Development of Lipid-based Nanoparticles for in vivo Targeted Delivery of Imaging Agents into Breast Cancer Cells
Final rept. 15 Sep 2008-14 Mar 2010
PENNSYLVANIA UNIV PHILADELPHIA
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Breast cancer represents a unique disease in oncology, in that specific markers have been identified and are routinely used for diagnosis and targeted therapy. Targeted delivery of a combined imaging and therapy agent to cancer cells is an avenue to develop a new generation of effective and selective anticancer agents. The goal of this proposal is to develop novel nanoparticles for in vivo breast cancer targeting. The nanoparticles consist of a cholesterol ester core surrounded with a lipid monolayer shell containing an imaging agent and metal chelating groups that can attach proteins of interest through specific His6 tagging. We have synthesized nanoparticle building blocks as well as imaging agents consisting from the near infrared fluorophore pyropheophorbide a conjugated with core or shell lipids. Varying the core composition we have assembled a series of the nanoparticles with size from 8 nm for smallest one to 20 nm for largest nanoparticle. We have shown that the nanoparticles with cholesterol oleate core have supreme shelf-life and stability at the conditions close to physiological. We have prepared a number of lipid nanoparticles with His6-tagged targeting proteins, which were successfully tested in vitro for specific targeting of model cell lines. We have shown that due to multivalent nature of the targeting nanoparticles the wide spectrum of proteins from natural low affinity receptor 104 M-1 to antibody Fab fragment 107 M-1 can be used in nanoparticle composition. Time course analysis of the nanoparticle binding to the cell surface revealed that the shell loaded imaging agent is much more effective than the core loaded one.
- Medicine and Medical Research