A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment

项目摘要/摘要 三阴性乳腺癌(TNBC)占乳腺癌病例的15%-20%。缺乏针对性 治疗和不良的预后导致了寻找分子靶点以改善结果的重大努力。 虽然人们对肿瘤的分子异质性的了解越来越多，但靶向药物的临床试验 到目前为止都令人失望。化疗药物如蒽环类和紫杉烷类仍然是 早期和转移性TNBC的医疗管理骨干。这种方法对正常的 增加肿瘤细胞，导致治疗负担和不良副作用。这些药物是给那些 患者希望受益大于风险。改善结果的一个重要方法是 开发纳米载体以实现对肿瘤的靶向传递并降低毒性。迄今为止，抗肿瘤药物 目前FDA批准的纳米药物(Doxil和Abraxane)的活性与 免费的药品。对于一种可以克服不同生理障碍的方法的需求尚未得到满足 以更具体的方式提供更高浓度的药物。我们的长期目标是开发一个平台来 改进化疗药物，以实现更安全和更有效的治疗。目标是开发一种 克服肿瘤特异性递送中的多个障碍的平台。我们提出了一种生物相容的，非 免疫原性，自组装的基于多肽的纳米纤维前体(NFP)。其中至关重要的因素 有效的疗法是：(A)共同提供最佳的联合疗法的药物比例，(B)控制形状 促进药物摄取，(C)电荷辅助肿瘤穿透，(D)酶诱导的肿瘤保留(ETR)， 以及(E)NFP将采用的pH激活的受控药物释放方法。NFP的高聚乙二醇量 最大限度地减少被资源捕获的可能性。我们最重要的假设是，这样一个多路平台将显著 作为药物载体使用时，可提高疗效和安全性。我们的初步数据显示，NFP 与游离阿霉素相比，加入阿霉素的治疗效果更好，宿主毒性最小。 毒品和多西西林。我们的基本原理是最大限度地将NFP输送到肿瘤，这需要我们了解 NFP的物理化学性质(如大小和表面电荷、ETR动力学和药物)的贡献 释放谱)在其生物分布和吸收、渗透和保留方面。我们的具体目标将集中在 (Aim1)改进不同的物理化学性质，包括大小、形状、电荷和功能 影响NFP体内行为的结构域；以及(目标2)评价受控药物的治疗效果。 释放NFP作为化疗的载体。这些信息将对多种药物的最佳配方至关重要。 联合用药在最有效的药物比例上能显著改善治疗结果。同时我们将利用 为了开发NFP的最佳特性，这些信息将有助于药物设计 其他恶性肿瘤涉及NFP的联合治疗。

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.