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：
7221923
负责人：
Russell J Mumper
金额：
$ 2.9万
依托单位：
UNIVERSITY OF KENTUCKY
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 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7221923
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 Engineering Environment Enzymes Epidermal Growth Factor Receptor Exotoxins Folate Gadolinium Glycoproteins Goals 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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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 (p-gp) 的过度表达而极易产生多重耐药性。主要假设是，含有脂质纳米颗粒（NP）的紫杉醇使用转化生长因子-α（TGF-β-包被的纳米颗粒）靶向表皮生长因子受体（EGFR），可以有利地克服人类乳腺癌细胞对紫杉醇或紫杉醇的耐药性。初步的体外和体内研究表明这些纳米粒子可以克服耐药性，因此构成了该提议的基础，并且 EGF 受体存在于大多数乳腺癌中。与正常细胞相比，TGF-β 已显示出与一类高亲和力 EGFR 结合位点的结合，解离常数<5.3 nM。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）紫杉醇纳米颗粒制剂；一种是非靶向的 (PEG-NP)，另一种是靶向的 (TGF-?? PEG-NP) 具体目标#2：在小鼠中进行药代动力学、生物分布和器官毒性研究具体目标#3：在携带敏感和耐药人 MDA-MB-231 乳腺癌细胞的裸鼠异种移植模型中，使用非靶向 PEG-NP 和靶向 (TGF-???n PEG-NP) 制剂与紫杉醇进行肿瘤功效研究过度表达 EGF 受体 (EGFR) 一个高度跨学科的团队已经组建，提供纳米技术/药物输送、临床肿瘤学和肿瘤生物学方面的专业知识。肯塔基大学 Mumper 博士的实验室将开发和表征所有 NP 制剂，并进行体外细胞毒性、体内药代动力学、生物分布和肿瘤功效研究。亚当斯博士！|肯塔基大学的实验室将开发紫杉醇耐药乳腺癌细胞，协助体外细胞毒性研究和体内研究，并评估体外和体内 EGFR 表达。路易斯维尔大学的 Tseng 博士实验室将进行与乳腺癌细胞中纳米颗粒的组织相容性和作用机制相关的所有结构分析实验。该提案的创新涉及生物相容性纳米颗粒的纳米模板工程、克服多药耐药性以及利用纳米技术设计细胞靶向癌症疗法。