UCLA Multifunctional Mesoporous Silica Nanoparticle Platform for Treatment of Pancreas Cancer

 描述(申请人提供)：绕过胰腺导管腺癌(PDAC)间质屏障的纳米载体允许(I)比例控制协同吉西他滨(GEM)/紫杉醇PTX)组合，(Ii)克服吉西他滨(GEM)代谢的限速步骤，以及(Iii)降低FOLFIRINOX毒性(一种包括伊立替康的有效4药方案)可能显著影响PDAC的生存。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)利用支撑的脂质双层(LBL)实现稳定和高剂量的GEM或伊立替康的载药；(Ii)从单个MSNP载体提供协同的PTX/GEM递送，在人源性PDAC肿瘤和小鼠自发的Kras(KPC)转基因模型中进行有效性测试；(Iii)在相同的动物模型中提供大剂量的伊立替康胶囊递送以减少毒性；(Iv)通过IRGD多肽实现载体靶向或跨细胞转移，这也可能防止转移；(V)提供一种小分子转化生长因子抑制物(转化生长因子βI)，通过干扰周细胞覆盖来提供血管通路。为了实现这些目标，目标1将使用LBL包裹的MSNP纳米载体来优化GEM在小鼠人源性PDAC肿瘤以及自发KPC模型中的传递和疗效。基于初步数据显示LBL包被的MSNPs可以提供GEM/PTX的协同组合的工作假设是，PTX诱导的氧化应激对基质的扰动将增强GEM的摄取。我们还将向肿瘤提供纳米启用的GEM-双膦酸盐，减少一种限速酶(DCK)的表达，DCK负责通过磷酸化激活GEM。目的2将努力证明LBL包衣纳米载体的生物相容性如何用于改善伊立替康对GEM耐药肿瘤的毒性和有效性。基于显示MSNP高度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极大地降低伊立替康的毒性。这可能导致有效的FOLFIRINOX方案的扩大使用。目的3将致力于证明靶向递送IRGD-MSNP，通过IRGD共递送促进纳米载体的细胞转运，或通过转化生长因子-B I改善血管通达，可以增强MSNP纳米载体的化疗疗效，包括AIMS 1和2中开发的载体。我们预计多功能MSNPs递送GEM/PTX和伊立替康将在模拟人类PDAC的健壮动物模型中提高存活率和降低化疗毒性。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)正在对人类PDAC患者进行测试，预计这些结果将通过提供有效和安全的纳米载体而产生立竿见影的积极影响。

 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).