Using Targeted Lipid Nanoparticles to Deliver Chemotherapeutic Agents against Pancreatic Cancer

项目摘要/摘要 胰腺癌仍然是一种毁灭性的疾病，5年生存率不到10%。胰腺癌 是攻击性的，而且没有好的工具来早期发现。确诊时，肿瘤通常是通过手术治疗的。 不能切除。在这个阶段，患者通常用不同的化疗药物或他们的 联合用药虽然有效，但也有显著的副作用，限制了它们的剂量。有关键的，也有未满足的 需要有选择地和精确地只针对肿瘤，并提供高剂量的化疗，同时节省 使周围的健康组织免受化疗药物的有害影响。胰腺癌细胞依赖于 胞外半胱氨酸/半胱氨酸对生长和生存的影响。胱氨酸分子被输送到 胰腺癌细胞通过XCT胱氨酸转运蛋白。胰腺癌的特征是 与健康胰腺相比，表面XCT转运蛋白的过度表达。多利克制药有限责任公司获得专利 药物输送系统使用靶向脂质体纳米粒，TLN，携带抗癌药物作为货物并具有 针对XCT转运体的特殊设计的表面分子。我们的研究表明，TLN选择性地联合 在原位胰腺肿瘤小鼠体内定位于胰腺癌细胞，并减少原位和 胰腺皮下肿瘤。DoricPharma将检查服用吉西他滨的TLN是否会替代其他器官 和组织因为它的毒性。在目标1中，我们将(A)表征负载了TLN的物理化学性质 吉西他滨和(B)测定吉西他滨在TLN中的药物动力学和生物分布 在给患有原位人类胰腺肿瘤的小鼠单次静脉注射后。在目标2中，我们将确定 包埋吉西他滨的TLN对原发和转移性肿瘤的抗肿瘤疗效和减毒作用。 我们设想TLNS系统将成为提供化疗药物的黄金标准，因为它 选择性地将抗癌药物输送到癌细胞，从而提高活性并降低毒性。此阶段I STTR将确定TLN是否为胰腺癌提供了更好和更有效的治疗方法。此外, 该项目将定位TLN用于IND使能研究(SBIR第二阶段)，之后DoricPharma LLC将寻求 人类I期临床试验的伙伴关系。总体而言，TLN代表了化疗的范式转变 选择性地将药物输送到肿瘤，将增加抗肿瘤效果并降低毒性。总的来说， TLN将提高癌症患者的寿命和生活质量。

PROJECT SUMMARY/ABSTRACT Pancreatic cancer continues to be a devastating disease with less than 10% 5-year survival. Pancreatic cancer is aggressive and there are no good tools for early detection. By the time of diagnosis, the tumor is often surgically unresectable. At this stage, patients are often treated with different chemotherapeutic agents or their combination, which while potent, have significant side-effects, limiting their dose. There is critical and an unmet need to selectively and precisely target the tumor only and deliver high doses of chemotherapy while sparing the surrounding healthy tissue from the deleterious effects of the chemotherapeutics. Pancreatic cancer cells depend on extracellular cystine/cysteine for growth and survival. The cystine molecules are transported into the pancreatic cancer cell through the xCT cystine transporter. Pancreatic cancer is characterized by an overexpression of surface xCT transporters compared to the healthy pancreas. Doric Pharma LLC’s patented drug delivery system uses targeted liposomal nanoparticles, TLNs, carry the anticancer drug as cargo and have specially designed surface molecules that target xCT transporters. Our studies show that TLNs selectively co- localize to pancreatic cancer cells in mice with orthotopic pancreatic tumors and reduce both orthotopic and subcutaneous pancreatic tumors. DoricPharma will examine if TLNs delivering gemcitabine spare other organs and tissues from its toxicity. In Aim 1 we will (a) characterize the physicochemical properties of TLNs loaded with gemcitabine and (b) determine the pharmacokinetics and biodistribution of gemcitabine encapsulated in TLNs after a single IV dose given to mice with orthotopic human pancreatic tumors. In Aim 2 we will determine the antitumor efficacy and reduced toxicity of gemcitabine encapsulated in TLNs for primary and metastatic tumors. We envision the TLNs system becoming a gold-standard for the delivery of chemotherapeutics because it selectively delivers anticancer drugs to cancer cells which improves activity and reduces toxicity. This Phase I STTR will determine if TLNs offer a superior and more efficacious treatment for pancreatic cancer. In addition, this project will position TLNs for IND- enabling studies (SBIR Phase II), after which DoricPharma LLC will seek partnerships for human phase I clinical trials. Overall, TLNs represent a paradigm shift for chemotherapy by selectively delivering agents to the tumor which will increase antitumor efficacy and reduce toxicity. Overall, TLNs will enhance the life span and the quality of life in cancer patients.