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Poster De Conférence Année : 2017

Modified antimetabolites-loaded lipid nanocapsules to enhance antitumor immunity

Résumé

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. 
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Dates et versions

hal-02616009 , version 1 (24-05-2020)

Identifiants

  • HAL Id : hal-02616009 , version 1
  • OKINA : ua16114

Citer

Giovanna Lollo, Martina Bocchiardo, Kevin Matha, Marion Pitorre, Guillaume Bastiat, et al.. Modified antimetabolites-loaded lipid nanocapsules to enhance antitumor immunity. 44th Annual Meeting & Exposition of the Controlled Release Society, 2017, Boston, United States. , 2017. ⟨hal-02616009⟩
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