Combinatorial nanotechnology-based regimens for pancreatic cancer chemoprevention

描述（由申请人提供）：过去二十年的研究证明，在寻找胰腺癌的可行治疗方案方面是失败的。随着许多癌症发病率的持续下降，胰腺癌的发病率和死亡率预计将继续增加。由于缺乏合适的治疗方式和<5%的诊断后生存机会，另一种方法在于化学预防，使用可以抑制或逆转这种疾病进展的合适药物。我们的小组是第一个报告了一种新的组合方法，低浓度的阿司匹林，姜黄素和萝卜硫素（ACS）通过基于纳米技术的口服药物递送系统使用固体脂质纳米颗粒（SLN）。这些初步研究的结果，在体外和体内，显示出显着的协同降低细胞活力，增加细胞凋亡和显着减少胰腺上皮内肿瘤（PanIN）时，使用这种新的方法。虽然这些数据似乎对胰腺癌的化学预防很有希望，但许多新的问题仍然没有答案。在这项提案中，我们的重点是进一步研究一个理想的长期口服给药的ACS的配方策略，使用第二代的SLN共轭壳聚糖（c-SLN），改善胰腺组织的靶向。此外，我们还将研究胰腺癌的毒性特征、药代动力学和生物分布。 组织，并确保在转基因小鼠模型中的功效。总的来说，基于我们强有力的初步结果和相关出版物，我们相信该提案的结果将为考虑ACS纳米方案与c-SLN作为胰腺癌化学预防的可行方法奠定基础。

DESCRIPTION (provided by applicant): The past two decades of research have proved unsuccessful in finding a viable treatment option for pancreatic cancer. As many cancer rates continue to decline, pancreatic cancer incidence and mortality is expected to increase going forward. Due to lack of suitable treatment modalities and <5% chances of survival upon diagnosis, an alternative approach lies in chemoprevention, using suitable agents that can inhibit or reverse the progression of this disease. Our group was the first to report a novel combinatorial approach of low concentrations of aspirin, curcumin and sulforaphane (ACS) administered via a nanotechnology-based oral drug delivery system using solid-lipid nanoparticles (SLNs). Results from these pilot studies, both in vitro and in vivo, showed significant synergistic decrease in cell viability, increased cell apoptosis and significant reducton in pancreatic intraepithelial neoplasms (PanINs) when using this novel approach. While these data appear to be promising for pancreatic cancer chemoprevention, many new questions remain unanswered. In this proposal, we are focused on further investigation of an ideal formulation strategy for long-term oral administration of ACS, using a second generation of SLNs conjugated with chitosan (c-SLN) for improved targeting of the pancreatic tissues. Additionally, we will look at toxicity profiles, pharmacokinetics and biodistribution in pancreatic tissue and ensure efficacy in a transgenic mouse model. Overall, based on our strong preliminary results and related publications, we believe the outcomes of this proposal will establish the groundwork to consider the ACS nano-regimen with c-SLNs as a viable approach for the chemoprevention of pancreatic cancer.