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，没有找到一种可行的胰腺癌治疗方案。随着许多癌症的发病率继续下降，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诊断后的生存机会<5%，另一种方法是化学预防，使用合适的药物来抑制或逆转这种疾病的进展。我们的研究小组首次报道了一种新的低浓度阿司匹林、姜黄素和萝卜硫素（ACS）的组合方法，该方法通过基于纳米技术的口服给药系统使用固体脂质纳米颗粒（sln）给药。这些体外和体内的初步研究结果表明，使用这种新方法可显著降低细胞活力，增加细胞凋亡，并显著减少胰腺上皮内肿瘤（PanINs）。虽然这些数据似乎对胰腺癌的化学预防很有希望，但许多新的问题仍未得到解答。在本提案中，我们将重点进一步研究长期口服ACS的理想配方策略，使用第二代壳聚糖偶联sln （c-SLN）来改善胰腺组织的靶向性。此外，我们将研究其在胰腺中的毒性、药代动力学和生物分布

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.