Poly(ethylene glycol) Cross-Linked Antibody Nanoparticles for Tunable Biointeractions

Liver accumulation of nanoparticles is a major challengein nanoparticle-mediateddelivery as it can reduce the delivery of the nanoparticles to theirintended site and lead to liver damage and toxicity. Recent studieshave shown that particle engineering, e.g., nanoparticle composition,can influence liver uptake and allow homing of nanoparticles to specificorgans or tissues. Herein, we investigated the role of nanoparticlecross-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 architecturesranging from 2-arm (at molecular weights of 600 Da, 2.5 kDa, and 5kDa) to 4-arm and 8-arm via a mesoporous silica templating method.The molecular architecture of PEG modulated not only the targetingability of the AbNPs in model cell lines but also their interactionwith phagocytes in human blood. Increasing the PEG arm length from600 Da to 5 kDa also reduced the uptake of the nanoparticles in theliver by 85%. Tumor accumulation of Herceptin AbNPs cross-linked witha 5 kDa 2-arm-PEG was 50% higher compared with control AbNPs and displayedsimilar liver uptake as free Herceptin. This study highlights therole of PEG cross-linking in receptor targeting and liver uptake,which influence tumor targeting, and combined with the versatilityand multifunctionality of the antibody nanoparticle platform couldlead to the development of organ-selective targeted antibody nanoparticleassemblies.