%0 Journal Article %A Deniz Ali Bölükbas %A Stefan Datz %A Charlotte Meyer-Schwickerath %A Malamati Vreka %A Sabine van Rijt %A Oliver Eickelberg %A Georgios Stathopoulos %A Thomas Bein %A Silke Meiners %T Combinatorial delivery of targeted mesoporous silica nanoparticles for lung cancer therapy %D 2016 %R 10.1183/13993003.congress-2016.PA2841 %J European Respiratory Journal %P PA2841 %V 48 %N suppl 60 %X Mesoporous silica nanoparticles (MSNs) offer unique features for drug delivery such as incorporation of a wide variety of cargos as well as functionalization for controlled drug release. The pores of the MSNs can be closed with a cap enabling pH-responsive opening in the endolysosomal compartments of the cells. Additionally, surface functionalization of MSNs allows for cell specific targeting, leading to MSN binding, uptake, and drug release only in the targeted cells.Here, we report the synthesis of MSNs bearing pH-responsive protein caps, functionalized with ligands that specifically bind to the growth factor receptor EGFR, or to the cytokine receptor CCR2, respectively. Our aim was to target lung cancer cells overexpressing EGFR as well as tumor-associated macrophages overexpressing CCR2. The pores of the MSNs were sealed at neutral pH conditions, whereas pH reduction induced stimuli-responsive cargo release in vitro. EGFR-targeted MSNs were preferentially taken up by lung cancer cells that overexpress EGFR, whereas CCR2-targeted MSNs were more uptaken by macrophages compared to CCR2-negative alveolar epithelial cells in vitro. Uptake rates were dependent on the presence of the receptors as assessed by confocal microscopy and flow cytometry. Biodistribution studies revealed that intratracheal application of MSNs resulted in MSN deposition in the alveolar space with preferential uptake in early tumor lesions and macrophages. In contrast, i.v. administration resulted in significant deposition of the MSNs into the liver but not into flank tumors. We currently investigate the combinatorial cytotoxic effects of EGFR- and CCR2- targeted MSNs in lung tumors of Kras mutant mice in vivo. %U