EGFR Targeted Nanoparticles to Overcome Paclitaxel Resistant Breast Cancer

描述(申请人提供)：这项提案的目标是利用有针对性的纳米系统来克服和治疗耐多药乳腺癌。乳腺癌与许多癌症一样，由于p-糖蛋白(p-gp)的过度表达，极易产生多药耐药。主要的假设是紫杉醇脂类纳米粒(NPs)靶向于表皮生长因子受体(EGFR)，使用转化生长因子-α(TGF-？W)包裹的纳米粒可以有利地克服人乳腺癌细胞对紫杉醇或非靶向NPs的耐药性。初步的体外和体内实验支持这些NPs可以克服耐药性，从而形成了这一提议的基础。EGF受体存在于大多数乳腺癌中，与正常细胞相比，EGF受体的水平非常高。转化生长因子-？？已被证明与一类高亲和力的EGFR结合位点，其解离常数为5.3 nM。 这项为期四年的建议有三个具体目标，如下： 具体目标1：开发两种改进的聚乙二醇化紫杉醇纳米粒制剂；一种是非靶向(聚乙二醇纳米粒)，另一种是靶向(转化生长因子？？Peg-nps) 特定目标2：在小鼠体内进行药代动力学、生物分布和器官毒性研究 具体目标#3：在携带高表达EGF受体(EGFR)的敏感和耐药的人MDA-MB-231乳腺癌细胞的裸鼠异种移植模型中，进行非靶向聚乙二醇纳米粒和靶向(转化生长因子-β-聚乙二醇纳米粒)制剂与紫杉醇的肿瘤疗效研究 已经组建了一个高度跨学科的团队，提供纳米技术/药物输送、临床肿瘤学和肿瘤生物学方面的专业知识。肯塔基大学的S实验室将开发和鉴定所有NP制剂，并进行体外细胞毒性、体内药代动力学、生物分布和肿瘤疗效研究。肯塔基大学的实验室将开发对紫杉醇耐药的乳腺癌细胞，协助进行体外细胞毒性研究和体内研究，并评估EGFR在体外和体内的表达。曾博士！|路易斯维尔大学的S实验室将进行所有与乳腺癌细胞中NPs的组织相容性和作用机制有关的结构分析实验。 这项提议的创新涉及生物兼容纳米颗粒的纳米模板工程，克服多重耐药，以及使用纳米技术设计细胞靶向癌症治疗。

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.