Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer

亚 100 nm 且可扩展的自我治疗纳米颗粒可靶向胰腺癌的自噬

• 批准号: 10604147
• 负责人: Tzu-yin Lin
• 金额: $ 40万
• 依托单位: THERANOSTEC, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604147
• 关键词: Abraxane; Address; Aggressive behavior; Aminoquinolines; Animal Model; Animals; Antineoplastic Agents; Autophagocytosis; COVID-19; Cancer Etiology; Cancer cell line; Cells; Cessation of life; Chemicals; Chemoresistance; Chloroquine; Clinic; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Communication; Development; Digestion; Disease; Drug Delivery Systems; Drug Kinetics; Drug resistance; Exhibits; Feasibility Studies; Filtration; Formulation; Foundations; Freeze Drying; Functional disorder; Future; Goals; Growth; Hydroxychloroquine; In Vitro; Lead; Link; Liposomes; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Mediating; Methods; Microfluidics; Modality; Molecular; Names; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Nutrient; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Performance; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Process; Progression-Free Survivals; Property; Publishing; RNA vaccine; Recurrence; Reporting; Reproducibility; Research; Resistance; Role; Series; Side; Site; Small Business Innovation Research Grant; Solid; Starvation; Sterilization; Survival Rate; System; Testing; Therapeutic; Tissues; Toxic effect; Translating; Treatment Failure; Validation; Xenograft Model; anti-cancer; anticancer activity; base; cGMP production; cancer cell; cancer recurrence; cancer stem cell; chemotherapy; clinical application; clinical translation; commercialization; design; effective therapy; experience; first-in-human; gemcitabine; improved; in vivo; inhibition of autophagy; inhibitor; large scale production; microfluidic technology; nanocarrier; nanodrug; nanoformulation; nanomedicine; nanoparticle; nanoparticle delivery; next generation; novel; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; patient derived xenograft model; phase 2 study; pre-clinical; preclinical study; prevent; response; scale up; side effect; standard of care; stem-like cell; systemic toxicity; targeted agent; therapeutic nanoparticles; therapy outcome; tumor; tumorigenesis

Title: Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer Project Summary The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is less than 10% and the lack of effective treatment is one of the major impediments for the clinical management of PDAC. Pancreatic cancer stem-like cells (PCSCs) have been linked to tumor metastasis, drug resistance, and aggressive behaviors and the enrichment of PCSC after chemotherapy is associated with more aggressive tumor rebound. Autophagy is the process of “self-digestion” and it is especially needed for the rapid proliferation in cancer cells. PDAC cells, particularly PCSCs, highly rely on elevated autophagy. Therefore, autophagy is a promising target in PDAC to improve treatment and overcome chemoresistance. Autophagy inhibition with aminoquinoline drugs, such as chloroquine (CQ) or hydroxychloroquine (HCQ), have been tested in several clinical trials including PDAC patients. Promisingly, an initial clinical benefit was observed when combined with chemotherapeutic drugs, such as gemcitabine and Abraxane in neoadjuvant setting. However, CQ/HCQ have limited potency for autophagy inhibition and potential side effects, and the concentrations of CQ/HCQ required to inhibit autophagy are not consistently achievable in the clinic due to the lack of a specific delivery approach. The overall goal of this SBIR phase I application is to develop sub-100 nm and scalable self-therapeutic nanoparticles as next-generation autophagy inhibitors to improve PDAC treatment in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA. Recently, we have developed an Autophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition and specific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that contains pure bisaminoquinoline (BAQ) derivative itself as the building block which has outstanding autophagy inhibiting- and lysosomal disrupting- capabilities. AiSN is 30x more effective than CQ and HCQ in vitro, and effectively kills PCSCs. As a self-delivered nanoparticle without a carrier, AiSN can efficiently accumulate at the PDAC tumor sites and effectively inhibit autophagy in PDAC animal models. AiSN successfully prevented tumorigenesis in PCSC-derived animal models and demonstrated superior anti-cancer efficacy in both PDAC- and PCSC-derived xenograft models as both a monotherapy and a combination therapy. These results were recently published in Nature Communications and built a strong foundation for this Phase I application, in which we plan to 1) develop a microfluidic approach for optimization of the AiSN formulation (smaller size, better stability and reproducibility) to further enhance its tumor penetration and support future large scale-production, and 2) investigate the pharmacokinetics, tumor penetration, and anti-cancer efficacy of the microfluidic assisted manufacturing AiSN in animal models. The successful completion of the proposed research will make the AiSN ready for next step of IND-enabling studies seeking IND approval. The proposed AiSN with greatly enhanced potency and specific delivery properties will significantly improve the efficacy and minimize the toxicity in the treatment of PDAC.

