Combination Chemo‐Immunotherapy for Pancreatic Cancer Using the Immunogenic Effects of an Irinotecan Silicasome Nanocarrier Plus Anti‐PD‐1

Abstract

There is an urgent need to develop new life‐prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo‐immunotherapy response in an orthotopic Kras‐dependent pancreatic cancer model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death‐ligand 1 (PD‐L1) expression. ICD is characterized by calreticulin expression and high‐mobility group box 1 (HMGB1) release in dying Kras‐induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti‐PD‐1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD‐L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo‐immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti‐PD‐1 leads to significantly enhanced survival improvement, and is far superior to anti‐PD‐1 plus either free irinotecan or Onivyde.

An Update on Mesoporous Silica Nanoparticle Applications in Nanomedicine

“…In another study, Liu et al used MSNs coated with lipid bilayers (silicasome) to deliver activated platinum chemo agent used for immunogenic chemotherapy in a pancreatic ductal adenocarcinoma (PDAC) preclinical model [ 387 , 388 ]. The silicasome coating improved the colloidal stability of this nanocarrier after the intravenous injection.…”

Nanocarriers for Biomedicine: From Lipid Formulations to Inorganic and Hybrid Nanoparticles

“…Lipid bilayer-coated mesoporous silica particles, also called silicasomes, show a number of useful properties suitable for biomedical application. For example, there is a series of reports dedicated to the development of drug delivery systems based on irinotecan and AZD1080, inhibitor of enzymes responsible for phosphorylation, for treatment of alimentary canal cancers [247][248][249][250][251]. In particular, application of silicasomes was shown to demonstrate improved biodistribution and delivery of AZD1080 to the sites of colorectal tumor CT26 and pancreas KPC cancer models [247].…”

“…Similar modification allows authors to achieve excellent encapsulation capability of irinotecan, improved pharmacokinetics and 6-fold higher amount of drug in colorectal and pancreatic cancer cells after 48 h of treatment over free drug and its liposomal formulation [248]. Moreover, lipid-decorated silica particles have perspectives in various approaches of cancer treatment including chemotherapy and chemo-immunotherapy of pancreatic cancer [249,250].…”

The Role of Autophagy at the Nano/Bio Interface - Underlying Mechanisms and Therapeutic Potential in Cancer

“…The levels of programmed cell death-1 (PD-1) with its ligand (PD-L1), two major immune checkpoints, have been reported to be upregulated by autophagy inhibitors in different cancers such as melanoma, ovarian cancer, and gastric cancer [73]. Liu et al developed a lipid bilayer-coated MSNP, also known as a silicasome, for chemo-immunotherapy [74]. Irinotecan, a weak-basic chemo-drug, neutralizes the acidic lysosomal pH, leading to autophagy inhibition and PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells.…”

“…Irinotecan, a weak-basic chemo-drug, neutralizes the acidic lysosomal pH, leading to autophagy inhibition and PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells. Therefore, checkpoint blockade therapy, combined with silicasome-empowered irinotecan delivery, synergistically enhanced the anti-tumor effect in an orthotopic PDAC mouse model [74]. Similarly, legumainresponsive Au nanoparticles were loaded with DOX and autophagy inhibitor HCQ [75].…”