Image-guided ultrasound therapy and drug delivery in pancreatic cancer

胰腺导管腺癌（PDAC）是一种侵袭性和浸润性癌症，具有中等的 生存期6个月，5年生存率6%。尽管最近的进展 由于对PDAC发展的认识不足，缺乏有效的治疗方法。发生时 诊断，不到15%的患者有资格手术，由于存在局部晚期 疾病和微转移。在这里，我们考虑一个替代的范例，其中超声 原发性肿瘤的治疗（消融或热疗）与全身药物递送相结合 颗粒和免疫疗法，可以有效地治疗剩余的原发性肿瘤和转移。 我们假设，超声治疗胰腺癌，与 吉西他滨纳米颗粒（角鲨烯-吉西他滨纳米组装体（Sq-Gem-NAs））的递送 和免疫疗法，可以有效和安全地治疗胰腺癌。我们最近 证实了将纳米颗粒递送到肿瘤中消融边缘的50倍增强 跨越上皮癌和高度侵袭性间充质表型的模型。我们进一步 证明了将热疗与药物和免疫疗法相结合可以提高生存率;我们 扩展初步数据的结果，以显示系统性癌症的完全消退。我们也 证明角鲨烯-吉西他滨缀合物的合成及其自组装， 纳米粒子已知角鲨烯-吉西他滨缀合可延长肿瘤细胞的循环。 完整的药物，并且缀合物在抗性癌症中比游离药物具有更大的功效。此外，本发明还 我们已经合成了一种与角鲨烯共轭的正电子发射断层扫描螯合剂， 用于评估颗粒的药代动力学和生物分布 超声波治疗这种颗粒可以靶向胰腺癌， 循环或温度敏感。免疫佐剂（CpG）与免疫调节剂的组合， 掺入检查点抑制剂（aPD-1），超声可增强反应 疗法因此，我们的具体目标是：1）制造和表征Sq-Gem-NAs和Sq- BAT缀合物并评估它们与其他脂质的自组装，2）测定它们的分子量， 具有和不具有plectin-1靶向部分和超声的Sq-Gem NAs的生物分布 健康小鼠和患有PDAC肿瘤的小鼠，以及3）比较 用Sq-Gem-NAs以及超声和免疫治疗方案治疗的PDAC小鼠。两 将评估消融和热疗超声方案。

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and invasive cancer, with a median survival of 6 months and a 5-year survival rate of 6%. Although recent advances have been made in the understanding of PDAC development, effective therapies are lacking. At the time of diagnosis, less than 15% of patients qualify for surgery due to the presence of locally advanced disease and micrometastases. Here, we consider an alternative paradigm in which ultrasound therapy (ablation or hyperthermia) of the primary tumor is combined with systemic drug delivery particles and immunotherapy that can effectively treat remaining primary tumor and metastases. We hypothesize that ultrasound therapy of pancreatic cancer, performed in combination with delivery of gemcitabine nanoparticles (squalene-gemcitabine nanoassemblies (Sq-Gem-NAs)) and immunotherapy, can effectively and safely treat pancreatic cancer. We recently demonstrated 50 fold enhancement of delivery of nanoparticles to the ablated margin in tumor models that span epithelial cancer and highly invasive mesenchymal phenotypes. We further demonstrated enhanced survival combining hyperthermia with drug and immunotherapy; we extend the result in preliminary data to show complete regression of systemic cancer. We also demonstrate the synthesis of squalene-gemcitabine conjugates and their self-assembly as nanoparticles. Squalene-gemcitabine conjugation is known to extend the circulation of the intact drug and the conjugate has greater efficacy than free drug in resistant cancers. Further, we have synthesized a positron emission tomography chelator conjugated to squalene to be used to assess the pharmacokinetics and biodistribution of the particles with and without ultrasound therapy. Such particles can be targeted to pancreatic cancer and can be long circulating or temperature sensitive. The combination of an immune adjuvant (CpG) with a checkpoint inhibitor (aPD-1) is incorporated and response shown to be enhanced by ultrasound therapy. Our specific aims are therefore to: 1) fabricate and characterize Sq-Gem-NAs and Sq- BAT conjugates and evaluate their self-assembly with other lipids, 2) determine the biodistribution of Sq-Gem NAs with and without plectin-1 targeted moieties and ultrasound in both healthy mice and mice with PDAC tumors and 3) compare the therapeutic response of PDAC mice treated with the Sq-Gem-NAs and ultrasound and immunotherapy protocols. Both ablation and hyperthermia ultrasound protocols will be evaluated.