标题：以胰腺癌自噬为靶点的亚100纳米可伸缩自疗纳米粒 项目摘要 胰腺导管腺癌(PDAC)的5年生存率不到10%，且缺乏有效的治疗方法 治疗是阻碍PDAC临床治疗的主要障碍之一。胰腺癌干样变 细胞(PCSCs)与肿瘤转移、耐药和侵袭行为有关， 化疗后PCSC的丰富与更具侵袭性的肿瘤反弹有关。自噬是 这是一种“自我消化”的过程，对于癌细胞的快速增殖尤为必要。PDAC信元， 尤其是PCSCs，高度依赖于升高的自噬。因此，自噬是PDAC的一个很有前途的目标 改善治疗，克服化疗耐药。氨基喹啉类药物对自噬的抑制作用 氯喹(CQ)或羟基氯喹(HCQ)已经在包括PDAC在内的几个临床试验中进行了测试 病人。有希望的是，当与化疗药物联合使用时，观察到了初步的临床益处，如 如吉西他滨和亚伯沙尼在新佐剂环境中。然而，CQ/HCQ对自噬的效力有限 抑制和潜在副作用，以及抑制自噬所需的CQ/HCQ浓度 由于缺乏特定的分娩方法，在临床上始终可以实现。本次SBIR的总体目标是 第一阶段的应用是开发100 nm以下的可伸缩的自我治疗纳米颗粒作为下一代 自噬抑制剂在临床前动物模型中改善PDAC治疗，提供关于 第二阶段研究的可行性，最终将导致IND向FDA提交申请。最近，我们开发了一种 自噬抑制剂自给纳米粒(AiSN)，提供卓越的自噬抑制和 特异性给药，以改善PDAC对HCQ的治疗。AiSN是一种自我治疗的纳米颗粒，含有 纯双氨基喹啉(BAQ)衍生物本身就是具有显著抑制自噬作用的积木-- 以及溶酶体的破坏能力。在体外，AiSN的效果是CQ和HCQ的30倍，并有效地杀死 PCSCs。作为一种无载体的自传递纳米粒子，AiSN可以有效地在PDAC肿瘤处蓄积 并有效抑制PDAC动物模型的自噬。AiSN成功地阻止了肿瘤的发生 PCSC来源的动物模型，并在PDAC和PCSC来源的动物模型中显示出优越的抗癌效果 异种移植模型既可作为单一疗法，也可作为联合疗法。这些研究结果最近发表在了 自然通信，并为这一阶段的应用程序奠定了坚实的基础，我们计划在此阶段1)开发 AiSN处方优化的微流控方法(体积小、稳定性好、重现性好) 以进一步增强肿瘤的渗透性，支持未来的大规模生产，以及2)研究 微流控制剂AiSN的药代动力学、肿瘤渗透性和抗癌效果 在动物模型中。拟议研究的成功完成将使AiSN为下一步做好准备 寻求IND批准的启用IND的研究。建议的AiSN具有极大增强的效力和特定的 给药特性将显著提高PDAC的疗效，并将其毒性降至最低。