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• W2004465404 abstract "Human cancer is a complex disease caused by genetic instability and accumulation of multiple molecular alterations. Tumor growth and metastasis depend on the development of a neovasculature by a process called angiogenesis, which is controlled by numerous pro‐ and antiangiogenic factors. Therefore, vascular targeting emerges as an attractive therapeutic approach, since angiogenic blood vessels express distinctive molecular markers with direct access by the therapeutic agent. Moreover, ablation of immature angiogenic vessels causes reduction of the interstitial pressure gradient in the tumor periphery, improving drug delivery through the highly permeabilized vessel wall. Hence, additional therapeutic gains will be expected by “starving” tumor cells to death and by increasing the concentration of the therapeutic agent in the target cell. The present work, is aimed at investigating the ability of a system consisting of a ligand coupled to the extremity of poly(ethylene glycol)‐grafted liposomes, containing doxorubicin (DXR), to simultaneously target human tumor cells and endothelial cells of tumor blood vessels. Cellular association studies were conducted by flow cytometry, fluorimetry and confocal microscopy with rhodamine‐labeled liposomes. Competitive inhibition and mechanistic assays were also performed by fluorimetry. Cytotoxicity was evaluated with the MTT assay and biodistribution performed on Balb/c nude female mice bearing orthotopic implanted tumors was analyzed by radioactivity counts of a lipid and a drug tracer ([3H]CHE and [14C]DXR, respectively). Our results show a substantial increase in the levels of association for ligand‐targeted liposomes, in vitro as well as ex vivo, in tumor cells removed from patients, after mastectomy or tumorectomy. These results suggest that internalization occurs, most likely through the clathrin‐mediated endocytic pathway. Cytotoxicity studies show that ligand‐targeted liposomes are more cytotoxic than the control formulation (4 to 180‐fold), against tumor and endothelial cells, indicating that binding and internalization of the system are contributing to a more efficient delivery of the payload to the target cells. In vivo experiments report a higher tumor accumulation of the radiolabeled targeted system over non‐targeted liposomes (approximately 18‐fold). The observed improved tumor targeting is likely due to a strong vascular targeting component that is taking place in vivo. The data generated so far indicate that the same technological platform is able to target two distinct cell populations within the tumor niche. Overall, these results represent a novel and a valuable contribution for delivery strategies to the tumor and its microenvironment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A129." @default.
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• W2004465404 date "2009-12-10" @default.
• W2004465404 modified "2023-10-18" @default.
• W2004465404 title "Abstract A129: Targeted delivery of therapeutics to tumor cells and the tumor microenvironment" @default.
• W2004465404 doi "https://doi.org/10.1158/1535-7163.targ-09-a129" @default.
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