Novel Nanoparticle Therapy for Pancreatic Cancer

描述（申请人提供）：胰腺导管腺癌（PDAC）预后不佳，在所有胃肠道恶性肿瘤中5年生存率最低。尽管许多化疗药物在体外或小鼠体内有效抑制PDAC的生长，但这些药物在临床试验中对人类受试者无效。这种缺乏有效性的主要原因有两个。首先，很难提供足够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，因为它们不能靶向癌症表面的特定蛋白质或受体。由于没有肿瘤特异性，肠外化疗导致潜在有效药物到达肿瘤的浓度低，对其他器官的毒性发生率高。其次，某些有希望的治疗方法，如RNAi，会被血液中的核酸酶分解；因此，为了达到破坏肿瘤生长的效果，这些化合物必须以更高的剂量给予或不受环境影响。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方法。我们已经在人类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。利用这一靶点，我们开发了无毒的生理性磷酸硅酸钙纳米颗粒（NPs），与非靶向载体相比，它具有增强的肿瘤摄取和传递能力。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NPs中的方法，这是对传统方法的重大改进。在基因治疗方面，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Kras。我们假设，通过使用肿瘤选择性递送载体的纳米技术的应用，PDAC的治疗可能会得到显著改善，其中药物或基因治疗通过封装得到保护。为了检验这一假设，我们计划实施以下具体目标：1)优化新一代pdac特异性纳米颗粒，并利用单分子光谱验证治疗药物的包封性；2)确定靶向NPs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；3)在体外和体内研究靶向负载纳米颗粒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，以改善治疗和患者的生存与这种毁灭性的恶性肿瘤。

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.