Translational Development of a Targeted and Stroma-penetrating Nanoparticle Drug for Pancreatic Cancer Therapy

项目摘要 低效率的药物输送和侵袭性的肿瘤生物学是抵抗治疗的主要原因。 胰腺癌。致密的纤维性肿瘤间质的存在产生了药物传递障碍，并促进了 胰腺癌细胞的侵袭性生物学和耐药性。我们已经开发了一种有针对性的基质 透入性透明质酸纳米粒，携带伊立替康的活性代谢物SN38。临床前研究结果 研究表明，纳米颗粒/药物显著增强了对导管癌细胞的输送，以产生 在耐药胰腺癌患者来源的异种移植(PDX)模型中有很强的治疗效果。 重要的是，穿透间质的纳米地毯具有调节肿瘤间质的独特性质，从而允许 纳米地毯可以穿过基质屏障，但保留保护性的基质结构。用于临床翻译 这个新的纳米地毯，我们的SBIR第一阶段研究集中在重新设计一种无标记基质穿透配体， ATFMMP14(R2)，由尿激酶型纤溶酶原激活剂受体(UPAR)结合域和 MMP14的催化结构域，遵循FDA Pre-IND团队的建议。我们已经开发了 具有大规模生产能力的无标签ATFMMP14(R2)在无内毒素细菌中的表达 系统。我们还证明了ATFMMP14(R2)偶联的HANP/SN38具有类似的肿瘤靶向性 His标记的第一代ATFmmp14(R1)-HANP/SN38在胰腺组织中的能力和治疗效果 癌症PDX模型。拟议的第二阶段项目旨在通过以下方式加快翻译进程 重要的研究新药(IND)--使临床前研究成为可能。在目标1中，我们将优化并最终确定 在GLP/GMP条件下用于大规模生产的Migra-NP01纳米制剂。到时候我们会的 Migra-NP01的体内外特性表征，包括生物物理和生化参数 体外和全身毒性、药代动力学/药效学、生物分布和清除性 和荷瘤小鼠(目标2)。在这些研究期间，我们将建立标准操作规程(SOP) 和用于药物开发的Migra-NP01的质量控制(QC)指标(目标2)。接下来，我们将确定一个 不同病理和遗传的胰腺PDX模型中Migra-NP01的最佳剂量和治疗方案 特征和对化疗的敏感性(目标3)。最后，胰腺PDX肿瘤的治疗反应将 与基因表达特征相关联，以确定潜在的迁徙预测生物标记物 NP01治疗(目标3)。本翻译研究项目的成果包括：1)获得期末考试 用于Migra-NP01生产GLP/GMP的优化纳米配方Migra-NP01 和2)测定系统毒性、生物分布、 Migra-NP01在正常小鼠和胰腺PDX肿瘤荷瘤小鼠中的治疗剂量/程序。结果 SBIR第二阶段项目的实施将对今后提交IND申请产生重大影响 FDA批准对晚期胰腺癌患者进行一期临床试验。

Project Summary Low efficiency in drug delivery and aggressive tumor biology are the major causes of resistance to therapy in pancreatic cancer. The presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cells. We have developed a targeted stroma penetrating hyaluronic acid nanoparticle carrying SN38, an active metabolite of irinotecan. Results of preclinical studies demonstrated significantly enhanced nanoparticle/drug delivery into ductal carcinoma cells to produce strong therapeutic effects in drug resistant pancreatic cancer patient derived xenograft (PDX) models. Importantly, the stroma-penetrating nanodrug has unique properties to modulate tumor stroma that allows the nanodrug to pass through the stromal barrier but retain a protective stromal structure. For clinical translation of this novel nanodrug, our SBIR phase I study focused on the re-engineering a tagless stroma penetrating ligand, ATFmmp14 (R2), that consists of a urokinase plasminogen activator receptor (uPAR) binding domain and a catalytic domain of MMP14, following the recommendation of the FDA Pre-IND team. We have developed the tagless ATFmmp14(R2) with the capacity of large scale production in an endotoxin-free bacterial expressing system. We also demonstrated that ATFmmp14 (R2) conjugated HANP/SN38 has comparable tumor targeting ability and therapeutic efficacy to the first generation of His-tagged ATFmmp14(R1)-HANP/SN38 in pancreatic cancer PDX models. The proposed phase II project aims to accelerate the translational process by conducting important Investigational New Drug (IND)-enabling preclinical studies. In Aim 1, we will optimize and finalize nanoformulation of MIGRA-NP01 for large-scale production under GLP/GMP conditions. We will then characterize in vitro and in vivo properties of MIGRA-NP01, including biophysical and biochemical parameters in vitro, and systemic toxicity, pharmacokinetics/pharmacodynamics, biodistribution, and clearance in normal and tumor bearing mice (Aim 2). During those studies, we will establish the Stand Operating Protocols (SOPs) and metrics for quality control (QC) of MIGRA-NP01 for drug development (Aim 2). Next, we will determine an optimized dose and schedule for MIGRA-NP01 in pancreatic PDX models with different pathological and genetic features, and sensitivity to chemotherapy (Aim 3). Finally, therapeutic responses of pancreatic PDX tumors will be correlated with the gene expression signatures to identify the potential predicative biomarkers for MIGRA- NP01 treatment (Aim 3). The outcomes of this translational research project include: 1) obtaining the final optimized nanoformulation of MIGRA-NP01 with established SOPs for the GLP/GMP production of MIGRA-NP01 and producing two lots of the GLP grades of MIGRA-NP01; and 2) determining systemic toxicity, biodistribution, therapeutic dose/schedule of the MIGRA-NP01 in normal mice and pancreatic PDX tumor bearing mice. Results of the SBIR phase II project should have a great impact on the future submission of an IND application for the FDA approval of a phase 1 clinical trial in advanced pancreatic cancer patients.