Novel Nanoparticle Therapy for Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）预后差，5年生存率在所有胃肠道恶性肿瘤中最低。尽管许多化学治疗剂在体外或小鼠中有效抑制PDAC的生长，但这些药物在临床试验中施用于人类受试者时失败。缺乏有效性的主要原因有两个。首先，很难提供足够剂量的化疗药物并避免全身毒性，因为大多数用于PDAC的药物不是“肿瘤选择性”的，因为它们无法靶向癌症表面的特定蛋白质或受体。在没有肿瘤特异性的情况下，胃肠外化疗给药导致到达癌症的潜在有效药剂浓度低，并且对其他器官的毒性发生率高。其次，某些有前景的治疗方法，如RNAi，会被血流中的核酸酶分解;因此，这些化合物必须以更高的剂量给予或保护免受环境影响，以实现破坏肿瘤生长的有效性。关于靶向，肿瘤特异性受体抗原的表征显著改善了许多恶性肿瘤的癌症治疗。我们在人胰腺癌细胞中发现了一种膜结合生长受体，称为胆囊收缩素或CCK受体。使用这个目标，我们已经开发出无毒的生理性磷硅酸钙纳米颗粒（NP），与非靶向载体相比，其具有增强的肿瘤摄取和递送。我们的研究团队已经开发出一种将基因治疗或化疗药物封装在纳米粒中的方法，这比传统方法有了显着的改进。关于基因治疗，我们选择了两个已被证明可以驱动PDAC生长的靶基因：胃泌素和突变的Kras。我们假设，PDAC的治疗可能会显着改善，通过应用纳米技术使用肿瘤选择性运载工具，其中药物或基因治疗的保护，通过封装。为了检验这一假设，我们计划实现以下具体目标：1）优化新一代PDAC特异性纳米颗粒，并使用单分子光谱学验证治疗剂的改善的包封，以及2）确定靶向NP的药代动力学参数，包括最大耐受剂量、生物分布和生物利用度，和3）检查靶特异性负载的纳米颗粒在体外和体内抑制胰腺癌细胞生长的安全性和有效性。我们的长期目标是开发新的有效策略，以改善这种毁灭性恶性肿瘤患者的治疗和生存。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with the poorest 5-year survival of all gastrointestinal malignancies. Although numerous chemotherapeutic agents have been effective in inhibiting growth of PDAC in vitro or in mice, these agents fail when administered to human subjects in clinical trials. There are two principle reasons for this lack of effectiveness. First, it is difficult to provide an adequate dos of chemotherapeutic agents and avoid systemic toxicity because most agents used for PDAC are not 'tumor- selective', in that they fail to target specific proteins or receptors on the cancer surface. Without tumor specificity, parenteral chemotherapy administration leads to a low concentration of potentially effective agents reaching the cancer and a high incidence of toxicity to other organs. Second, certain promising treatments, such as RNAi, are broken down by nucleases in the blood stream; hence, these compounds have to be given in higher doses or protected from the environment in order to achieve effectiveness in disrupting tumor growth. Regarding targeting, characterization of tumor-specific receptor antigens has significantly improved cancer therapeutics in many malignancies. We have identified a membrane bound growth receptor in human pancreatic cancer cells called the cholecystokinin or CCK- receptor. Using this target, we have developed nontoxic, physiologic calcium phosphosilicate nanoparticles (NPs) with enhanced tumor uptake and delivery compared to untargeted vehicles. Our research team has developed a means to encapsulate either gene therapy or chemotherapeutic agents in NPs, representing a significant improvement over traditional methods. With regard to gene therapy, we have chosen two target genes that have been shown to drive growth of PDAC: gastrin and mutated Kras. We hypothesize that treatment of PDAC may be significantly improved through the application of nanotechnology using tumor-selective delivery vehicles in which drugs or gene therapy are protected through encapsulation. In order to test this hypothesis we plan to carry out the following Specific aims: 1) Optimize a new generation of PDAC-specific nanoparticles and verify improved encapsulation of therapeutic agents using single molecule spectroscopy and 2) Determine pharmacokinetic parameters for targeted NPs including the maximum tolerated dose, biodistribution and bioavailability, and 3) Examine the safety and efficiency of target-specific loaded nanoparticles to inhibit growth of pancreatic cancer cells in vitro and in vivo. Our long term goal is to develop novel effective strategies to improve therapy and survival of patients with this devastating malignancy.