Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC)
cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a
liposome) was introduced to provide encapsulated
irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace
irinotecan in
FOLFIRINOX, the liposomal formulation is currently prescribed as a second-line treatment option (in combination with
5-fluorouracil and
leucovorin) for patients with metastatic PDAC who failed
gemcitabine therapy. However, the toxicity of Onivyde remains a concern that needs to be addressed for use in CRC as well. Our goal was to custom design a mesoporous
silica nanoparticle (MSNP) carrier for encapsulated
irinotecan delivery in a robust CRC model. This was achieved by developing an orthotopic
tumor chunk model in immunocompetent mice. With a view to increase the production volume and to expand the disease applications, the carrier design was improved by using an
ethanol exchange method for coating of a supported
lipid bilayer (LB) that entraps a protonating agent. The encapsulated protonating agent was subsequently used for remote loading of
irinotecan. The excellent
irinotecan loading capacity and stability of the LB-coated MSNP carrier, also known as a "silicasome", previously showed improved efficacy and reduced toxicity when compared to an in-house liposomal carrier in a PDAC model.
Intravenous injection of the silicasomes in a well-developed orthotopic
colon cancer model in mice demonstrated improved pharmacokinetics and
tumor drug content over free
drug and Onivyde. Moreover, improved
drug delivery was accompanied by substantially improved efficacy, increased survival, and reduced bone marrow and GI toxicity compared to the free
drug and Onivyde. We also confirmed that the custom-designed
irinotecan silicasomes outperform Onivyde in an orthotopic PDAC model. In summary, the Ir-silicasome appears to be promising as a treatment option for CRC in humans based on improved efficacy and the carrier's favorable safety profile.