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）：化学放疗是癌症管理中的重要治疗范式。鉴于其重要性，肿瘤学的主要研究目标之一是开发药剂以进一步改善化学疗法的治疗指数。在这种应用中，一类代理DNA修复抑制剂（DRI）具有很高的潜力。但是，DRIS的临床翻译已被药物输送挑战所阻止。尽管传统的药物输送方法无法克服这些挑战，但纳米颗粒（NP）药物的发展提供了前所未有的机会。 NPS在肿瘤中的优先积累，正常组织中的低分布和受控的释放性能都是化学放疗中应用的有利特征。我们的小组是第一个开发NP DRI，NP Wortmannin（WTMN）的人，并证明了其在改善放射疗法方面的潜力。我们也是第一个证明NP治疗剂比其在化学放疗中的小分子对应物更有效的人之一。我们假设NP的递送可以克服药物递送挑战，并促进化学放疗中DRI的临床翻译。该应用的总体目的是开发和评估NP DRI进行化学放疗。对于Engineer NP DRI，我们计划在非润湿模板（PRINT）NP平台中利用粒子复制，该平台能够制造具有精确控制大小，形状，药物加载和药物释放的NP。重要的是，印刷过程已经经历了临床开发过程，这将增强快速的临床翻译。头颈鳞状细胞癌（HNSCC）将被用作模型疾病，因为化学放疗是该疾病的最常见和有效治疗方法。我们的应用程序具有三个具体目标。第一个目标将集中在理解和优化关键因素（例如释放药物）上，这些因素可能会影响印刷NP WTMN的功效和毒性。我们的第二个目标将在与WTMN共同交付化学治疗的范围内可以改善化学放疗。我们的目标是设计可以与WTMN共同使用Docetaxel或Cisplatin的NP，这是HNSCC中的两种通常使用的化学治疗剂。这些NP将在HNSCC的小鼠模型中评估，并与化疗和NP WTMN分别进行比较。第三个目标将研究聚ADP核糖聚合酶抑制剂（PARPIS）在化学放疗中的潜力的NP制剂。 Parpis是DRIS，众所周知可以通过化学疗法和放射疗法协同作用。这种双重敏化为它们提供了化学放疗中的独特潜力。总而言之，我们的应用旨在将纳米医学的进步应用于改进化学疗法。我们的工作可以导致NP DRI的快速临床发展进行化学放疗。它可以直接转化为HNSCC患者和其他难以治疗癌症患者的治疗率提高和提高的生存率。我的长期研究目标是利用和利用NP疗法（例如DRI）来改善化学放疗治疗范式。