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Abstract
Background: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes.

Results: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®.

Conclusion: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.

Affiliations

Tae Hyeon Choi # 1 2, Ran Ji Yoo # 1 3 4, Ji Yong Park 1 5, Ji Yoon Kim 1 5, Young Chan Ann 1 6, Jeongbin Park 2, Jin Sil Kim 1, Kyuwan Kim 1, Yu Jin Shin 1 7 8, Yong Jin Lee 9, Kyo Chul Lee 9, Jisu Park 7 8 10, Hyewon Chung 7 8 10, Seung Hyeok Seok 7 8 10, Hyung-Jun Im 11 12 13, Yun-Sang Lee 14 15 16 17 18
1Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea.
2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
3Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, South Korea.
4Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
5Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea.
6School of Dentistry, Seoul National University, Seoul, South Korea.
7Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
8Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
9Division of Applied RI, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
10Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea.
11Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea. iiihjjj@snu.ac.kr.
12Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea. iiihjjj@snu.ac.kr.
13Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. iiihjjj@snu.ac.kr.
14Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea. wonza43@snu.ac.kr.
15Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, South Korea. wonza43@snu.ac.kr.
16Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea. wonza43@snu.ac.kr.
17Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. wonza43@snu.ac.kr.
18Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea. wonza43@snu.ac.kr.
#Contributed equally.