RT Journal Article
SR Electronic
T1 Photodynamic therapy induced by a combination of scintillating liposome and radiolabeled antibody
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 97
OP 97
VO 62
IS supplement 1
A1 Wooseung Lee
A1 Miyeon Jeon
A1 Seung Ki Baek
A1 Hyung-Jun Im
YR 2021
UL http://jnm.snmjournals.org/content/62/supplement_1/97.abstract
AB 97Introduction: The scintillating nanoparticles could be used for ionizing radiation induced photodynamic therapy (PDT) with the high tissue penetration depth to overcome the limitation of conventional PDT. We recently developed radiolabeled europium (Eu) and photosensitizer (PS) loaded liposome (Eu/PS lipo) which can be used for radioisotope induced PDT (1). Herein, we demonstrated photodynamic therapy effect by combining our scintillating liposome and 177Lu labeled human epidermal growth factor receptor 2 (HER2) targeting antibody. Methods: The Eu/PS lipo was synthesized based on a self-assembly method as shown in the Figure 1. The liposome was prepared by using phosphatidylcholine derivatives. The Eu3+ ion was chelated to diethylenetriaminepentaacetic acid (DTPA) (Eu-DTPA). Victoria blue-BO (VBBO) was selected for the PS. Eu-DTPA and VBBO were loaded on the hydrophilic core and the hydrophobic layer respectively of the liposome. Trastuzumab (Tz), a HER2 targeting antibody, was labeled with 177Lu for targeted radionuclide therapy. A HER2 positive ovarian cancer cell line, SKOV-3 was used and the HER2 positivity was confirmed by confocal imaging, flow cytometry and western blot. The radioluminescence of Eu/VBBO lipo was tested by mixing with 177Lu-Tz (100 μCi) and Eu/VBBO lipo. ROS production and in vitro PDT effect were demonstrated with various groups in the presence of 177Lu-Tz (low 10 uCi or high 50 uCi). Tz and Eu/VBBO lipo were performed in vivo imaging at different time points, and major organs were also conducted ex vivo imaging after the in vivo imaging. Results: The hydrodynamic size of Eu/VBBO lipo was approximately 80 nm. Eu/VBBO lipo had a high stability for 14 days in PBS solution and cell media (Supporting figure 1). High HER2 expression level of SKOV-3 was confirmed by confocal imaging, flow cytometry, and western blot comparing to 4T1 which is a HER2 negative cell (Supporting figure 2). A bright radioluminescence can be observed by combining Eu lipo and 177Lu-Tz, which was about 8-fold higher than Cerenkov luminescence (CL) of 177Lu-Tz. Also, the energy of radioluminescence can be transferred to VBBO to produce ROS with a transfer efficiency of 58% (Figure 2, Supporting figure 3). When Eu/VBBO lipo and 177Lu-Tz (10 μCi) was combined, ROS was effectively produced which was a similar amount with 100 μCi of 177Lu-Tz. Eu/VBBO lipo alone did not show any cytotoxicity. Furthermore, in vitro PDT experiment was performed in SKOV-3 cells. 177Lu-Tz (10 uCi) combined with Eu/VBBO lipo showed the 2.5-fold higher cell killing effect compared to177Lu-Tz (50 uCi) alone (Figure 3, Supporting figure 4). Finally, Tz and Eu/VBBO lipo were conducted in vivo and ex vivo Imaging by IVIS. It was clearly observed that both Tz and Eu/VBBO lipo showed substantial tumor uptake aspects according to the in vivo and ex vivo images (Figure 4). Conclusions: Eu/VBBO lipo and 177Lu-Tz combination demonstrated its abilities for radioluminescence emission, ROS production, and PDT effect. Combination of Eu/VBBO lipo and low dose 177Lu-Tz (10 uCi) elicited higher cancer cell killing effect than high dose 177Lu-Tz (50 uCi) alone. The Tz and Eu/VBBO lipo showed substantially high tumor uptake efficiencies at tumor bearing model. Therefore, we propose a novel treatment strategy using Eu/VBBO lipo and targeted radionuclides. After further validation, this strategy could lower the systemic adverse effect while enhance the treatment efficacy of 177Lu conjugated theranostic radiopharmaceuticals. References: (1) Lee W, Jeon M, Choi J, Oh C, Kim G, Jung S, Kim C, Ye SJ, Im HJ. Europium-Diethylenetriaminepentaacetic Acid (Eu-DTPA) Loaded Radioluminescence Liposome Nano-Platform for Effective Radioisotope-Mediated Photodynamic Therapy. ACS Nano. 2020;10.1021/acsnano.0c04324. doi:10.1021/acsnano.0c04324