Using Targeted Lipid Nanoparticles to Deliver Chemotherapeutic Agents against Pancreatic Cancer

项目总结/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 是侵略性的，没有好的工具来早期检测。到确诊时，肿瘤往往是手术切除的。 无法切除在此阶段，患者通常用不同的化疗剂或其组合治疗。 组合，虽然有效，但有显著的副作用，限制了它们的剂量。有一个关键的和未满足的 需要选择性地和精确地靶向肿瘤，并提供高剂量的化疗，同时保留肿瘤细胞。 周围健康组织免受化疗药物的有害作用。胰腺癌细胞依赖 对细胞外胱氨酸/半胱氨酸的生长和存活的影响。胱氨酸分子被转运到 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转运蛋白过度表达。Doric Pharma LLC的专利 药物递送系统使用靶向脂质体纳米颗粒TLN，携带抗癌药物作为货物， 专门设计的针对xCT转运蛋白的表面分子。我们的研究表明，TLN选择性地协同- 定位于具有原位胰腺肿瘤的小鼠中的胰腺癌细胞，并减少原位和 皮下胰腺肿瘤DoricPharma将检查递送吉西他滨的TLN是否会保留其他器官 和组织的毒性在目标1中，我们将（a）表征负载有以下物质的TLN的物理化学性质： 吉西他滨和（B）确定包封在TLN中的吉西他滨的药代动力学和生物分布 在给予具有原位人胰腺肿瘤的小鼠单次IV剂量后。在目标2中，我们将确定 本发明提供了包封在TLR中的吉西他滨对原发性和转移性肿瘤的抗肿瘤功效和降低的毒性。 我们设想TLN系统成为化疗药物递送的金标准，因为它 选择性地将抗癌药物递送到癌细胞，这提高了活性并降低了毒性。这项I期 STTR将确定TLN是否为胰腺癌提供上级和更有效的治疗。此外，本发明还提供了一种方法， 该项目将为IND启动研究（SBIR第二阶段）定位TLN，之后DoricPharma LLC将寻求 人类I期临床试验的合作伙伴关系。总体而言，TLN代表了化疗的范式转变， 选择性地将药剂递送至肿瘤，这将增加抗肿瘤功效并降低毒性。总体而言， 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.