UCLA Multifunctional Mesoporous Silica Nanoparticle Platform for Treatment of Pancreas Cancer

加州大学洛杉矶分校多功能介孔二氧化硅纳米颗粒平台用于治疗胰腺癌

• 批准号: 8959561
• 负责人: Timothy R Donahue
• 金额: $ 51.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959561
• 关键词: Abraxane; Address; Albumins; Animal Model; Antineoplastic Agents; Binding; Blood Vessels; Chemotherapy-Oncologic Procedure; Collaborations; Cytidine Deaminase; Data; Deoxycytidine Kinase; Dose; Drug Combinations; Drug Targeting; Encapsulated; Engineering; Enzymes; FDA approved; Failure; Fluorouracil; Glass; Goals; Human; Lead; Life; Lipid Bilayers; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolism; Modeling; Mus; Neoplasm Metastasis; Oncologist; Outcome; Oxidative Stress; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peptides; Pericytes; Pharmaceutical Preparations; Phosphorylation; Poor Vascular Access; Regimen; Research; Resistance; Safety; Scientist; Series; Silicon Dioxide; Site; Staging; Surgeon; Testing; Therapeutic Agents; Tissues; Toxic effect; Toxicity due to chemotherapy; Transforming Growth Factor beta; Transgenic Model; Work; Xenograft procedure; acronyms; base; biomaterial compatibility; bisphosphonate; cell killing; chemotherapeutic agent; chemotherapy; design; drug metabolism; efficacy testing; gemcitabine; improved; inhibitor/antagonist; interdisciplinary approach; irinotecan; killings; multidisciplinary; nano; nanocarrier; nanoparticle; neoplastic cell; novel; novel diagnostics; novel therapeutics; oxaliplatin; preclinical study; prevent; public health relevance; ratiometric; resistance mechanism; response; small molecule; targeted delivery; transcytosis; tumor; uptake

 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).

 DESCRIPTION (provided by applicable): 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 （一种有效的4药疗法，包括伊立替康）可能会显着影响PDAC的存活率。我们多学科方法的长期目标是使用理性设计的介孔二氧化硅纳米颗粒（MSNP）为PDAC患者提供有效，安全和生命的化学疗法。我们的目标是使用支持的脂质双层（LBL），在高级临床前研究中开发和实施高级临床前研究中的MSNP纳米载体； （ii）从单个MSNP载体提供协同的PTX/GEM递送，在人体衍生的PDAC肿瘤以及小鼠中的赞助者 - 蛋白KRAS（KPC）转基因模型中进行有效测试； （iii）提供高剂量封装的伊立康递送，以降低同一动物模型中的毒性； （iv）实现IRGD胡椒的载体靶向或转介术，这也可能预防转移； （v）提供一个小分子TGF-β抑制剂（TGF-ßI），该抑制剂通过干扰周细胞覆盖范围提供血管通道。为了实现这些目标，AIM 1将使用LBL涂层的MSNP纳米载体来优化小鼠和赞助KPC模型的人类衍生PDAC肿瘤中的GEM递送和效率。基于初步数据的工作假设表明，LBL涂层的MSNP可以提供协同的GEM/PTX组合，是PTX诱导的氧化应激会增强GEM的摄取。我们还将将纳米型的宝石 - 双膦酸盐传递到肿瘤，其限制酶（DCK）的表达降低，该酶（DCK）通过磷酸化负责GEM激活。 AIM 2将努力证明如何使用LBL涂层的纳米载体的生物相容性来提高耐颗粒肿瘤中伊立替康递送的毒性和效率。根据显示高度MSNP生物相容性的初步数据的工作假设是，LBL-MSNP的高药物载荷能力和稳定性将大大降低伊立替康毒性。这可能导致潜在的Folfirinox方案的扩大使用。 AIM 3将努力证明，IRGD共同交付促进IRGD-MSNP，促进纳米载体的跨胞菌病或TGF-ßI通过提高血管通道的改善，可以提高MSNP纳米载体的化学治疗效率，包括通过AIM-ifs and inf shif inf inif and irif infins and irifs and irif infins和2。将改善生存率并降低模拟人PDAC的强大动物模型中的化学疗法毒性。预计这些结果将通过提供高效且安全的纳米载体来立即产生积极的影响，这些纳米载体可以由我们的多学科团队（包括材料科学家，化学家，肿瘤生物学家，肿瘤学家，肿瘤学家和外科人）在人类PDAC患者中测试的新型诊断和治疗。