EGFR Targeted Nanoparticles to Overcome Paclitaxel Resistant Breast Cancer

EGFR 靶向纳米颗粒克服紫杉醇耐药乳腺癌

• 批准号: 7355582
• 负责人: Russell J Mumper
• 金额: $ 23.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-12 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355582
• 关键词: Affinity; Albumin-Stabilized Nanoparticle Paclitaxel; Alcohols; Antineoplastic Agents; Attributes of Chemicals; Back; Binding; Binding Sites; Biocompatible; Biodistribution; Biological Assay; Biology; Blood; Breast Cancer Cell; Breast Cancer Treatment; Brij-78; Cancer Patient; Cell Line; Cell surface; Cells; Class; Clinical; Clinical Oncology; Colorectal Adenocarcinoma; Data; Development; Dissociation; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Elements; Endothelial Cells; Engineering; Environment; Enzymes; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Exotoxins; Folate; Gadolinium; Glycoproteins; Goals; Growth Factor Receptors; High Pressure Liquid Chromatography; Histocompatibility; Histology; Human; In Vitro; Inbred BALB C Mice; KB Cells; Kentucky; Knowledge; Lead; Ligands; Lipids; Literature; Malignant Neoplasms; Mammary Neoplasms; Methods; Multi-Drug Resistance; Mus; Nanotechnology; Neurons; Normal Cell; Normal tissue morphology; Nude Mice; Oils; Organ; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Phase; Phospholipids; Plague; Polysorbates; Principal Investigator; Protein Overexpression; Pseudomonas; Publishing; Purpose; Rate; Research; Research Personnel; Research Proposals; Resistance; Resistance development; Sensory; Solid; System; Tail; Targeted Toxins; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Toxin; Transforming Growth Factor alpha; Tumor Biology; Tumor Tissue; Universities; Vascular Endothelial Growth Factors; Veins; Water; Work; Xenograft Model; Xenograft procedure; base; biomaterial compatibility; cancer cell; cancer therapy; cetyl alcohol; cytotoxic; cytotoxicity; folate-binding protein; improved; in vivo; innovation; malignant breast neoplasm; melting; mouse model; nanoparticle; nanoscience; nanosystems; neoplastic cell; novel; programs; prototype; receptor; receptor binding; receptor expression; receptor recycling; research study; size; surfactant; tumor; uptake

The goal of this proposal is to utilize a targeted nanosystem to overcome and treat multi-drugresistant breast cancer. Breast cancer, like many cancers are highly prone to multi-drugresistance 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-a)-coated nanoparticles may advantageously overcome resistance in human breast cancer cells over Taxol or untargeted NPs. Preliminaryin-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-a has been shown to bind to a single class of high-affinity EGFR bindingsites with dissociation constant <5.3nM. 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-a PEG-NPs) Specific Aim #2: Perform pharmacokinetic, biodistribution,and organ toxicity including hemocompatibility and histocompatibility studies in mice Specific Aim #3: Perform tumor efficacy studies with both untargeted PEG-NPs and targeted (TGF-a PEG-NPs) formulations versus Taxol in a nude mouse xenograft model bearing sensitive and resistant humanMDA-MB-231 breast cancer cells that overexpress the EGF-receptor (EGFR) A highly interdisciplinaryteam providing expertise in nanotechnology/drug delivery, clinicaloncology, and tumor biology has been assembled. Dr. Mumper's labs at the Universityof Kentucky will develop and characterize all NP formulations and perform in-vitro cytotoxicity, hemocapatibilitystudies, and in-vivo pharmacokinetic,biodistribution, and tumor efficacy studies. Dr. Adam's labs at the Universityof Kentucky will develop paclitaxel-resistant breast cancer cells, perform in-vitro and in-vivoangiogenesis studies, and assess EGFR expression both in-vitro and in-vivo. Dr. Tseng's labs at the University of Louisvillewill perform all structural analysis experiments relating to histocompatibility and the mechanisms of action of NPs in the breast cancer cells and endothelial 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.

本提案的目标是利用靶向纳米系统来克服和治疗多重耐药乳腺癌。