One of our long-term objectives in the nano-biotechnology area is to develop highly biocompatible carbon nanotube biological conjugates for targeted imaging, drug delivery and cancer therapy. In this proposal, we plan to develop new functionalization chemistry for single-walled nanotubes (SWNTs) to achieve tumor specific delivery of chemotherapeutics. We also plan to utilize the intrinsic optical properties (Raman &photoluminescence) of nanotubes for detection and imaging for monitoring and understanding the biodistribution and treatment efficacy of SWNT-drug complexes. We hope to fully demonstrate the novelty of using carbon nanotubes for biomedical applications owing to the unique structural, chemical and physical properties of SWNTs including, (1) one-dimensional structure (diameter ~1nm, tunable length) and high surface area ~1000m2/g, (2) non-toxic chemical composition: carbon, (3) strong Raman spectroscopic lines for raman tags and (4) band-gap fluorescence or photoluminescence properties in the near IR (NIR) for fluorescence imaging and detection. These distinguish SWNTs from various other nanomaterials and make them ideally suited for biological applications. We have promising preliminary results showing that SWNTs can be functionalized to render biocompatibility in vivo in mice. SWNTs are non-toxic when administered intravenously at high doses. Nanotubes retained in the reticuloendothelial system (RES) and are gradually excreted out of the body via the biliary and renal pathways. Our preliminary data also indicate that paclitaxel- SWNT conjugate is superior to the Cremophor ELP solubilized paclitaxel (PTX) for cancer therapy. In this R01 proposal we will extend such efforts and perform systematic studies to identify an optimal nanotube functionalization scheme using branched hydrophilic molecules. We will then attach paclitaxel via cleavable ester bonds to the functionalized nanotubes for tumor treatment with low side toxicity effects to normal organs. We will investigate in vivo blood circulation, biodistribution, tumor uptake, and distribution within tumor for functionalized SWNTs and SWNT-drug conjugates, for understanding the treatment results and identifying the best SWNT-PTX conjugate with the optimal tumor treatment efficacy and lowest side effect toxicity. We will investigate the tumor treatment efficacy of SWNT-PTX by passive targeting and compare with Cremophor ELP and Abraxane in mice xenograft tumor models. We will also carry out targeted drug delivery for highly efficient tumor killing using SWNT-PTX conjugates co-functionalized with RGD peptide for specific integrin recognition and binding to tumors. Finally, we will combine heat-shock protein 90 (Hsp90) inhibitions and SWNT-PTX treatment to investigate if Hsp90 inhibitor affords enhancement of paclitaxel tumor treatment efficacy.
This project will use a novel one-dimensional molecule, single-walled carbon nanotube (SWNT) for cancer drug delivery and for cancer imaging using their intrinsic optical properties. These nano-technological advances will lead to new formulations for chemotherapy drugs such as paclitaxel to afford higher cancer treatment efficacy and lower toxic side effects than currently FDA approved Taxol and Abraxane, providing doctors with better drugs to battle cancer using nanotechnology.
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