Limited progress in achieving nanoparticle (NP)-mediated tissue-selective delivery of drugs and imaging agents in vivo by rational design exists in part because the vascular endothelium is a formidable barrier to this type of therapy in vivo. Two fundamental roadblocks to achieving the ultimate goals of nanomedicine are the lack of appropriate tumor/tissue specific targets and a lack of basic information regarding the interaction and processing of blood-borne NP by the endothelium. We have used a systems biology approach coupled with nanotechnology-based tissue fractionation and subfractionation proteomics to enable the rapid identification of and validation of new cancer targets (Nature (2003) 429:629-35). Here, we propose to use these targets toward directing new NPs to solid tumors in vivo. We have assembled a unique team with key expertise in chemistry, nanotechnology, immunology, tumor biology, molecular imaging, membrane trafficking, and vascular cell biology. We will integrate our existing capabilities to investigate the in vivo behavior and interactions of a variety of new endothelial cell (EC)-targeted NPs. This project's hypothesis is that NPs can be actively targeted to solid tumors/select tissues via specific antibodies recognizing EC surface proteins and that targeting NP to caveolae may further enhance tissue/tumor penetration by facilitating transport not only into the ECs but perhaps more importantly across the endothelium for direct access to underlying tissue tumor cells. To this end, we propose the following specific aims: 1) To generate and characterize various new NPs that specifically bind select lung- and tumor-induced EC surface proteins in caveolae; 2) To define cell surface dynamics and intracellular trafficking pathways of NP specifically targeting caveolae in ECs grown in culture; 3) To investigate tissue/tumor targeting and EC processing of antibody-conjugated NPs in vivo after intravenous administration; 4) To test the ability of tumor-targeting NPs to deliver drugs specifically in rat tumor models by assessing their bioefficacy in vivo. By accomplishing these four specific aims, we will gain a better and much more detailed understanding of NP targeting, endothelial processing, and tissue/tumor penetration than is known at present. This will facilitate translation of NP technology from bench to clinic by creating new in vivo imaging agents for diagnostics as well as new multifunctional therapeutics capable of bypassing biological barriers for direct delivery to cancer cells.
