Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer

Abstract

Colorectal cancer with peritoneal metastases is currently treated by cytoreductive surgery and locoregional chemotherapeutics. This standard treatment is associated with high morbidity, mortality, and recurrence rate. To augment the existing therapy, we developed a liposome-based delivery system containing 1,2-stearoyl-3-trimethylammonium-propane chloride (DSTAP), a cationic lipid, to localize a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity (PerC) for enhancing the immune response against cancer that had spread to the PerC. The liposomes delivered by intraperitoneal injection increased peritoneal retention of R848 by 14-fold while retarding its systemic absorption, leading to a 5-fold decreased peak plasma concentration compared to free R848 in mice. Within the PerC, the DSTAP-liposomes were found in ~40% of the dendritic cells by flow cytometry. DSTAP-R848 significantly upregulated interferon α (IFN-α) in the peritoneal fluid by 2-fold compared to free R848, without increasing the systemic level. Combined with oxaliplatin, a cytotoxic agent inducing immunogenic cell death, DSTAP-R848 effectively inhibited the progression of CT26 murine colorectal tumor in the PerC, while the combination with free R848 only showed a mild effect. Moreover, the combination of oxaliplatin and DSTAP-R848 significantly increased infiltration of CD8+ T cells in the PerC compared to oxaliplatin combined with free R848, indicating enhanced immune response against the tumor. The results suggest that DSTAP-R848 exhibits potential in augmenting existing therapies for treating colorectal cancer with peritoneal metastases via immune activation.

Simultaneous Chromatographic Quantitation of Drug Substance and Excipients in Nanoformulations Using a Combination of Evaporative Light Scattering and Absorbance Detectors

“…Resiquimod (R848) is a small molecule immunotherapeutic investigated for the treatment of different cancers and infectious diseases. , We developed R848-loaded cationic liposomes comprising of DSTAP, DSPC, and Chol (Lipo-R848) to retain the drug in the peritoneal cavity for enhanced therapy of peritoneal metastases of colorectal cancer . To evaluate the storage stability of Lipo-R848, we utilized the HPLC-UV/vis-ELS method described above to monitor the concentration of the drug and all excipients.…”

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

“…In order to prevent side effects after the systemic administration of TLR agonists, new methods of administering them are currently being researched to reduce the exposure of the patient’s healthy tissues to drugs and to better confine the drugs to the tumor. For this purpose, the use of liposomes [ 132 , 133 , 134 ], hydrogels [ 116 , 135 ], immune implants [ 136 ], and pH-responsive nanoparticles [ 137 ], which include a TLR agonist alone or in combination with other drugs, is being investigated.…”

Application of lipid-based nanoparticles in cancer immunotherapy

“…TLR7/8/9 agonists are widely studied as antitumor adjuvants. Imidaziquinoline-like TLR 7/8 agonists, including imiquimod and resiquimod (R848), was loaded into the liposomal formulation to prolong its retention time in blood circulation ( 96 ). When considering the poor water solubility of TLR7/8 agonists, NEs formulation is also a suitable delivery platform to improve drug solubility thus the drug loading ( 63 ).…”