Targeted Nanotherapy for Pancreatic Cancer

拟议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。 虽然存在许多常规和联合化疗方法来治疗胰腺癌，但重要的是 效果的发生不会增加患者的存活率(甚至不会增加2个月)。结缔组织发育不全 (以过度纤维化和细胞外基质沉积为特征)导致在 肿瘤，从而诱导化疗耐药。此外，某些信号通路，异常的肿瘤细胞 膜脂结构/组成与药物外排过表达所致的药物摄取受限 相关蛋白还导致癌症进展/转移和耐药性。最近的FDA- 批准(于9月9日6,2013)联合治疗方案[NaB-纳米粒(即，紫杉醇纳米粒， Abraxane®)加GEM]略微改善了(仅1.8个月)总生存期(8.5个月与6.7个月 仅用宝石)。研究还表明，PTX改变了肿瘤微环境(TME)，并减少了 促结缔组织增生症，从而改善了胰腺肿瘤对GEM的摄取。我们认为这种PTX介导的 通过使用无与伦比的肿瘤特异性药物可以进一步提高略微改善的治疗结果 抗体靶向PTX纳米粒制剂。我们假设抗体引导的、肿瘤特异性的 靶向递送PPNPs将提高PTX在胰腺肿瘤和宏细胞肿瘤中的生物利用度 微转移灶通过减少抑制肿瘤生长和增加肿瘤细胞对GEM的敏感性 促结缔组织增生、TME改变和SHH/CXCL12/CXCR4、miR-21介导的致癌信号通路。 这项提案考察了两个层次的目标panca。第一种是MUC13靶向传递PTX至 胰腺肿瘤作为我们的PPNPs选择性/优先到达并积聚在肿瘤/转移性肿瘤中 损伤。我们的初步数据表明，MUC13靶向纳米粒有效地靶向胰腺 肿瘤。第二个层次的治疗是静脉注射GEM。第一级目标将是 显著改变TME，从而促进对创业板的更好反应。这是一种新型的联合疗法 这种方法将提高药物对肿瘤部位的特异性载药量，从而产生更好的抗癌效果 将副作用降至最低。为了实现这些目标，提出了三个具体目标：目标1：评估化学药物 PPNPs在Panca细胞中的敏化和TME。目的2：研究药代动力学/动力学(PK/PD) PPNPs/GEM在含有PANCA的异种移植小鼠模型中的安全性。目标3：实现 MUC13靶向PPNP制剂在临床相关转基因中的疗效评价 小鼠和患者来源的异种移植(PDX)模型。这一建议通过以下方式带来了更好的治疗方式 改变肿瘤间质(旁分泌)的串扰和化疗敏化，这被认为是 潘卡疗法的主要障碍。建议的研究是基于最近的临床观察， 因此，这种方法的临床翻译将是容易和快速的。

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.