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

基本信息

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
项目类别：
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

项目摘要

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：低于100 nm和可伸缩的自治疗纳米颗粒，以靶向胰腺癌的自噬项目摘要胰腺导管腺癌（PDAC）的5年生存率小于10％，缺乏有效治疗是PDAC临床管理的主要障碍之一。胰腺癌茎状细胞（PCSC）已与肿瘤转移，耐药性和侵略性行为有关化学疗法后PCSC的富集与更具侵略性的肿瘤反弹有关。自噬是癌细胞快速增殖的“自我消化”过程尤其需要。 PDAC细胞，特别是PCSC，高度依赖于自噬。因此，自噬是PDAC中有希望的目标改善治疗并克服化学抗性。氨基喹啉药物的自噬抑制，例如氯喹（CQ）或羟基氯喹（HCQ）已在包括PDAC在内的几项临床试验中进行了测试患者。有希望的是，当与化学治疗药物结合使用时，观察到了最初的临床益处作为新辅助环境中的吉西他滨和阿布拉烷。但是，CQ/HCQ的自噬效力有限抑制和潜在副作用，以及抑制自噬所需的CQ/HCQ浓度不是由于缺乏特定的分娩方法，在诊所中始终可实现。这个SBIR的总体目标第一阶段的应用是开发低于100 nm和可扩展的自我治疗纳米颗粒作为下一代自噬抑制剂可改善临床前动物模型中PDAC治疗 II期研究的可行性最终将导致向FDA提交IND。最近，我们开发了自噬抑制剂自保留的纳米糖（AISN），可为自噬抑制和特定的药物输送以改善对HCQ的PDAC治疗。 AISN是一种自我治疗的纳米颗粒，包含纯双氨基喹啉（BAQ）衍生物本身是具有出色自噬抑制 - 和溶酶体破坏 - 功能。 AISN在体外比CQ和HCQ更有效，并有效地杀死 PCSC。作为没有载体的自由交付的纳米颗粒，AISN可以有效地在PDAC肿瘤处积累位点并有效抑制PDAC动物模型中的自噬。 AISN成功阻止了肿瘤发生 PCSC衍生的动物模型，并在PDAC和PCSC衍生异种移植模型既是单一疗法又是联合疗法。这些结果最近发表在自然通讯并为本阶段应用建立了强大的基础，我们计划进行1）一种用于优化AISN公式的微流体方法（尺寸较小，稳定性和可重复性）为了进一步增强其肿瘤的渗透并支持未来的大规模生产，2）研究微流体辅助制造AISN的药代动力学，肿瘤渗透和抗癌效率在动物模型中。拟议研究的成功完成将使AISN准备下一步寻求IND批准的辅助研究。提议的AISN具有大大提高的效力和特定的递送特性将显着提高效率，并最大程度地减少PDAC治疗的毒性。