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.

该研究提案的长期目标是开发一种靶向紫杉醇纳米疗法， 可与吉西他滨（GEM）联合用于治疗胰腺癌（PanCa）。 尽管有许多传统和联合化疗方法可以治疗PanCa，但显着的一面 在不增加患者存活率的情况下发生效果（甚至不增加2个月）。结缔 （其特征在于过度纤维化和细胞外基质沉积）导致次优的药物递送， 肿瘤，从而诱导化学抗性。此外，某些信号通路，异常肿瘤细胞 膜脂质结构/组成和药物外排过度导致的药物摄取受限 相关蛋白也导致癌症进展/转移和耐药性。最近FDA- 批准（9月）6，2013）联合治疗方案[nab-纳米颗粒（即，紫杉醇纳米颗粒， Abraxane®）加GEM]的总体生存期略有改善（仅1.8个月）（8.5个月对6.7个月 单独使用GEM）。研究还表明，PTX改变了肿瘤微环境（TME）， 结缔组织增生，从而改善胰腺肿瘤中GEM的吸收。我们认为这种PTX介导的 通过使用独特的肿瘤特异性免疫抑制剂， 抗体靶向PTX纳米颗粒制剂。我们假设抗体引导的肿瘤特异性 PPNP的靶向递送将提高PTX在胰腺肿瘤和巨噬细胞中的生物利用度。 微转移病灶，以减弱肿瘤生长，并通过减少肿瘤细胞对GEM的敏感性 结缔组织增生、改变的TME和SHH/CXCL 12/CXCR 4、miR-21介导的致癌信号通路。 本提案审查了两个层面的泛钙方案。第一种是将PTX靶向递送至MUC 13。 胰腺肿瘤，因为我们的PPNP选择性/优先到达并积聚在肿瘤中/转移性 病变我们的初步数据表明，MUC 13靶向纳米颗粒有效靶向胰腺癌。 肿瘤的第二级治疗是静脉注射吉西他滨。第一级目标是 这将大大改变TME，从而促进对GEM的更好反应。这种新型的联合治疗 这种方式将增强肿瘤部位的特异性药物负载，诱导更大的抗癌效果， 使副作用最小化。为了实现这些目标，提出了三个具体目标：目标1：评价化疗， PPNP在PanCa细胞中的致敏和TME。目的2：研究药物动力学/动力学（PK/PD） PPNP/GEM在含有PanCa异种移植小鼠模型的基质组分中的安全性。目标3： 评价MUC 13靶向PPNP制剂在临床相关转基因小鼠中的治疗功效 小鼠和患者来源的异种移植物（PDX）模型。这一建议导致了一种更好的治疗方式， 改变肿瘤间质（旁分泌）串扰和PanCa中的化学增敏作用， PanCa疗法的主要障碍。拟议的研究是基于最近的临床观察， 因此，这种方法的临床转化将是容易和快速的。