Stealth Brusatol and Docetaxel-loaded Nanoparticles for Targeted Prostate Cancer Therapy

用于前列腺癌靶向治疗的隐形 Brusatol 和多西紫杉醇纳米颗粒

基本信息

批准号：
10224723
负责人：
Simeon Kolawole Adesina
金额：
$ 34.76万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224723
关键词：
Adverse effects Affect Amides Animals Antioxidants Binding Biodistribution Biological Assay Brucea Cancer Model Carbon Carboxylic Acids Cell Culture Techniques Cell Death Cell Line Cell Survival Cells Chemoresistance Clinical Combination Drug Therapy Combined Modality Therapy Confocal Microscopy DNA strand break Diffusion Dose Drug Evaluation Drug resistance Emulsions Ensure FOLH1 gene Flow Cytometry Fluorescent Dyes Formulation Freeze Drying Goals Heterogeneity In Vitro Incidence LNCaP Ligand Binding Ligands Lysine Malignant neoplasm of prostate Measures Methods Molecular Weight Morphology Mus Natural regeneration Oils Organic solvent product PC3 cell line Particle Size Pathway interactions Patients Pharmaceutical Preparations Phase Physiological Polyvinyl Alcohol Population Principal Investigator Problem Solving Prostate Cancer therapy Prostatic Neoplasms Protein Biosynthesis Protein Synthesis Inhibitors Quality of life Radiation therapy Reaction Reactive Oxygen Species Relapse Reporting Resistance Rhodamine 123 Series Signal Transduction Site Solvents Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure Surface Suspensions System Testing Time Toxic effect Treatment Efficacy Water Xenograft Model Xenograft procedure amino group aqueous base cancer cell cancer site castration resistant prostate cancer chemotherapeutic agent chemotherapy clinical translation cytotoxic cytotoxicity density docetaxel drug development drug release profile efficacy study experimental study hydroethidine improved in vivo in vivo evaluation indexing innovation nanoparticle nanoparticle delivery nanoparticle drug neoplastic cell novel nuclear factor-erythroid 2 prevent programs response tool tumor tumor heterogeneity tumor microenvironment uptake zeta potential

项目摘要

ABSTRACT Most chemotherapeutic agents are proliferation dependent in their mechanisms of action and are active against rapidly dividing cells. This is a challenge because prostate cancer is clinically slow growing. In addition, prostate cancer is heterogeneous and the drugs currently in use do not kill all populations of tumor cells leading to relapse and regeneration of the tumor. Resistance to docetaxel is another great challenge with chemotherapy of prostate cancer. Brusatol is a protein synthesis inhibitor in cells and it has specific inhibitory activity on nuclear factor erythroid 2-related factor 2 (Nrf2). Because it inhibits protein synthesis, it can kill all tumor cells regardless of heterogeneity. As a result of its non-selective mechanism of action, and other challenges to its clinical translation, the active targeting or site-specific delivery of brusatol to tumors is essential. In addition, the effect of brusatol on Nrf2 is short-lived. The sustained release of brusatol from a delivery system can ensure a prolonged effect on Nrf2 similar to repeated dosing. In addition to its cytotoxic effects, brusatol can also prevent the development of drug resistance and reverse the resistance to other drugs. The innovation and advantages of these approach are numerous. The nanoparticle platform is essential: (a) to prevent or reduce toxicity to healthy cells (the drugs will be released in the tumor microenvironment as a result of the EPR effect and active targeting by binding to PSMA), (b) for sustained drug release and thereby reverse the short-lived effect on Nrf2, (c) to increase drug concentration in the tumor and thereby increase therapeutic efficacy. In addition, combination therapy of brusatol and docetaxel in a nanoparticle platform allows targeting multiple pathways with the resultant improvement in therapeutic efficacy. Furthermore, combination of both drugs can prevent and/or reverse resistance to docetaxel by well- known reported mechanisms. This can solve the problem of docetaxel resistance. Finally, the brusatol- and docetaxel-loaded nanoparticles as a result of accumulation within the tumor microenvironment can augment and improve the efficacy of radiotherapy. Docetaxel, in addition to its cytotoxicity greatly increases the ROS levels while brusatol inhibits the antioxidant response. This effects greatly increase ROS levels specifically within the tumor. Since radiotherapy exerts its effects by increasing ROS and causing DNA strand breaks, the nanoparticle platform holds the promise to significantly augment radiotherapy within the tumor microenvironment. Our hypothesis is that the fabrication of stealth, targeted, brusatol- and docetaxel-loaded nanoparticles will reverse the transient brusatol effect on Nrf2 by sustained, continuous release from nanoparticles. Nanoparticle combination therapy will: (1) suppress and/or reverse chemoresistance to docetaxel (2) reduce adverse effects, and (3) increase therapeutic efficacy as a result of affecting multiple proliferation pathways of cancer cells and site-specific delivery. To achieve the goals of the proposal, we have the following aims: (1) Fabrication, characterization and optimization of stealth, targeted brusatol- and docetaxel-loaded nanoparticles and controls. (2) Cytotoxicity and cellular internalization studies, flow cytometry analyses and other in vitro studies will be carried done using fluorescent dye- and drug-loaded nanoparticles. (3) Biodistribution, maximum tolerable dose (MTD) and efficacy studies will be done in mice.

