Reprogramming Tumor Microenvironment by Nanoparticle

纳米粒子重编程肿瘤微环境

• 批准号: 9241775
• 负责人: Priyabrata Mukherjee
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-22 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241775
• 关键词: Antibodies; Apoptosis; Biodistribution; Blood Circulation; CSF2 gene; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Cetuximab; Clinical; Coculture Techniques; Collagen; Data; Deposition; Desmoplastic; Devices; Diagnosis; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Epidermal Growth Factor Receptor; Epithelial; Event; Extracellular Matrix Proteins; FGF2 gene; Fibroblasts; Gold; Growth; Growth Factor; IL8 gene; In Vitro; Individual; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Monoclonal Antibody C225; Mus; Nanoconjugate; Nanotechnology; Neoplasm Metastasis; Nodal; Organ; Outcome; PGF gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Play; Polyethylene Glycols; Primary Neoplasm; Property; Proteins; Resistance; Role; Scheme; Signal Transduction; Smooth Muscle Actin Staining Method; Testing; Therapeutic; Time; Tissues; Toxic effect; Transforming Growth Factor beta; Transgenic Organisms; Treatment Efficacy; Tumor stage; United States; Unresectable; base; chemotherapy; cytokine; drug sensitivity; effective therapy; gemcitabine; implantation; improved; in vivo; innovation; migration; mouse model; nanoparticle; neoplastic cell; novel therapeutic intervention; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; perpetrators; stellate cell; treatment strategy; tumor; tumor growth; tumor microenvironment; uptake

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a notoriously dismal prognosis and is the 4th leading cause of cancer related deaths in the United States. Unfortunately, 80- 85% patients are diagnosed with unresectable, incurable advanced stage tumors putting the median survival at <6 months and the overall 5-year survival at <5%. Therefore, new therapeutic strategies are urgently needed to improve the dismal outcome in PDAC patients. PDAC is characterized by a robust desmoplastic reaction. Desmoplastic reaction endows PDAC with a unique microenvironment that promotes tumor growth, metastasis and resists tumor cells to chemotherapy, collectively resulting in a dismal prognosis. Hence, new treatment strategies are urgently needed to inhibit desmoplasia where nanotechnology could play a pivotal role. Although the mechanism is still not clear and slowly emerging, a number of PCC/PSC secreted factors are recognized to play critical roles facilitating bidirectional crosstalk between PCCs and PSCs that promotes desmoplasia. We demonstrate in the preliminary data that AuNP inhibits proliferation of both PCCs and PSCs and efficiently disrupts the PCC-PSC crosstalk by reducing secretion of a number of critical factors. Therefore, AuNP provides potential opportunities to improve the dismal prognosis in PDAC by simultaneously inhibiting multiple pathways involved in desmoplasia. We also demonstrate in the preliminary data that an AuNP-based targeted drug delivery system efficiently targets and inhibits proliferation of both PCCs and PSCs exploiting overexpression of EGFR in these cells. Since the overproduction of -SMA positive PSCs which sometimes account for ~90 % of the total fibrotic mass, depletion of both PSCs and PCCs by AuNP-based targeted drug delivery system is expected to reduce the extent of cross talk and cut down the formation of the huge fibrotic tissue. Decrease in fibrotic mass will allow better drug penetration and delivery, thereby increasing drug sensitivity. Furthermore, nanoconjugates having higher circulation time will soak the fibrotic mass for a longer duration and hence penetrate more efficiently into the fibrotic tissue. Therefore, in the present proposal, we will use a two-pronged approach; 1) disrupting PCC-PSC crosstalk by gold nanoparticle alone and understanding the molecular mechanism, and 2) depleting both PCC and PSC by an AuNP-based targeted drug delivery system to inhibit desmoplasia. We will use three specific aims to accomplish these objectives; Aim 1: Interrogating disruption of PCC-PSC crosstalk by gold nanoparticles; Aim 2: Disrupting PCC-PSC cross-talk tuning pharmacokinetics of a targeted drug delivery system; Aim 3: Improving gemcitabine therapy by reprogramming tumor microenvironment by gold nanoparticle. After decades of ineffective therapeutic strategies against the epithelial component in PDAC, it is only recently realized that the massive stromal tissue is not an innocent bystander but plays critical roles in PDAC progression. Bidirectional crosstalk between PSC and PCC is considered to be the key molecular event that drives desmoplasia. No effective therapeutic strategy currently exists to disrupt PCC-PSC crosstalk. Therefore, the two pronged approach, as proposed in this application, of disrupting PCC-PSC crosstalk (signaling blockade) and abrogating the key components participating in desmoplasia, namely PCCs and PSCs (cellular blockade) is thus highly innovative and provides an exciting opportunity to enhance therapeutic efficacy in PDAC. Successful completion of the aims proposed will help to understand the molecular mechanism of desmoplasia, provide a new and innovative way to inhibit it, and device new therapeutic strategies to enhance drug sensitivity that will inhibit tumor growth, metastasis and improve prognosis in PDAC where practically no effective therapy is currently available.

胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤之一， 预后差，是美国癌症相关死亡的第四大原因。不幸的是，80- 85%的患者被诊断为不可切除、不可治愈的晚期肿瘤， <6个月，总5年生存率<5%。因此，迫切需要新的治疗策略 以改善PDAC患者的不良结局。 PDAC的特征在于强烈的促结缔组织增生反应。促结缔组织增生反应赋予PDAC独特的 促进肿瘤生长、转移和抵抗肿瘤细胞化疗的微环境， 共同导致了令人沮丧的预后。因此，迫切需要新的治疗策略来抑制 纳米技术可以发挥关键作用。虽然机制尚不明确， 虽然PCC/PSC分泌因子的出现缓慢，但已认识到它们在促进PCC/PSC的发生中发挥着关键作用。 促进结缔组织增生的PCC和PSC之间的双向串扰。我们展示了 初步数据表明，AuNP抑制PCCs和PSC的增殖，并有效地破坏PCC-PSC 减少串扰的一些关键因素的分泌。因此，AuNP提供了潜在的机会 通过同时抑制参与PDAC的多种途径来改善PDAC的不良预后， 结缔组织增生我们还在初步数据中证明，基于AuNP的靶向药物递送系统 有效地靶向并抑制PCCs和PSC的增殖，利用这些细胞中EGFR的过表达， 细胞由于β-SMA阳性PSC的过度产生，其有时占总量的~90 纤维化质量，通过基于AuNP的靶向药物递送系统消耗PSC和PCC， 减少串扰的程度，减少巨大纤维组织的形成。纤维化肿块减少 将允许更好的药物渗透和递送，从而增加药物敏感性。此外，委员会认为， 具有较高循环时间的纳米缀合物将浸泡纤维化团块较长的持续时间 更有效地渗透到纤维化组织中。因此，在现时的建议中，我们会采用双管齐下的方法， 方法; 1）通过单独的金纳米颗粒破坏PCC-PSC串扰，并理解分子 和2）通过基于AuNP的靶向药物递送系统耗尽PCC和PSC两者，以抑制 结缔组织增生我们将使用三个具体目标来实现这些目标：目标1： 金纳米颗粒引起的PCC-PSC串扰;目的2：破坏PCC-PSC串扰调谐药物动力学 靶向给药系统;目标3：通过重编程肿瘤改善吉西他滨治疗 金纳米颗粒的微环境。 经过几十年对PDAC中上皮成分的无效治疗策略， 最近认识到，大量的间质组织不是无辜的旁观者，但在PDAC中起着关键作用 进展PSC和PCC之间的双向串扰被认为是关键的分子事件， 驱动结缔组织增生。目前不存在有效的治疗策略来破坏PCC-PSC串扰。因此，我们认为， 如本申请中所提出的，中断PCC-PSC串扰（信令 阻断）和废除参与结缔组织增生的关键组分，即PCC和PSC（细胞 阻断）因此是高度创新的，并提供了增强治疗功效的令人兴奋的机会。 PDAC。成功地完成所提出的目标将有助于理解的分子机制， 结缔组织增生，提供了一种新的和创新的方式来抑制它，并设备新的治疗策略，以提高 药物敏感性，将抑制肿瘤生长，转移和改善预后的PDAC，其中几乎没有 目前已有有效的治疗方法。