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The blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand-mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both in vitro and in vivo. Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.68‰ and 1.67‰, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.31‰ and 8.32‰ at 3 h. Ex vivo imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB in vivo as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma., Graphical abstract Fluorophores (DiO, DiI and DiD) were loaded into liposomes and disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using this method, we investigated the integrity of liposomes and disks traversing BBB and BBTB both in vitro and in vivo.fx1

Tongcheng Dai,1 Na Li,1 Lingzhi Zhang,1 Yuanxing Zhang,1,2 Qin Liu1,2 1State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 2Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai, People’s Republic of China Abstract: Nanoparticles functionalized with active target ligands have been widely used for tumor-specific diagnosis and therapy. The target ligands include antibodies, peptides, proteins, small molecules, and nucleic acid aptamers. Here, we utilize dipeptide Ser–Glu (DIP) as a new ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for pancreatic cancer target imaging. We demonstrate that in the first step, Ser–Glu-conjugated NPs (NPs-DIP) efficiently bind to AsPC-1 and in the following NPs-DIP are internalized into AsPC-1 in vitro. The peptide transporter 1 inhibition experiment reveals that the targeting effects mainly depend on the specific binding of DIP to peptide transporter 1, which is remarkably upregulated in pancreatic cancer cells compared with varied normal cells. Furthermore, NPs-DIP specifically accumulate in the site of pancreatic tumor xenograft and are further internalized into the tumor cells in vivo after intravenous administration, indicating that DIP successfully enhanced nanoparticles internalization efficacy into tumor cells in vivo. This work establishes Ser–Glu to be a new tumor-targeting ligand and provides a promising tool for future tumor diagnostic or therapeutic applications. Keywords: imaging, pancreatic cancer, PEPT1 transporter, Ser–Glu, target ligand

Active targeting-ligands have been increasingly used to functionalize nanoparticles for tumour-specific clinical applications. Here we utilize nucleotide adenosine 5'-monophosphate (AMP) as a novel ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for tumour-targeted imaging. We demonstrate that AMP-conjugated NPs (NPs-AMP) efficiently bind to and are following internalized into colon cancer cell CW-2 and breast cancer cell MDA-MB-468 in vitro. RNA interference and inhibitor assays reveal that the targeting effects mainly rely on the specific binding of AMP to adenosine A1 receptor (A1R), which is greatly up-regulated in cancer cells than in matched normal cells. More importantly, NPs-AMP specifically accumulate in the tumour site of colon and breast tumour xenografts and are further internalized into the tumour cells in vivo via tail vein injection, confirming that the high in vitro specificity of AMP can be successfully translated into the in vivo efficacy. Furthermore, NPs-AMP exhibit an active tumour-targeting behaviour in various colon and breast cancer cells, which is positively related to the up-regulation level of A1R in cancer cells, suggesting that AMP potentially suits for more extensive A1R-overexpressing cancer models. This work establishes AMP to be a novel tumour-targeting ligand and provides a promising strategy for future diagnostic or therapeutic applications.