UCLA Multifunctional Mesoporous Silica Nanoparticle Platform for Treatment of Pancreas Cancer

 描述（由申请人提供）：纳米载体绕过胰腺导管腺癌（PDAC）中的基质屏障，以允许（i）协同吉西他滨（GEM）/紫杉醇（PTX）组合的比例控制，（ii）克服吉西他滨（GEM）代谢中的限速步骤，和（iii）降低FOLFIRINOX毒性（一种有效的4种药物方案，包括伊立替康），可显著影响PDAC生存期。我们多学科方法的长期目标是使用合理设计的介孔二氧化硅纳米颗粒（MSNP）为PDAC患者提供有效，安全和延长生命的化疗。我们的目标是在先进的临床前研究中开发和实施MSNP纳米载体，以：（i）使用支持的脂质双层（LBL）实现稳定和高剂量的GEM或伊立替康负载;（ii）提供来自单个MSNP载体的协同PTX/GEM递送，在人源性PDAC肿瘤以及小鼠中的自发Kras（KPC）转基因模型中进行功效测试;（iii）提供高剂量包封的伊立替康递送以降低相同动物模型中的毒性;（iv）通过iRGD肽实现载体靶向或转胞吞作用，这也可以防止转移;（v）递送小分子TGF-β 1抑制剂（TGF-β 1），其通过干扰周细胞覆盖提供血管通路。为了实现这些目标，目标1将使用LBL包被的MSNP纳米载体来优化GEM在小鼠中的人源性PDAC肿瘤以及自发性KPC模型中的递送和功效。基于显示LBL包被的MSNP可以递送协同GEM/PTX组合的初步数据，工作假设是PTX诱导的氧化应激引起的基质扰动将增强GEM摄取。我们还将提供纳米使能的GEM-双膦酸盐到肿瘤中，降低限速酶（dCK）的表达，该酶负责通过磷酸化激活GEM。目的2将奋进证明LBL-包衣纳米载体的生物相容性如何用于改善伊立替康递送在GEM-耐药性肿瘤中的毒性特征和功效。基于显示高度MSNP生物相容性的初步数据，工作假设是LBL-MSNP的高载药量和稳定性将显著降低伊立替康毒性。这可能导致强效FOLFIRINOX方案的扩大使用。目的3将奋进证明iRGD-MSNP的靶向递送、通过iRGD共递送促进纳米载体转胞吞或通过TGF-β 1改善血管通路可增强MSNP纳米载体（包括目的1和2中开发的载体）的化疗功效。我们预期通过多功能MSNP递送GEM/PTX和伊立替康将在模拟人类PDAC的稳健动物模型中改善存活率并降低化疗毒性。这些结果预计将通过提供有效和安全的纳米载体产生直接的积极影响，这些纳米载体可以被置于我们的多学科团队（包括材料科学家，化学家，肿瘤生物学家，肿瘤学家和外科医生）在人类PDAC患者中测试的新型诊断和治疗方法中。

 DESCRIPTION (provided by applicant): Nanocarriers that circumvent the stromal barrier in pancreatic ductal adenocarcinoma (PDAC) to allow (i) ratiometric control of a synergistic gemcitabine (GEM)/paclitaxel PTX) combination, (ii) overcome rate limiting steps in gemcitabine (GEM) metabolism, and (iii) reduce FOLFIRINOX toxicity (a potent 4-drug regimen that includes irinotecan) could significantly impact PDAC survival. The long-term goal of our multidisciplinary approach is to use rational-designed mesoporous silica nanoparticles (MSNP) to provide efficacious, safe and life-prolonging chemotherapy to PDAC patients. Our objectives are to develop and implement MSNP nanocarriers in advanced preclinical studies to: (i) achieve stable and high dose GEM or irinotecan loading, using a supported lipid bilayer (LBL); (ii) provide synergistic PTX/GEM delivery from a single MSNP carrier, with efficacy testing in human-derived PDAC tumors as well as the spontaneous Kras (KPC) transgenic model in mice; (iii) provide high dose encapsulated irinotecan delivery to reduce toxicity in the same animal models; (iv) achieve carrier targeting or transcytosis by iRGD peptide, which may also prevent metastasis; (v) deliver a small molecule TGF-ß inhibitor (TGF-ßi) that provides vascular access by interference in pericyte coverage. In order to attain these objectives, Aim 1 will use LBL-coated MSNP nanocarriers to optimize GEM delivery and efficacy in human derived PDAC tumors in mice as well as the spontaneous KPC model. The working hypothesis, based on preliminary data showing that LBL-coated MSNPs can deliver a synergistic GEM/PTX combination, is that stromal perturbation by PTX-induced oxidative stress will enhance GEM uptake. We will also deliver nano-enabled GEM-bisphosphonate to tumors with reduced expression of a rate-limiting enzyme (dCK) that is responsible for GEM activation through phosphorylation. Aim 2 will endeavor to demonstrate how the biocompatability of LBL-coated nanocarriers can be used to improve the toxicity profile and efficacy of irinotecan delivery in GEM-resistant tumors. The working hypothesis, based on preliminary data showing a high degree of MSNP biocompatibility, is that the high drug loading capacity and stability of LBL-MSNP will dramatically reduce irinotecan toxicity. This could lead to the expanded use of the potent FOLFIRINOX regimen. Aim 3 will endeavor to demonstrate that targeted delivery of iRGD-MSNP, promotion of nanocarrier transcytosis by iRGD co-delivery, or improvement of vascular access by TGF-ßi can enhance the chemotherapeutic efficacy of MSNP nanocarriers, including the carriers developed in Aims 1 and 2. We anticipate the delivery of GEM/PTX and irinotecan by multifunctional MSNPs will improve survival and reduce chemotherapy toxicity in robust animal models simulating human PDAC. These results are expected to have an immediate positive impact by providing efficacious and safe nanocarriers that can be placed into the pipeline of novel diagnostics and therapeutics being tested in human PDAC patients by our multidisciplinary team (that includes materials scientists, chemists, tumor biologists, an oncologist, and a surgeon).