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Principal Investigator: Timothy R Donahue
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2019
Award: $433,388
Funding agency: National Cancer Institute
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).
Terms: <1-OHP><2'-Deoxycytidine Kinase><5-FU><5-Fluracil><5FU><ARA-C Kinase><Abraxane><Address><Adventitial Cell><Albumins><Animal Model><Animal Models and Related Studies><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Asotax><Bisphosphonates><Blood Vessels><Body Tissues><Bone-Derived Transforming Growth Factor><Bristaxol><Campto><Cancer Drug><Cancers><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy, Cancer, General><Chemotherapy-Oncologic Procedure><Collaborations><Combination Chemotherapy Regimen><Cristobalite><Cytidine Aminohydrolase><Cytidine Deaminase><Data><Deoxycytidine Kinase><Difluorodeoxycytidine><Dose><Drug Combinations><Drug Synergism><Drugs><EC 2.7.1.74><Encapsulated><Engineering><Enzyme Gene><Enzymes><Epidermal Growth Factor-Related Transforming Growth Factor><FDA approved><Failure><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Glass><Goals><Heterograft><Heterologous Transplantation><Human><Intermediary Metabolism><Lead><Life><Lipid Bilayers><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Medication><Metabolic><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Murine><Mus><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Oncologist><Oxidative Stress><Paclitaxel><Paclitaxel (Taxol)><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Pb element><Peptides><Pericapillary Cell><Pericytes><Perivascular Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphorylation><Platelet Transforming Growth Factor><Poor Vascular Access><Praxel><Protein Phosphorylation><Quimioterapia><Regimen><Research><Resistance><Rouget Cells><Safety><Sand><Scientist><Secondary Neoplasm><Secondary Tumor><Series><Silica><Silicon Dioxide><Site><Surgeon><TGF A><TGF B><TGF-alpha><TGF-beta><TGF-α><TGF-β><TGFalpha><TGFbeta><TGFα><TGFβ><Taxol><Taxol A><Taxol Konzentrat><Testing><Tissues><Toxic effect><Toxicities><Toxicity due to chemotherapy><Transforming Growth Factor alpha><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Model><Tridymite><Tumor Cell><Tumor-Specific Treatment Agents><Xenograft><Xenograft procedure><Xenotransplantation><acronyms><anti-cancer drug><anticancer agent><anticancer drug><base><biocompatibility><biomaterial compatibility><biphosphonate><bisphosphonate><camptosar><cancer chemotherapy><cancer metastasis><cell killing><chemotherapeutic agent><chemotherapy><chemotherapy toxicity><dFdC><dFdCyd><design><designing><diphosphonate><drug metabolism><drug/agent><efficacy testing><gemcitabine><heavy metal Pb><heavy metal lead><improved><inhibitor><inhibitor/antagonist><interdisciplinary approach><irinotecan><lipid bilayer membrane><malignancy><model of animal><model organism><multidisciplinary><multidisciplinary approach><nano><nano carrier><nano encapsulated><nano particle><nano particle delivery><nano-sized particle><nanocarrier><nanoencapsulated><nanoencapsulation><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplasm/cancer><neoplastic cell><new diagnostics><new drug treatments><new drugs><new therapeutics><new therapy><next generation diagnostics><next generation therapeutics><novel><novel diagnostics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><oxaliplatin><oxaliplatine><pathway><pre-clinical study><preclinical study><prevent><preventing><public health relevance><ratiometric><resistance mechanism><resistant><resistant mechanism><response><safety assessment><site targeted delivery><small molecule><survival outcome><systemic toxicity><targeted delivery><transcytosis><transgenic trait><tumor><tumor cell metastasis><uptake><vascular><xeno-transplant><xeno-transplantation>