Image-guided ultrasound therapy and drug delivery in pancreatic cancer

胰腺导管腺癌(PDAC)是一种侵袭性和侵袭性的癌症， 生存6个月，5年生存率6%。尽管最近的进展是 在对PDAC发展的认识上，缺乏有效的治疗方法。在那个时候 诊断，只有不到15%的患者有资格接受手术，因为存在局部晚期 疾病和微转移。在这里，我们考虑另一种模式，在这种模式中，超声波 原发肿瘤的治疗(消融或热疗)结合全身给药。 颗粒和免疫疗法，可以有效地治疗残留的原发肿瘤和转移。 我们假设，超声治疗胰腺癌，联合应用 吉西他滨纳米粒(角鲨烯-吉西他滨纳米组装体(SQ-Gem-Nas))的输送 而免疫疗法，可以有效、安全地治疗胰腺癌。我们最近 显示纳米粒子对肿瘤消融边缘的输送增加了50倍 跨越上皮癌和高侵袭性间充质表型的模型。我们进一步 显示高温与药物和免疫疗法相结合可提高存活率；我们 将结果扩展到初步数据，以显示系统性癌症的完全消退。我们也 展示角鲨烯-吉西他滨结合物的合成及其自组装为 纳米粒子。已知角鲨烯-吉西他滨结合可延长血液循环。 完整的药物和结合物在耐药癌症中比游离药物有更大的疗效。此外， 我们合成了角鲨烯偶联的正电子发射断层显像剂 用于评价有无微粒的药代动力学和生物分布 超声波治疗。这种颗粒可以靶向治疗胰腺癌，而且可能很长 循环的或温度敏感的。一种免疫佐剂(CpG)与一种 加入了检查点抑制物(apd-1)，并显示超声增强了反应 心理治疗。因此，我们的具体目标是：1)制备和表征Sq-Gem-Nas和Sq-Gem-Nas-Sq-Gem-Nas和Sq-Gem-Nas-Sq-Gem-Nas BAT结合物并评价其与其他脂质的自组装，2)确定 含与不含plectin-1靶向及超声的SQ-Gem纳米粒在体内的生物分布 健康小鼠和PDAC肿瘤小鼠的治疗效果比较 使用SQ-Gem-Nas、超声波和免疫治疗方案治疗PDAC小鼠。两者都有 将对消融和热疗超声方案进行评估。

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.