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

标题：亚100纳米和可扩展的自我治疗纳米颗粒靶向胰腺癌中的自噬 项目摘要 胰腺导管腺癌（PDAC）的5年生存率低于10%，缺乏有效的治疗方法， 治疗是PDAC临床管理的主要障碍之一。胰腺干细胞样癌 细胞（PCSC）与肿瘤转移、耐药性和侵袭行为有关， 化疗后PCSC的富集与更具侵袭性的肿瘤反弹有关。自噬是 这是一个“自我消化”的过程，尤其是癌细胞快速增殖所需要的。PDAC细胞， 特别是PCSC，高度依赖于升高的自噬。因此，自噬是PDAC中有希望的靶点， 改善治疗和克服耐药性。用氨基喹啉类药物抑制自噬，如 氯喹（CQ）或羟氯喹（HCQ）已在包括PDAC在内的几项临床试验中进行了测试 患者令人鼓舞的是，当与化疗药物联合使用时，观察到了初步的临床益处，例如 与吉西他滨和Abraxane一样。然而，CQ/HCQ对自噬的效力有限 抑制和潜在的副作用，以及抑制自噬所需的CQ/HCQ的浓度， 由于缺乏特定的输送方法，在诊所中始终可以实现。本SBIR的总体目标 第一阶段的应用是开发亚100纳米和可扩展的自我治疗纳米粒子作为下一代 自噬抑制剂，以改善临床前动物模型中的PDAC治疗，提供关于 II期研究的可行性，最终将导致向FDA提交IND申请。最近，我们开发了一种 自噬抑制剂自递送纳米药物（AiSN），其提供上级的自噬抑制效力， 特异性药物递送以改善HCQ的PDAC治疗。AiSN是一种自我治疗的纳米颗粒， 纯的双氨基喹啉（BAQ）衍生物本身作为结构单元，具有出色的自噬抑制作用， 和溶酶体破坏能力。AiSN在体外比CQ和HCQ有效30倍， PCSC。作为一种无载体的自递送纳米颗粒，AiSN可以有效地在PDAC肿瘤处积聚 在PDAC动物模型中有效抑制自噬。AiSN成功地阻止了肿瘤发生， PCSC衍生的动物模型，并在PDAC和PCSC衍生的动物模型中表现出上级抗癌功效。 异种移植模型作为单一疗法和组合疗法。这些结果最近发表在 自然通讯，并建立了坚实的基础，为这个第一阶段的应用，我们计划1）发展 用于优化AiSN配方的微流体方法（尺寸更小，稳定性和再现性更好） 以进一步增强其肿瘤穿透力并支持未来的大规模生产，以及2）研究 微流体辅助制造AiSN的药代动力学、肿瘤渗透和抗癌功效 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IND使能研究。所提出的AiSN具有大大增强的效力和特异性， 递送性质将显著提高PDAC治疗的功效并使毒性最小化。

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.