Liver accumulation of nanoparticles is a major challenge in nanoparticle-mediated delivery as it can reduce the delivery of the nanoparticles to their intended site and lead to liver damage and toxicity. Recent studies have shown that particle engineering,e.g.,nanoparticle composition,can influence liver uptake and allow homing of nanoparticles to specific organs or tissues. Herein,we investigated the role of nanoparticle cross-linking on liver uptake. We developed a series of antibody nanoparticles (AbNPs) using various poly(ethylene glycol) (PEG) molecule (e.g.,different arm numbers and arm lengths) cross-linkers. Specifically,AbNPs based on Herceptin were engineered with PEG cross-linker architectures ranging from 2-arm (at molecular weights of 600 Da,2.5 kDa,and 5 kDa) to 4-arm and 8-arm via a mesoporous silica templating method. The molecular architecture of PEG modulated not only the targeting ability of the AbNPs in model cell lines but also their interaction with phagocytes in human blood. Increasing the PEG arm length from 600 Da to 5 kDa also reduced the uptake of the nanoparticles in the liver by 85. Tumor accumulation of Herceptin AbNPs cross-linked with a 5 kDa 2-arm-PEG was 50 higher compared with control AbNPs and displayed similar liver uptake as free Herceptin. This study highlights the role of PEG cross-linking in receptor targeting and liver uptake,which influence tumor targeting,and combined with the versatility and multifunctionality of the antibody nanoparticle platform could lead to the development of organ-selective targeted antibody nanoparticle assemblies.
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