Pancreatic ductal adenocarcinoma (PDAC) is essentially a death sentence and is currently being treated by two major drug regimens, namely gemcitabine, and a 4-drug combination known as FOLFIRINOX (oxaliplatin, 5-fluorouracil, Irinotecan, and leucovorin). In addition to the contributions of late diagnosis and early metastatic spread to mortality, a major treatment obstacle is the abundant dysplastic stroma, which provides a barrier to vascular access of chemotherapeutic agents at the tumor site as well as expression of cytidine deaminase, which leads to rapid destruction of gemcitabine. While FOLFIRINOX leads to better survival outcome, the high toxicity levels of irinotecan and oxaliplatin often prevent its use as a first-line treatment regimen. Recently, two therapeutic regimes making use of nanotechnology, was approved by FDA for the treatment of PDAC, namely the use of Abraxane, an albumin nanosphere that is capable of stromal suppression by the delivery of paclitaxel, as well as Onyvide, a liposomal formulation that delivers Irinotecan. In order to improve nanocarrier delivery of paclitaxel and irinotecan, we developed a mesoporous silica nanoparticle (MSNP) platform that improves drug delivery by increased loading capacity, ability to perform synergistic drug delivery and reduced toxicity due to the stability of the platform over liposomes. My talk will outline the use of lipid bilayer coating of the MSNP for the ratiometric combination of gemcitabine with paclitaxel, with the possibility to achieve synergistic drug delivery at orthotopic PDAC tumors sites, where suppression of the stroma allows increased uptake of activated gemcitabine. I will also demonstrate how the use of a lipid bilayer coated MSNP could be used for remote drug loading of irinotecan, with the ability to outperform a liposomal equivalent because of the increased drug loading capacity and stability, including reduced levels of liver, bone marrow and gastrointestinal tract toxicity. I will also discuss the use of the MSNP delivery system to develop synergistic perturbation of the immune system to attempt to link the improved chemotherapy cytotoxicity to improved tumor immunity.

Engineered approach to pancreatic cancer using mesoporous silica nanocarriers & immune perturbation

252nd National Meeting (2016)

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