Tumor-permeable nanoparticles for enhanced pancreatic cancer immunochemotherapy

项目总结： 胰腺导管腺癌(PDA)是一种高度致命性的癌症，5年生存率不到9%。 需要安全有效的治疗PDA的新方法。目前，化疗(例如 吉西他滨，NAB-紫杉醇)是首选治疗方法，因为大多数患者(80%)的肿瘤是 初次诊断时不能手术切除。然而，即使这些治疗选择的效果也是有限的。 由于肿瘤微环境免疫抑制程度高，肿瘤穿透性差。 血管密度高，间质致密。为了克服这些治疗障碍，申请人最近 吉西他滨(GEM)、紫杉醇(PTX)联合应用的免疫化疗方案 和吲哚胺2，3-双加氧酶1(IDO1)抑制剂NLG919通过PGEM纳米载体。初步数据 显示PGEM载体穿透到实验肿瘤的核心，更重要的是，两者 亲水性的宝石和多种性质不同的疏水剂可以负载到PGEM胶束上。 事实上，与PTX和NLG919共负载的PGEM诱导了更好的抗肿瘤免疫反应，并 在PANC02异种移植模型中抑制肿瘤生长非常有效，很可能是通过协同作用 PTX和GEM的肿瘤杀伤作用及NLG919逆转IDO介导的作用 免疫抑制。在本申请中，申请人提议通过以下方式进一步改进PGEM载体 优化每个构建基元的单元(目标1)。此外，申请者将测试体内靶向 使用接近模拟人PDA的肿瘤模型对不同的PGEM纳米载体的效率进行研究。这个 纳米制剂的药代动力学、生物分布和渗透性(目标2)及其治疗 将对效果和基本机制(目标3)进行评估。 成功完成拟议的目标不仅将提供一个有效的方案 PDA免疫化疗，还提供了一个载体平台，可以扩展到靶向联合给药 多种不同的亲水性和疏水性试剂，可用于各种组合疗法。

Project Summary: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a 5-year survival rate less than 9%. New treatments for PDA that are both safe and effective are needed. Currently, chemotherapy (e.g. gemcitabine, nab-paclitaxel) is the preferred treatment, as the tumors in majority of patients (80%) are surgically non-resectable at initial diagnosis. However, even these therapeutic choices have limited efficacy because of the highly immunosuppressive tumor microenvironment and poor tumor penetration due to low density of blood vessels and dense stroma. To overcome these treatment obstacles, the applicant recently developed an immunochemotherapy regimen based on co-delivery of gemcitabine (GEM), paclitaxel (PTX) and indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 through a PGEM nanocarrier. Preliminary data showed that the PGEM carrier penetrated to the core of experimental tumors, and, importantly, both hydrophilic GEM and multiple hydrophobic agents with distinct properties could be loaded onto PGEM micelles. Indeed, PGEM co-loaded with PTX and NLG919 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth in PANC02 xenograft model, most likely through a synergistic tumor killing effect of PTX and GEM, as well as the effect of NLG919 in reversing IDO-mediated immunosuppression. In this application, the applicant proposes to further improve the PGEM carrier by optimizing the units of each constructing motif (Aim 1). In addition, the applicant will test the in vivo targeting efficiency of different PGEM nanocarriers using tumor models that closely mimic human PDA. The pharmacokinetics, biodistribution and penetration of the nanoformulations (Aim 2), as well as their therapeutic effect and the underlying mechanism (Aim 3) will be evaluated. The successful completion of the proposed aims will not only provide an effective regimen for improved PDA immunochemotherapy, but also provide a carrier platform that can be extended to targeted co-delivery of multiple distinct hydrophilic and hydrophobic agents for various combination therapies.