期刊
ACS NANO
卷 15, 期 9, 页码 15191-15209出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c05713
关键词
nanoparticle; antibody; targeting; biodistribution; liver accumulation; liver endothelial cells; polypept(o)ides
类别
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB 1066/3 2021 213555243]
The study found that PB-antibody conjugates with different numbers of antibodies accumulate in the liver, and an increase in the number of antibodies leads to higher accumulation. These conjugates are primarily captured in the liver via Fc receptors on liver sinusoidal endothelial cells, and low antibody numbers and the use of F(ab')2 antibody fragments can achieve cell type-specific targeting and minimize unwanted liver accumulation.
Despite considerable progress in the design of multifunctionalized nanoparticles (NPs) that selectively target specific cell types, their systemic application often results in unwanted liver accumulation. The exact mechanisms for this general observation are still unclear. Here we asked whether the number of cell-targeting antibodies per NP determines the extent of NP liver accumulation and also addressed the mechanisms by which antibody-coated NPs are retained in the liver. We used polysarcosine-based peptobrushes (PBs), which in an unmodified form remain in the circulation for >24 h due to the absence of a protein corona formation and low unspecific cell binding, and conjugated them with specific average numbers (2, 6, and 12) of antibodies specific for the dendritic cell (DC) surface receptor, DEC205. We assessed the time-dependent biodistribution of PB-antibody conjugates by in vivo imaging and flow cytometry. We observed that PBantibody conjugates were trapped in the liver and that the extent of liver accumulation strongly increased with the number of attached antibodies. PB-antibody conjugates were selectively captured in the liver via Fc receptors (FcR) on liver sinusoidal endothelial cells, since systemic administration of FcR-blocking agents or the use of F(ab')(2) fragments prevented liver accumulation. Cumulatively, our study demonstrates that liver endothelial cells play a yet scarcely acknowledged role in liver entrapment of antibody-coated NPs and that low antibody numbers on NPs and the use of F(ab')(2) antibody fragments are both sufficient for cell type-specific targeting of secondary lymphoid organs and necessary to minimize unwanted liver accumulation.
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