The goal of this proposal is to utilize a targeted nanosystem to overcome and treat multi-drug resistant breast cancer. Breast cancer, like many cancers are highly prone to multi-drug resistance due to the overexpression of p-glycoprotein (p-gp). The main hypothesis is that paclitaxel containing lipid nanoparticles (NPs) targeted to the epidermal growth factor receptor (EGFR) using transforming growth factor-alpha (TGF-???w-coated nanoparticles may advantageously overcome resistance in human breast cancer cells over Taxol or untargeted NPs. Preliminary in-vitro and in-vivo supports that these NPs may overcome resistance, and thus forms the basis of this proposal. The EGF-receptor is present in the majority of breast cancers and is present at very high levels as compared to normal cells. TGF-?? has been shown to bind to a single class of high-affinity EGFR binding sites with dissociation constant <5.3 nM.? ? The four year proposal has three Specific Aims, as follows:? ? Specific Aim #1: Develop two improved pegylated (PEG) paclitaxel NP formulations; one being untargeted (PEG-NPs) and the other being targeted (TGF-?? PEG-NPs) ? Specific Aim #2: Perform pharmacokinetic, biodistribution, and organ toxicity studies in mice ? Specific Aim #3: Perform tumor efficacy studies with both untargeted PEG-NPs and targeted (TGF-???n PEG-NPs) formulations versus Taxol in a nude mouse xenograft model bearing sensitive and resistant human MDA-MB-231 breast cancer cells that overexpress the EGF-receptor (EGFR)? ? A highly interdisciplinary team providing expertise in nanotechnology/drug delivery, clinical oncology, and tumor biology has been assembled. Dr. Mumper!|s labs at the University of Kentucky will develop and characterize all NP formulations and perform in-vitro cytotoxicity, in-vivo pharmacokinetic, biodistribution, and tumor efficacy studies. Dr. Adams!| labs at the University of Kentucky will develop paclitaxel-resistant breast cancer cells, assist with in-vitro cytotoxicity studies and in-vivo studies, and assess EGFR expression both in-vitro and in-vivo. Dr. Tseng!|s labs at the University of Louisville will perform all structural analysis experiments relating to histocompatibility and the mechanisms of action of NPs in the breast cancer cells. ? ? The innovation of this proposal relates to nanotemplate engineering of biocompatible nanoparticles, overcoming multi-drug resistance, and the use of nanotechnology to engineer a cell-targeted cancer therapy.?
