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A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment

改善肿瘤靶向和化疗的多重方法

基本信息

批准号：
10443575
负责人：
Benedict Shek Hang Law
金额：
$ 42.6万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443575
关键词：
Abraxane Affect Animals Anthracycline Behavior Biodistribution Biological Models Breast Cancer Model Breast Cancer Treatment Bypass Characteristics Charge Chemicals Clinical Trials Combined Modality Therapy Custom Data Development Disease Doxorubicin Doxorubicin Hydrochloride Liposome Drug Carriers Drug Combinations Drug Design Drug Kinetics ERBB2 gene Effectiveness Environment Enzymes Excision Exhibits FDA approved Formulation Goals Heterogeneity Hormonal In Situ Incidence Kinetics Label Length Liposomes Lymphatic System Malignant Neoplasms Medical Modification Molecular Molecular Target Morbidity - disease rate Neoplasm Metastasis Normal Cell Outcome PET/CT scan Patients Penetration Peptide Hydrolases Peptides Pharmaceutical Preparations Physiological Play Polyethylene Glycols Prognosis Property Radioisotopes Recurrence Regimen Reticuloendothelial System Risk Role Safety Shapes Site Surface System Testing Therapeutic Thick Time Tissues Toxic effect Treatment Efficacy Treatment outcome Vertebral column X-Ray Computed Tomography analog anti-cancer base biomaterial compatibility cancer clinical trial chemotherapeutic agent chemotherapy controlled release design dosage drug release profile effective therapy efficacy evaluation flexibility fluorophore improved improved outcome in vivo malignant breast neoplasm mortality nanocarrier nanofiber nanomedicine nanoparticle neoplastic cell novel optical imaging receptor salinomycin side effect stem cells targeted agent targeted delivery targeted treatment taxane therapeutic evaluation therapeutically effective triple-negative invasive breast carcinoma tumor tumor growth tumor heterogeneity uptake

项目摘要

Project Summary/Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases. The lack of targeted therapies and poor prognosis have resulted in a major effort to discover molecular targets to improve outcomes. While there is increasing understanding of the molecular heterogeneity of tumors, clinical trials of targeted agents have thus far been disappointing. Chemotherapeutic agents such as anthracycline and taxanes remain the backbone of medical management for both early and metastatic TNBC. This approach is toxic to normal in addition to tumor cells, leading to treatment burden and undesired side effects. These drugs are given to the patients in hope of the benefits to outweigh the risks. One significant approach to improve outcomes is the development of nanocarriers to achieve targeted delivery to tumors and reducing toxicity. To date, antitumor activities of the current FDA-approved nanomedicines (Doxil and Abraxane) have been moderate compared to the free drugs. There is an unmet need for an approach that can overcome different physiological barriers to deliver higher concentration of drugs in a more specific manner. Our long-term goal is to develop a platform to improve chemotherapeutics for achieving safer and more effective treatments. The objective is to develop a platform to overcome multiple barriers in tumor-specific delivery. We propose a biocompatible, non- immunogenic, self-assembling peptide-based nanofiber precursor (NFP). The factors that are essential in effective therapies are (a) co-delivering an optimal drug ratio of a combination therapy, (b) shape-controlled promotion of drug uptake, (c) charge-assisted tumor penetration, (d) enzyme-induced tumor retention (ETR), and (e) pH-activated controlled drug release approaches to be utilized by NFP. High PEG content of NFP minimizes its capture by the RES. Our overarching hypothesis is that such a multiplexed platform will significantly improve therapeutic efficacy and safety when used as a drug carrier. Our preliminary data have shown that NFP incorporated with doxorubicin has a superior therapeutic efficacy with minimal host toxicity compared to the free drug and Doxil. Our rationale is to maximize the delivery of NFP to the tumor, which requires us understand the contribution of NFP’s physicochemical properties (such as size and surface charges, ETR kinetics, and drug release profiles) in their biodistribution and uptake, penetration, and retention. Our specific aims will focus on the (Aim1) Refinement of different physicochemical properties, including size, shape, charge, and functional domains, affecting the in vivo behavior of NFP; and (Aim 2) Evaluation of the therapeutic efficacy of controlled- release NFP as a carrier of chemotherapy. This information will be critical for optimal formulation of multi-drug combinations in the most effective drug ratio to significantly improve the treatment outcomes. While we will utilize TNBC to develop the optimal characteristics of NFP, this information will be instrumental in designing drug combination involving NFP for other malignancies.

项目总结/摘要三阴性乳腺癌（TNBC）占乳腺癌病例的15-20%。缺乏针对性治疗和不良预后导致了发现分子靶点以改善结果的重大努力。尽管人们对肿瘤分子异质性的认识越来越多，但靶向药物的临床试验到目前为止都令人失望。蒽环类和紫杉烷类等化学药剂仍然是早期和转移性TNBC的医疗管理骨干。这种方法对正常的这会增加肿瘤细胞的增殖，导致治疗负担和不希望的副作用。这些药物是给希望获益大于风险的患者。改善结果的一个重要方法是开发纳米载体以实现靶向递送至肿瘤并降低毒性。迄今为止，抗肿瘤目前FDA批准的纳米药物（Doxil和Abraxane）的活性与免费药物。存在对能够克服不同生理障碍以使患者能够进行治疗的方法的未满足的需求。以更具体的方式递送更高浓度的药物。我们的长期目标是开发一个平台，改进化学治疗剂以实现更安全和更有效的治疗。目标是发展一个这是一个克服肿瘤特异性递送中的多重障碍的平台。我们提出了一种生物相容的，非- 免疫原性、基于自组装肽的NFP前体。这些因素是必不可少的，有效的治疗是（a）共同递送组合治疗的最佳药物比例，（B）形状控制的促进药物摄取，（c）电荷辅助的肿瘤穿透，（d）酶诱导的肿瘤滞留（ETR），和（e）NFP所使用的pH活化的受控药物释放方法。NFP的高PEG含量最大限度地减少其捕获的RES。我们的首要假设是，这样一个多路复用的平台将显着提高了作为药物载体治疗效果和安全性。我们的初步数据显示，与游离阿霉素相比，药物和Doxil。我们的基本原理是最大限度地将NFP递送到肿瘤，这需要我们了解NFP的作用机制。 NFP的物理化学性质（如大小和表面电荷，ETR动力学和药物释放曲线）在其生物分布和摄取、渗透和保留方面。我们的具体目标将集中在（目标1）细化不同的物理化学性质，包括尺寸、形状、电荷和功能结构域，影响NFP的体内行为;和（目的2）评价受控的NFP的治疗功效。释放NFP作为化疗的载体。这些信息对于多药物的最佳配方至关重要在最有效的药物比例组合，以显着改善治疗结果。我们将利用 TNBC开发NFP的最佳特性，这些信息将有助于设计药物涉及NFP的组合用于其他恶性肿瘤。