Abstract
Abstract The limited efficacy of protein drugs is related to their poor distribution in tumor tissue. We examined interstitial delivery of four model proteins of different molecular size and bioaffinity as formulated of non-formulated forms in multicellular layers (MCL) of human cancer cells. Model proteins were tumor necrosis factor-related apoptosis-including ligand (TRAIL), cetuximab, RNase A, and IgG. MCLs were cultured in Transwell inserts, exposed to drugs, then cryo-sectioned for image acquisition using fluorescence microscopy (fluorescent dye-labeled TRAIL, RNase A, IgG) or Immunohistochemistry (cetuximab). TRAIL and cetuximab showed partial penetration into MCLs, whereas RNase A and IgG showed little penetration. At 10-fold higher dose, a significant increase in penetration was observed for IgG only, while cetuximab showed an intense accumulation limited to the front layers. PEGylated TRAIL and a heparin-Pluronic nanogel formulation of RNase A showed significantly improved penetration that was attributed to increased stability and extracellular matrix binding, respectively. IgG penetration was significantly enhanced with PTX pretreatment as a penetration enhancer. MCL culture was successfully used for the evaluation of protein movement in the tumor interstitum. Four proteins showed limited interstitial penetration in MCL cultures. Bioaffinity, rather than molecular size, seems to have a positive effect on tissue penetration, although strong binding affinity may lead to sequestration in the front layers. Nanoformulations, such as PEGylation and heparin-Pluronic (HP) nanogel, or penetration enhancers are potential strategies to increase interstitial delivery of anticancer biologics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5708. doi:1538-7445.AM2012-5708
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