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

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.

Development of Facile and Versatile Platinum Drug Delivering Silicasome Nanocarriers for Efficient Pancreatic Cancer Chemo-Immunotherapy.

In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high-dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak-basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2-diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras-derived pancreatic cancer (PDAC) model is demonstrated.

Safety Considerations of Cancer Nanomedicine-A Key Step toward Translation.

The rate of translational effort of nanomedicine requires strategic planning of nanosafety research in order to enable clinical trials and safe use of nanomedicine in patients. Herein, the experiences that have emerged based on the safety data of classic liposomal formulations in the space of oncology are discussed, along with a description of the new challenges that need to be addressed according to the rapid expansion of nanomedicine platform beyond liposomes. It is valuable to consider the combined use of predictive toxicological assessment supported by deliberate investigation on aspects such as absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic profiles, the risk that may be introduced during nanomanufacture, unique nanomaterials properties, and nonobvious nanosafety endpoints, for example.

Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

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.