Novel Nanoparticle Therapy for Pancreatic Cancer

胰腺癌的新型纳米颗粒疗法

• 批准号: 8435991
• 负责人: MARK KESTER
• 金额: $ 31.33万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-19 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435991
• 关键词: Animal Model; Antigen Receptors; Binding; Biocompatible; Biodistribution; Biological Availability; Biology; Biomedical Engineering; Blood; Calcium; Cancer Etiology; Cessation of life; Cholecystokinin; Cholecystokinin Receptor; Clinic; Clinical Oncology; Clinical Trials; Development; Disease; Dose; Drug Combinations; Drug Kinetics; Early Diagnosis; Effectiveness; Encapsulated; Environment; Fluorescence Spectroscopy; Fluorouracil; Gastrins; Gene Targeting; Generations; Genes; Genetic; Goals; Growth; Human; Immune; In Vitro; Incidence; Inhibitory Concentration 50; Injury; Laboratories; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Membrane; Methods; Microscopy; Minerals; Molecular; Mus; Mutate; Nanotechnology; Normal tissue morphology; Organ; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Photons; Physiological; Prevention; Procedures; Proteins; Quality Control; RNA Interference; Reproducibility; Research; Resistance; Safety; Site; Small Interfering RNA; Solid Neoplasm; Specificity; Spectrum Analysis; Stream; Surface; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Biology; United States; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; drug standard; gastrointestinal; gene therapy; human subject; improved; in vitro testing; in vivo; interdisciplinary approach; killings; nanoparticle; novel; nuclease; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; particle; pre-clinical; public health relevance; receptor; response; single molecule; technology validation; tumor; tumor growth; tumor specificity; uptake

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.

描述（由申请人提供）：胰腺导管腺癌（PDAC）的预后较低，所有胃肠道恶性肿瘤的5年生存率最差。尽管许多化学治疗剂在体外或小鼠中有效抑制PDAC的生长，但在临床试验中对人类受试者施用时，这些药物失败了。这种缺乏效力的原因有两个主要原因。首先，很难提供足够的化学治疗剂并避免全身毒性，因为大多数用于PDAC的药物不是“肿瘤选择性”，因为它们无法靶向癌症表面上的特定蛋白质或受体。没有肿瘤特异性，肠胃外化疗会导致低浓度的潜在有效药物到达癌症，并且对其他器官的毒性发生率高。其次，某些有希望的治疗方法，例如RNAi，被血流中的核酸酶分解。因此，这些化合物必须以较高剂量给予或免受环境的保护，以实现破坏肿瘤生长的有效性。关于靶向，在许多恶性肿瘤中，肿瘤特异性受体抗原的表征显着改善了癌症治疗剂。我们已经确定了人类胰腺癌细胞中一种称为胆囊动蛋白或CCK受体的膜结合受体。使用此目标，与未靶向的车辆相比，我们已经开发了具有增强肿瘤吸收和递送的无毒的生理钙钙纳米颗粒（NP）。我们的研究团队开发了一种封装基因治疗或NPS化学治疗剂的方法，这比传统方法的显着改善。关于基因治疗，我们选择了两个靶基因，这些靶基因已被证明驱动PDAC的生长：胃蛋白和突变的KRAS。我们假设通过使用纳米技术使用肿瘤选择性递送工具，可以通过封装保护药物或基因治疗，可以显着改善PDAC的治疗。为了检验该假设，我们计划执行以下具体目的：1）优化新一代PDAC特异性纳米颗粒，并使用单分子光谱验证验证治疗剂的封装，并使用单分子光谱谱和2）确定针对目标NP的药代动力学参数，包括最大耐受剂量的剂量，生物量，生物效应和生物效应，以及BioDistribifity和Biodistrifififififififififion和Biodistribifient和Biodistrififific and Biodistififient and Biioavave和3）纳米颗粒以抑制体外和体内胰腺癌细胞的生长。我们的长期目标是制定新的有效策略，以改善这种毁灭性恶性肿瘤患者的治疗和生存。