A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment

项目概要/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。该信息对于多药物组合物的最佳配方将是至关重要的。 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。

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.