Paclitaxel and Itraconazole Co‐Encapsulated Micelle Prolongs the Survival of Spontaneous LSL‐Kras^G12D/+, LSL‐Trp53^R172H/+, Pdx‐1‐Cre Genetically Engineered Mouse Model of Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant gastrointestinal cancers with an extremely complex tumor microenvironment and a poor prognosis. The upregulation of Hedgehog (Hh) signaling pathway contributes to the abundance of stroma and barren blood vessels in the PDAC tumor microenvironment, creating a physical and biological barrier leading to strong inherent resistance to drugs. Therefore, inhibition of the Hh signaling pathway combined with chemotherapy has been explored in anti-PDAC chemotherapy. In this study, the paclitaxel (PTX) and itraconazole (ITA) co-encapsulated poly (ethylene glycol)-b-poly (d, l-lactide) (PEG-PLA) micelle (PIM) shows superior therapeutic outcome in PDAC. Pharmaceutically, PIM demonstrates optimized systemic pharmacokinetics and increases tumor drug accumulation due to its serum stability. Pharmacologically, through Hh inhibition and blood vessel normalization contributed by ITA and cytotoxicity contributed by PTX, PIM not only significantly inhibits the tumor growth of the human MIA PaCa-2 cell-derived orthotopic pancreatic cancer model but also significantly prolongs the survival of LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx-1-Cre (KPC) genetic engineered, spontaneous PDAC mice, a clinically relevant PDAC model with high similarity as human PDAC in terms of cancer histology and biology.

Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

“…This was not examined in detail in this work, but the anti‐tumor results show that any co‐loader impact on anti‐tumor efficacy was modest. This is not always the case, and one of the co‐loaders examined, itraconazole, was shown to enhance efficacy when co‐formulated with PTX and stabilize micelles . In general, benign and inert co‐loaders that are generally recognized as safe (which CLT and MIF are not) would avoid safety concerns and simplify data interpretation.…”

Responsive Nanomaterial Delivery Systems for Pancreatic Cancer Management

“…In addition, PIM significantly inhibited tumor growth and reduced Ki-67-positive cells, indicating suppressed proliferation. [40] Gene therapy has also shown potential but faces implementation challenges, which can be overcome using drug delivery systems such as NP formulations. [41] In an attempt to advance this technology, an amphiphilic polyglutamate amine (APA) polymeric NP for delivering miR-34a and siRNA targeting PLK1 was developed.…”

Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies

“…PIM showed excellent systemic pharmacokinetics and increased drug accumulation in the tumour site. Additionally, PIM normalized blood vessels and inhibited tumour growth in both a human orthotopic pancreatic cancer model and genetically engineered spontaneous pancreatic ductal adenocarcinoma mice (160). Liposomal nanodelivery systems have also been widely studied in various digestive tumours, such as hepatocellular carcinoma and gastric cancer (161)(162)(163).…”