Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin

Kuan Jiang (), Kaisong Tian, Yifei Yu, Ercan Wu, Min Yang, Feng Pan, Jun Qian and Changyou Zhan ()
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Kuan Jiang: Fudan University
Kaisong Tian: Fudan University
Yifei Yu: Fudan University
Ercan Wu: Fudan University
Min Yang: Fudan University
Feng Pan: Ministry of Education
Jun Qian: Ministry of Education
Changyou Zhan: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines.

Date: 2024
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DOI: 10.1038/s41467-024-50568-7

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