2 research outputs found
Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy
Tumor-induced expansion of myeloid-derived suppressor cells (MDSCs) is known to impair the efficacy of cancer immunotherapy. Among pharmacological approaches for MDSC modulation, chemotherapy with selected drugs has a considerable interest due to the possibility of a rapid translation to the clinic. However, such approach is poorly selective and may be associated with dose-dependent toxicities. In the present study, we showed that lipid nanocapsules (LNCs) loaded with a lauroyl-modified form of gemcitabine (GemC12) efficiently target the monocytic MDSC subset. Subcutaneous administration of GemC12-loaded LNCs reduced the percentage of spleen and tumor-infiltrating M-MDSCs in lymphoma and melanoma-bearing mice, with enhanced efficacy when compared to free gemcitabine. Consistently, fluorochrome-labeled LNCs were preferentially uptaken by monocytic cells rather than by other immune cells, in both tumor-bearing mice and human blood samples from healthy donors and melanoma patients. Very low dose administration of GemC12-loaded LNCs attenuated tumor-associated immunosuppression and increased the efficacy of adoptive T cell therapy. Overall, our results show that GemC12-LNCs have monocyte-targeting properties that can be useful for immunomodulatory purposes, and unveil new possibilities for the exploitation of nanoparticulate drug formulations in cancer immunotherapy
Modified antimetabolites-loaded lipid nanocapsules to enhance antitumor immunity
Introduction : Myeloidderived suppressor cells (MDSCs) are critical players of tumorinduced
immunosuppression in mouse models and cancer patients. They accumulate in the spleen and cancers of tumorbearing hosts where they suppress Tcell activation, proliferation and cytotoxic function [1]. Previous studies demonstrated that some anticancer agents, in addition to their cytotoxic effects on tumor cells, were able to affect MDSCs. This occurs for antimetabolites like 5fluorouracile (5FU) and Gemcitabine (Gem) [2]. In this work, the potential activity of novel lipophilic 5FU and Gem derivatives encapsulated into lipid nanocapsules (LNCs) to target monocytic (M)MDSC subset and tumor cells (pancreatic B6KPC3) was assessed. The aim was to study the immunogenic and anticancer properties of innovative nanosystems.
Methods: Gem and 5FU were modified to obtain monolauroylderivatives (GemC12 and 5FUC12). The
derivatives were purified by chromatography on silica column and characterized by nuclear magnetic
resonance. Blank and loadedLNCs were prepared using the phase inversion process [3]. Physicochemical characterization (size, dispersity, zeta potential and encapsulation efficiency) was performed. To study the in vitro induction of MMDSCs, the immunosuppressive activity and internalization assays of GemC12loaded LNCs, mouse bone marrow cells cultured in presence of GMCSF and IL6 were used. To investigate the efficacy of 5FUC12loaded LNCs, B6KPC3 cells were employed. Finally, as a preliminary
in vivo study, the biodistribution of fluorescentloaded LNCs (i.v. or s.c.) using tumorbearing mice (EG7OVA subcutaneous model) was evaluated.
Results: Lipophilic derivatives, 5FUC12 and GemC12, were synthetized. The yield of the products recovered was 60% and 40% for 5FUC12 and GemC12, respectively. Blank, 5FUC12 and GemC12loaded LNCs showed an average size of 60 nm, dispersity index below 0.1 and neutral surface charge. The encapsulation efficiency of drugs was close to 100%. In vitro and in vivo studies highlighted that GemC12loaded LNCs were internalized and depleted selectively MMDSCs. Using K6PC3, we demonstrated that 5FUC12loaded LNCs exerted a toxic effect comparable to the commercial 5FUsolution. In vivo studies following i.v. or s.c. administration of fluorescentloaded LNCs showed that LNCs reached peripheral tissues. As compared with i.v., following s.c. injection, fluorescent signal increased with time in the spleen, suggesting a slow LNCs absorption.
Conclusions : In the present study, lipophilic 5FUC12 and GemC12loaded LNC were obtained. GemC12
loaded LNCs were able to target MMDSCs in vivo and in vitro. Besides, 5FUC12loaded LNCs showed
efficacy as anticancer drug in a pancreatic cell line. Further in vitro and in vivo therapeutic evaluations would disclose the full potential of these novel LNCs.