool, thereby improving tumor uptake. Dosimetry evaluation of the healthy mouse models revealed that the highest absorbed radiation dose was in the spleen, followed by the liver and heart wall. In summary, these studies demonstrate the feasibility of using the [89Zr]Zr-DFO-HuL13 tracer for the detection of LAG-3 expression on TILs. Further clinical evaluation of the [89Zr]Zr-DFO-HuL13 tracer may be of significant help in the stratification and management of patients suitable for anti-LAG-3 therapy.
The irradiation of tumors in radiotherapy requires accurate 3D dosimetry. The Fricke 3D dosimeters, which were considered to be high potential of application in 3D dosimetry, suffer from a reduced temporal integrity of dose distribution caused by Fe 3+ ions diffusion. To overcome the drawback, we firstly synthesized a kind of amphiphilic molecules with critical micelle concentration of 0.45 g/L and hydrophile-lipophile balance value of 10, then prepared multiple emulsions by self-assembling those molecules in Fricke solution under liquid paraffin, and finally obtained Fricke hydrogel embedded with the multiple emulsions. The diffusion coefficient of Fe 3+ ions in the embedded Fricke hydrogel was measured to be 0.17 mm 2 /h. The hydrogel dosimeter exhibits considerable potential for use in dose verification applications.
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