Nanocarrier Co-formulation for Delivery of a TLR7 Agonist plus an Immunogenic Cell Death Stimulus Triggers Effective Pancreatic Cancer Chemo-immunotherapy.
Lijia LuoXiang WangYu-Pei LiaoChong Hyun ChangAndré E NelPublished in: ACS nano (2022)
Although toll-like receptor (TLR) agonists hold great promise as immune modulators for reprogramming the suppressive immune landscape in pancreatic ductal adenocarcinoma (PDAC), their use is limited by poor pharmacokinetics (PK) and off-target systemic inflammatory effects. To overcome these challenges as well as to attain drug synergy, we developed a lipid bilayer (LB)-coated mesoporous silica nanoparticle (silicasome) platform for co-delivery of the TLR7/8 agonist 3M-052 with the immunogenic chemotherapeutic agent irinotecan. This was accomplished by incorporating the C18 lipid tail of 3M-052 in the coated LB, also useful for irinotecan remote loading in the porous interior. Not only did the co-formulated carrier improve PK, but it strengthened the irinotecan-induced immunogenic cell death response by 3M-052-mediated dendritic cell activation at the tumor site as well as participating lymph nodes. The accompanying increase in CD8 + T-cell infiltration along with a reduced number of regulatory T-cells was associated with tumor shrinkage and metastasis disappearance in subcutaneous and orthotopic KRAS-mediated pancreatic carcinoma tumor models. Moreover, this therapeutic outcome was accomplished without drug or nanocarrier toxicity. All considered, dual-delivery strategies that combine chemo-immunotherapy with co-formulated TLR agonists or other lipid-soluble immune modulators predict successful intervention in heterogeneous PDAC immune landscapes.
Keyphrases
- toll like receptor
- regulatory t cells
- cell death
- inflammatory response
- dendritic cells
- nuclear factor
- immune response
- drug delivery
- lymph node
- small molecule
- photodynamic therapy
- oxidative stress
- randomized controlled trial
- fatty acid
- drug induced
- cancer therapy
- diabetic rats
- cell cycle arrest
- squamous cell carcinoma
- combination therapy
- cell proliferation
- high glucose
- signaling pathway
- machine learning
- early stage
- high throughput
- big data
- rectal cancer