Nanoparticle formulations of DNA repair inhibitors to improve chemoradiotherapy

DNA 修复抑制剂纳米颗粒制剂可改善放化疗

• 批准号: 8562388
• 负责人: Andrew Zhuang Wang
• 金额: $ 31.21万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562388
• 关键词: Affect; Artificial nanoparticles; Biodistribution; Characteristics; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Development; Disease; Disease model; Double Strand Break Repair; Drug Controls; Drug Delivery Systems; Drug Formulations; Engineering; Fluorouracil; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hepatotoxicity; Kinetics; Laboratories; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of cervix uteri; Malignant neoplasm of pancreas; Methods; Names; Normal Cell; Normal tissue morphology; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Process; Property; Radiation therapy; Radiation-Sensitizing Agents; Rectal Cancer; Research; Shapes; Techniques; Therapeutic; Therapeutic Index; Toxic effect; Translating; Translations; Treatment Efficacy; Work; base; chemoradiation; chemosensitizing agent; chemotherapy; common treatment; comparative efficacy; controlled release; cytotoxic; docetaxel; drug mechanism; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; mouse model; nanomedicine; nanoparticle; neoplastic cell; novel strategies; novel therapeutics; oncology; particle; prevent; public health relevance; small molecule; standard of care; tumor; wortmannin

DESCRIPTION (provided by applicant): Chemoradiotherapy is an important treatment paradigm in cancer management. Given its importance, one of the primary research objectives in oncology has been to develop agents to further improve chemoradiotherapy's therapeutic index. One class of agent, the DNA repair inhibitors (DRIs), holds high potential in such application. However, DRIs' clinical translation has been prevented by drug delivery challenges. While traditional drug delivery methods have been unable to overcome these challenges, the development of nanoparticle (NP) drug delivery vehicles offers an unprecedented opportunity. NPs' preferential accumulation in tumors, low distribution in normal tissue, and controlled release properties are all favorable characteristics for applications in chemoradiotherapy. Our group was the first to develop an NP DRI, NP wortmannin (Wtmn), and demonstrated its potential in improving radiotherapy. We are also one of the first to demonstrate that NP therapeutics are more effective than their small molecule counterparts in chemoradiotherapy. We hypothesize that NP delivery can overcome the drug delivery challenges and facilitate the clinical translation of DRIs in chemoradiotherapy. The overall objective of this application is to develop and evaluate NP DRIs for chemoradiotherapy. To engineer NP DRIs, we plan to utilize the Particle Replication in Non-Wetting Templates (PRINT) NP platform, which is capable of fabricating NPs with precise control over size, shape, drug loading and drug release. Importantly, PRINT has undergone the clinical development process, which will enhance rapid clinical translation. Head and neck squamous cell carcinoma (HNSCC) will be used as a model disease since chemoradiotherapy is the most common and effective treatment for this disease. Our application has three specific aims. The first aim will focus on understanding and optimizing the key factors, such as drug release, that can affect PRINT NP Wtmn's efficacy and toxicity. Our second aim will study to the extent which co-delivering a chemotherapeutic with Wtmn can improve chemoradiotherapy. We aim to engineer PRINT NPs that can either co-deliver docetaxel or cisplatin, two mostly commonly used chemotherapeutics in HNSCC, with Wtmn. These NPs will be evaluated in mouse models of HNSCC and compared to chemotherapy and NP Wtmn given separately. The third aim will study NP formulations of poly ADP ribose polymerase inhibitors (PARPIs)'s potential in chemoradiotherapy. PARPIs are DRIs and are known to act synergistically with both chemotherapy and radiotherapy. Such dual sensitization provides them unique potentials in chemoradiotherapy. In summary, our application aims to apply advances in nanomedicine to improving chemoradiotherapy. Our work can lead to the rapid clinical development of NP DRIs for chemoradiotherapy. It can directly translate into increased cure rates and improved survival in patients with HNSCC and other difficult to treat cancers. My long term research goal is to utilize develop and utilize NP therapeutics, such as DRIs, to improve the chemoradiotherapy treatment paradigm.

描述（由申请人提供）：放化疗是癌症治疗中的重要治疗范例。鉴于其重要性，肿瘤学的主要研究目标之一是开发药物以进一步提高放化疗的治疗指数。一类药物，DNA 修复抑制剂 (DRI)，在此类应用中具有很高的潜力。然而，DRI 的临床转化因药物输送挑战而受到阻碍。虽然传统的药物递送方法无法克服这些挑战，但纳米颗粒（NP）药物递送载体的发展提供了前所未有的机遇。纳米粒子在肿瘤中的优先积累、在正常组织中的低分布以及控释特性都是在放化疗中应用的有利特征。我们的团队率先开发了 NP DRI，即 NP 渥曼青霉素 (Wtmn)，并展示了其在改善放射治疗方面的潜力。我们也是最早证明 NP 疗法比放化疗中的小分子疗法更有效的公司之一。我们假设 NP 递送可以克服药物递送挑战并促进 DRI 在放化疗中的临床转化。该应用的总体目标是开发和评估用于放化疗的 NP DRI。为了设计纳米颗粒 DRI，我们计划利用非润湿模板中的颗粒复制 (PRINT) 纳米颗粒平台，该平台能够制造精确控制尺寸、形状、药物负载和药物释放的纳米颗粒。重要的是，PRINT已经经历了临床开发过程，这将增强快速的临床转化。头颈鳞状细胞癌（HNSCC）将被用作模型疾病，因为放化疗是该疾病最常见和最有效的治疗方法。我们的应用程序有三个具体目标。第一个目标将侧重于了解和优化可能影响 PRINT NP Wtmn 功效和毒性的关键因素，例如药物释放。我们的第二个目标是研究联合化疗与 Wtmn 可以在多大程度上改善放化疗。我们的目标是设计可以与 Wtmn 共同递送多西紫杉醇或顺铂这两种 HNSCC 最常用化疗药物的 PRINT NP。这些 NP 将在 HNSCC 小鼠模型中进行评估，并与单独给予的化疗和 NP Wtmn 进行比较。第三个目标是研究聚 ADP 核糖聚合酶抑制剂 (PARPI) 的 NP 制剂在放化疗中的潜力。 PARPI 是 DRI，已知与化疗和放疗具有协同作用。这种双重敏化为它们在放化疗中提供了独特的潜力。总之，我们的应用旨在应用纳米医学的进步来改善放化疗。我们的工作可以促进用于放化疗的 NP DRI 的快速临床开发。它可以直接转化为提高 HNSCC 和其他难以治疗的癌症患者的治愈率和生存率。我的长期研究目标是开发和利用 NP 疗法（例如 DRI）来改进放化疗的治疗模式。