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

基本信息

批准号：
7613400
负责人：
Russell J Mumper
金额：
$ 23.83万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-12 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7613400
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 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 Pseudomonas Publishing Research Research Personnel Research Proposals Resistance Resistance development Sensory Solid System Tail Targeted Toxins 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 vitro testing in vivo innovation malignant breast neoplasm melting mouse model nanoparticle nanoscience nanosystems neoplastic cell novel overexpression programs prototype receptor receptor binding receptor expression receptor recycling research study surfactant tumor uptake

项目摘要

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.

该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。与许多癌症一样，乳腺癌由于 p-糖蛋白的过度表达而极易产生多重耐药性（p-gp）。主要假设是含有脂质纳米粒子（NP）的紫杉醇靶向表皮生长使用转化生长因子-α（TGF-a）包被的纳米粒子可以有利地利用因子受体（EGFR）克服人类乳腺癌细胞对紫杉醇或非靶向纳米粒子的耐药性。初步体外和体内支持这些 NP 可以克服阻力，从而构成该提案的基础。 EGF 受体是存在于大多数乳腺癌中，并且与正常细胞相比，其含量非常高。 TGF-a已被显示可与一类高亲和力 EGFR 结合位点结合，解离常数 <5.3nM。该四年提案有以下三个具体目标：具体目标#1：开发两种改进的聚乙二醇化 (PEG) 紫杉醇 NP 制剂；一种是非靶向制剂 (PEG-NP) 另一个是目标（TGF-a PEG-NP）具体目标#2：执行药代动力学、生物分布和器官毒性，包括血液相容性和小鼠组织相容性研究具体目标#3：使用非靶向 PEG-NP 和靶向（TGF-a PEG-NP）进行肿瘤功效研究在具有敏感和耐药人类MDA-MB-231的裸鼠异种移植模型中制剂与紫杉醇的比较过度表达 EGF 受体 (EGFR) 的乳腺癌细胞高度跨学科的团队提供纳米技术/药物输送、临床肿瘤学和肿瘤方面的专业知识生物学已组装完毕。 Mumper 博士在肯塔基大学的实验室将开发并表征所有 NP 制剂并进行体外细胞毒性、血液能力研究以及体内药代动力学、生物分布、和肿瘤疗效研究。肯塔基大学亚当博士的实验室将开发抗紫杉醇乳房癌细胞，进行体外和体内血管生成研究，并评估体外和体内 EGFR 表达。曾博士在路易斯维尔大学的实验室将进行所有与以下相关的结构分析实验纳米粒子在乳腺癌细胞和内皮细胞中的组织相容性和作用机制。该提案的创新涉及生物相容性纳米粒子的纳米模板工程，克服了多方面的问题耐药性，以及利用纳米技术设计细胞靶向癌症疗法。