Decoding the pharmacokinetics of intravenous lentinan: A multiscale journey from the blood to hepatic Kupffer cells' lysosomes.

Lentinan (LNT), a natural polysaccharide, has been widely used as an immunomodulator in clinical therapy for decades. However, due to the difficulty of detection, its pharmacokinetics after intravenous injection have been less studied, limiting its further application. The aim of this study was to investigate the complete fate of intravenous LNT and the related mechanisms. Utilizing the latest radioisotope detection method, we quantified the blood concentration of intravenous LNT and confirmed the biphasic elimination characteristic of LNT. We obtained the relevant pharmacokinetic parameters, with T1/2α and T1/2β values of 0.304 and 5.934 h, respectively. Subsequent in vivo distribution studies demonstrated that Kupffer cells (KCs) were associated with the hepatic distribution and metabolism of LNT. In vitro experiments showed that LNT was transported to lysosomes for metabolism after it entered KCs. Mechanistic studies revealed that complement receptor 3 (CR3) recognizes and binds to LNT. In addition, the CR3/Src/Syk/FAK signaling pathway mediated the uptake of LNT by KCs and influenced the subsequent metabolism by regulating lysosomal acidification. In conclusion, this study revealed the in vivo fate and the related mechanisms of LNT from the macroscopic to microscopic levels, which will facilitate further explorations and studies of LNT and other β-glucans.