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.

该提案的目的是利用靶向纳米系统来克服和治疗多耐药的乳腺癌。像许多癌症一样，由于P-糖蛋白的过表达，乳腺癌很容易发生多腐烂（P-gp）。主要的假设是含有针对表皮生长的脂质纳米颗粒（NP）的紫杉醇使用转化生长因子-Alpha（TGF-A）涂层的纳米颗粒可能有利的因子受体（EGFR）克服紫杉醇或不靶向NP的人类乳腺癌细胞的耐药性。初步的in-vitro和in-Vivo 支持这些NP可以克服抵抗力，从而构成了该提议的基础。 EGF受体是与正常细胞相比，大多数乳腺癌存在于大多数乳腺癌中。 TGF-A一直以来显示与单一类高亲和力的EGFR结合材料结合，其解离常数<5.3nm。四年提案具有三个具体目标，如下：特定目的＃1：开发两个改进的Pegypate（PEG）紫杉醇NP配方；一个是未靶向的（PEG-NP）另一个是针对目标的（TGF-A PEG-NP）特定目的＃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的组织相容性研究特定目的＃3：使用未靶向的PEG-NP和有针对性的肿瘤功效研究（TGF-A PEG-NP）配方与紫杉醇在裸鼠异种移植模型中具有敏感和抗性的HumanMDA-MB-231 过表达EGF受体（EGFR）的乳腺癌细胞高度跨学科的演出，提供纳米技术/药物输送，临床学和肿瘤方面的专业知识生物学已经组装。肯塔基大学Mumper博士的实验室将发展并描述所有NP 配方并执行体外细胞毒性，血能力研究和体内药代动力学，生物分布，和肿瘤功效研究。肯塔基大学亚当博士的实验室将发展抗紫杉醇的乳房癌细胞，进行体外和体内生血管生成研究，并评估EGFR表达体内和体内。路易斯维尔大学大学的Tseng博士的实验室进行了有关的所有结构分析实验 NPS在乳腺癌细胞和内皮细胞中NP的作用机制。该提案的创新与生物相容性纳米颗粒的纳米板工程有关，克服了多种多样耐药性，并使用纳米技术来设计针对细胞的癌症疗法。