Targeted Nanotherapy for Pancreatic Cancer

胰腺癌靶向纳米治疗

• 批准号: 9186665
• 负责人: Subhash C. Chauhan
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186665
• 关键词: Abraxane; Adverse effects; Albumin-Stabilized Nanoparticle Paclitaxel; Albumins; Antibodies; Antibody-drug conjugates; Antineoplastic Agents; Apoptotic; Attenuated; Binding; Biodistribution; Biological Availability; CXCL12 gene; CXCR4 gene; Cancer Patient; Cell Line; Cell membrane; Cessation of life; Clinical; Coupled; Data; Deposition; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Efflux; Drug Transport; Drug resistance; Engineering; Environment; Exhibits; Extracellular Matrix; FDA approved; Fibrosis; Formulation; Goals; Growth; In Vitro; Investigation; Kinetics; Lead; Legal patent; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; MicroRNAs; Modality; Molecular; Mucin 1 protein; Neoplasm Metastasis; Oncogenic; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pluronics; Proteins; Publishing; Regulation; Research Proposals; Resistance; SHH gene; Safety; Signal Pathway; Site; Stromal Neoplasm; Survival Rate; System; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translations; Treatment Efficacy; Treatment Protocols; Xenograft Model; Xenograft procedure; base; cancer therapy; chemotherapy; clinically relevant; effective therapy; gemcitabine; improved; in vivo; innovation; intravenous administration; lipid structure; mouse model; nanoformulation; nanoparticle; nanotherapy; neoplastic cell; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; paracrine; resistance mechanism; response; targeted delivery; targeted treatment; therapy outcome; treatment choice; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

The long-term goal of the proposed research proposal is to develop a targeted paclitaxel nanotherapy that can be used for the treatment of pancreatic cancer (PanCa) in combination with Gemcitabine (GEM). Although many conventional and combinational chemotherapies exist to treat PanCa, significant side effects occur without increasing the survival of patients (not even 2 additional months). Desmoplasia (characterized by excessive fibrosis and extracellular matrix deposition) causes suboptimal drug delivery in tumors and thus induces chemo-resistance. Additionally, certain signaling pathways, abnormal tumor cell membrane lipid structure/composition and restricted drug uptake due to overexpression of drug efflux associated proteins also lead to cancer progression/metastasis and drug resistance. A recent FDA- approved (on Sept. 6, 2013) combination treatment regimen [nab-nanoparticles (i.e., paclitaxel nanoparticles, Abraxane®) plus GEM] has marginally improved (only 1.8 months) overall survival (8.5 months vs. 6.7 months with GEM alone). Studies have also shown that PTX altered tumor microenvironment (TME) and reduced desmoplasia, thus improved GEM uptake in pancreatic tumors. We believe that this PTX-mediated marginally improved therapeutic outcome can be further enhanced by using an inimitable tumor specific antibody targeted PTX nanoparticle formulation. We hypothesize that antibody-guided, tumor specific targeted delivery of PPNPs will enhance the bioavailability of PTX in pancreatic tumors and macro/ micro metastatic lesions to attenuate tumor growth and sensitize tumor cells to GEM via decreased desmoplasia, altered TME and SHH/CXCL12/CXCR4, miR-21 mediated oncogenic signaling pathways. This proposal examines two levels of targeting PanCa. The first is MUC13 targeted delivery of PTX to pancreatic tumors as our PPNPs selectively/preferentially reach and accumulate in the tumors/metastatic lesions. Our preliminary data demonstrates that MUC13 targeted nanoparticles effectively target pancreatic tumors. The second level of treatment is intravenous administration of GEM. The first level of targeting will considerably alter TME which will thus promote a better response to GEM. This novel combination therapeutic modality will enhance drug loading specifically to the tumor site, inducing greater anti-cancer effects while minimizing side effects. To achieve these goals, three specific aims are proposed: AIM 1: To Evaluate Chemo- sensitization and TME of PPNPs in PanCa Cells. AIM 2: To Investigate Pharmaco-kinetics/dynamics (PK/PD) and Safety of PPNPs/GEM in a stromal component containing PanCa xenograft mouse model. AIM 3: To Evaluate the Therapeutic Efficacy of MUC13 Targeted PPNP Formulation in clinically relevant transgenic mice and patient derived xenograft (PDX) models. This proposal leads to a better treatment modality by altering tumor-stromal (paracrine) cross-talk and chemo-sensitization in PanCa which are considered to be major roadblocks in PanCa therapeutics. The proposed studies are based on recent clinical observations, thus clinical translation of this approach will be easy and quick.

拟议的研究建议的长期目标是开发有针对性的紫杉醇纳米疗法 可用于治疗胰腺癌（PANCA）与吉西他滨（GEM）结合使用。 尽管存在许多常规和合并的化学疗法来治疗panca，但重要的一面 不增加患者的存活情况（甚至不增加2个月）。脱木质 （以纤维化过多和细胞外基质沉积为特征）在 肿瘤，从而诱导化学抗性。另外，某些信号通路，异常肿瘤细胞 膜脂质结构/组成和由于药物外的过表达而导致的药物摄取受限 相关的蛋白质还导致癌症进展/转移和耐药性。最近的FDA- 批准（2013年9月6日）组合治疗方案[NAB纳米颗粒（即紫杉醇纳米颗粒， Abraxane®）加上GEM]的总生存率略有改善（仅1.8个月）（8.5个月比6.7个月 独自一人）。研究还表明，PTX改变了肿瘤微环境（TME）并减少 脱木质，从而改善了胰腺肿瘤的宝石吸收。我们相信这种PTX介导的 通过使用独特的肿瘤特异性，可以进一步改善治疗结果 靶向PTX纳米颗粒配方的抗体。我们假设抗体引导，特异性肿瘤 针对PPNP的有针对性递送将增强胰腺肿瘤和宏观/的PTX的生物利用度 微型转移性病变可通过改善的 Desmoplasia，TME改变和SHH/CXCL12/CXCR4，miR-21介导的致癌信号通路。 该提案考试两个靶向panca的级别。首先是MUC13的靶向递送PTX 胰腺肿瘤作为我们的PPNP选择性地/优先触及和丙烯酸肿瘤/转移性 病变。我们的初步数据表明，MUC13靶向纳米颗粒有效靶向胰腺 肿瘤。第二级的治疗是静脉注射宝石。目标的第一级将 很大程度上改变了TME，从而可以促进对GEM的更好响应。这种新颖的组合疗法 模态将增强对肿瘤部位的药物载荷，诱导更大的抗癌作用，而 最小化副作用。为了实现这些目标，提出了三个具体目标：目标1：评估化学 PPNPS在PANCA细胞中的致敏和TME。 AIM 2：研究药物运动/动力学（PK/PD） PPNP/GEM在包含PANCA Xenographic House模型的基质组件中的安全性。目标3：到 评估MUC13靶向PPNP公式在临床相关转基因中的治疗功效 小鼠和患者衍生的异种移植（PDX）模型。该提议通过 改变肿瘤 - 基质（旁分泌）串扰和化学敏化panca，被认为是 panca疗法中的主要障碍。拟议的研究基于最近的临床观察结果 因此，这种方法的临床翻译将变得容易快捷。