EGFR Targeted Nanoparticles to Overcome Paclitaxel Resistant Breast Cancer

这项提议的目标是利用有针对性的纳米系统来克服和治疗多重耐药乳腺癌。 乳腺癌像许多癌症一样，由于P-糖蛋白的过度表达而高度容易产生多重耐药。 (P-gp)。主要的假设是紫杉醇含脂纳米粒(NPs)靶向于表皮生长 使用转化生长因子-α(转化生长因子-α)包被纳米粒的因子受体(EGFR)可能是有利的 克服人乳腺癌细胞对紫杉醇或非靶向纳米粒的耐药性。体外和体内初步研究 支持这些核动力源可以克服阻力，从而构成本提案的基础。EGF受体是 它存在于大多数乳腺癌中，与正常细胞相比，其含量非常高。转化生长因子-α已经成为 显示与一类高亲和力的EGFR结合位点，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；一种是非靶向的(聚乙二醇纳米粒) 另一种是靶向(转化生长因子-α-聚乙二醇纳米粒) 具体目标2：进行药物动力学、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 具体目标#3：用非靶向的聚乙二醇纳米粒和靶向的(转化生长因子-α聚乙二醇纳米粒)进行肿瘤疗效研究 不同剂型与紫杉醇在人敏感耐药人MDA-MB-231裸鼠移植瘤中的比较 过度表达表皮生长因子受体(EGFR)的乳腺癌细胞 一个高度跨学科的团队，提供纳米技术/药物输送、临床肿瘤学和肿瘤方面的专业知识 生物学已经组装好了。Mumper博士在肯塔基大学的实验室将开发和表征所有NP 制剂和进行体外细胞毒性，血容研究，体内药代动力学，生物分布， 和肿瘤疗效研究。亚当博士在肯塔基大学的实验室将开发出紫杉醇耐药乳房 进行体外和体内血管生成研究，并评估EGFR在体外和体内的表达。 曾博士在路易斯维尔大学的实验室将进行与以下各项有关的所有结构分析实验 纳米粒在乳腺癌细胞和内皮细胞中的组织相容性及其作用机制。 该方案的创新涉及生物兼容纳米颗粒的纳米模板工程，克服了多个 抗药性，以及利用纳米技术设计一种细胞靶向癌症疗法。

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.