抽象的大多数化学治疗剂都是增殖的，取决于其作用机理，并且迅速对抗分裂细胞。这是一个挑战，因为前列腺癌在临床上生长缓慢。此外，前列腺癌是异质性和目前正在使用的药物不会杀死所有导致复发和再生的肿瘤细胞种群肿瘤。对多西他赛的抗性是前列腺癌化学疗法的另一个巨大挑战。 Brusatol是细胞中蛋白质的抑制剂，它具有特异性抑制作用，对核因子2相关的核因子。因子2（NRF2）。因为它抑制蛋白质的合成，因此无论异质性如何，都可以杀死所有肿瘤细胞。由于它的非选择性的作用机理，以及其临床翻译，主动靶向或特定地点的其他挑战将brusatol递送到肿瘤至关重要。另外，布鲁萨尔对NRF2的影响是短暂的。持续释放来自输送系统的Brusatol可以确保对NRF2的长期影响，类似于重复给药。除了其细胞毒性效果，布鲁萨尔还可以防止耐药性的发展并扭转对其他药物的耐药性。这些方法的创新和优势很多。纳米颗粒平台至关重要：（a）预防或降低对健康细胞的毒性（由于EPR效应，药物将在肿瘤微环境中释放通过与PSMA结合进行主动靶向），（b）用于持续的药物释放，从而扭转了对NRF2的短暂影响，（C）为了增加肿瘤的药物浓度，从而提高了治疗功效。另外，联合疗法的纳米颗粒平台中的brusatol和多西他赛允许靶向多个途径治疗功效。此外，两种药物的组合都可以预防和/或反向对多西他赛的抵抗力已知的报告机制。这可以解决多西他赛电阻的问题。最后，brusatol-和多西他赛的负载由于肿瘤微环境内积累的结果，纳米颗粒可以提高并提高放疗。多西他赛除了其细胞毒性外，大大增加了ROS水平，而Brusatol抑制了抗氧化剂反应。这种影响大大提高了肿瘤内的ROS水平。由于放疗施加了通过增加ROS并引起DNA链断裂的影响，纳米颗粒平台有望显着增强肿瘤微环境中的放射疗法。我们的假设是，靶向，棕褐色和多西他赛的纳米颗粒的制造将逆转通过纳米颗粒的持续释放，瞬时勃鲁萨尔对NRF2的影响。纳米颗粒联合疗法意志：（1）抑制和/或反向化学抗性（2）减少不良反应，（3）增加治疗性由于影响癌细胞的多个增殖途径和特定部位的递送而导致的功效。实现提案的目标，我们有以下目的：（1）隐形的制造，表征和优化，针对性 brusatol-和多西他赛加载的纳米颗粒和控件。（2）细胞毒性和细胞内在化研究，流量细胞仪分析和其他体外研究将使用荧光染料和药物加载的纳米颗粒进行。（3）在小鼠中将进行生物分布，最大耐受剂量（MTD）和功效研究。