Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer
Autor: | Zhu Qin, Roland Böttger, Po-Han Chao, Suen Ern Lee, Griffin Pauli, Shyh-Dar Li |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
liposomes
Colorectal cancer medicine.medical_treatment Pharmaceutical Science Article 03 medical and health sciences chemistry.chemical_compound Peritoneal cavity 0302 clinical medicine Pharmacy and materia medica resiquimod medicine 030304 developmental biology 0303 health sciences business.industry Peritoneal fluid peritoneal metastasis of cancer Cancer Immunotherapy toll-like receptor agonist medicine.disease 3. Good health Oxaliplatin RS1-441 medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis drug delivery Cancer research Immunogenic cell death immunotherapy Resiquimod business medicine.drug |
Zdroj: | Pharmaceutics, Vol 13, Iss 1696, p 1696 (2021) Pharmaceutics Volume 13 Issue 10 |
ISSN: | 1999-4923 |
Popis: | 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. |
Databáze: | OpenAIRE |
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