Pharmacokinetics of an anticancer drug: liposomal formulation of docetaxel

Book of abstractInternational audienc

Pharmacokinetics of an anticancer drug: liposomal formulation of docetaxel

Book of abstractInternational audienc

Nanoliposomes harness tumor immunity in breast cancer model

International audienc

Nanoliposomes harness tumor immunity in breast cancer models

International audienceThe effect on the immune system of nanoparticles is poorly described. The aim of this study was to analyze in immuno-competent BalbC mice bearing or not 4T1 murine breast cancers, the impact on immune system of blank liposomes (i.e., Lipo) or blank immunoliposomes grafted with trastuzumab with a maleimide linker (i.e., ANC). Both nanoparticles were 120 nm of diameter and were pegylated. Mice were administered with saline solution (Control) or treated with either Lipo or ANC with single-dosing (SD) or multiple-dosing (MD). Impact on immunity in blood, spleen and tumors was monitored in a longitudinal fashion in blood for up to 8 weeks, and once per animal in spleen and tumors (i.e., D18 or D23). Immune cells were analyzed by flow cytometry. In tumor-free mice, in blood a transient increase in B-cells between D7 and D15 was found (p= 0,003; &amp;lt; 0,001 and 0,009, t test) for ANC-MD, Lipo-SD and Lipo-MD, respectively. Of note, mice treated with ANC-MD exhibited persistent increase in B-cells up to 8 weeks. Regarding T-cells, a transient increase of CD4+ and CD8+ lymphocytes from D0 to D15 was observed. In spleen, more CD4+ T-cells than CD8+ cells were found, both with Lipo and ANC. Blank Lipo or blank ANC did not impact the tumor growth as compared with Control, and tumor sizes were comparable among all groups. In tumor-bearing mice, in blood little difference between B-cells was observed among the groups. Considering T-cells, a significant diminution in CD4+ cells was observed throughout time in mice treated with either ANC or Lipo (p=0.029, Anova). Conversely, a sharp increase in CD8+ cells as compared with Control group was observed between D18 and D23 for all the treatment arms (p&amp;lt;0.05, Anova). Of note, ANC-MD and Lipo-MD showed significantly higher CD8+ as compared with SD treatments. In spleen, more CD8+ cells than CD4+ cells were found. Still, CD4+ T-cells tended to increase, including in the Control group, between D18 and D23, whereas no such increase was observed for CD8+ cells. In treated animals, a sharp increase in FOXP3 CD4+ Tregs was observed in spleen. In tumors, B-cells increased in Control group but decreased in both Lipo and ANC-treated animals. A marked decrease in CD4+ cells was observed in Control group, whereas little change was observed in treated mice. Conversely, a sharp increase in CD8+ was observed, especially in mice treated with Lipo-MD and ANC-SD. Interestingly, no Tregs were found in treated mice (i.e., either Lipo or ANC) on D23, whereas Tregs were still observed in Control group. As a conclusion, our data suggest that nanoparticles can reshape tumor immunity indeed. Little difference was found between ANC and Lipo, suggesting the immunomodulating features we observed are probably supported by the pegylated liposomes, and not the grafted trastuzumab. Increase in CD8+ cells in blood and tumors, associated with decrease in Tregs in tumors, suggest that liposomal nanoparticles could help turning cold tumors into hot ones. Citation Format: Mathilde Dacos, Guillaume Sicard, Benoit Immordino, Sarah Giacometti, Joseph Ciccolini, Anne Rodallec, Raphaelle Fanciullino. Nanoliposomes harness tumor immunity in breast cancer models [abstract].</jats:p

Granulocyte microvesicles with a high plasmin generation capacity promote clot lysis and improve outcome in septic shock

International audienceAbstract Microvesicles (MVs) have previously been shown to exert profibrinolytic capacity, which is increased in patients with septic shock (SS) with a favorable outcome. We, therefore, hypothesized that the plasmin generation capacity (PGC) could confer to MVs a protective effect supported by their capacity to lyse a thrombus, and we investigated the mechanisms involved. Using an MV-PGC kinetic assay, ELISA, and flow cytometry, we found that granulocyte MVs (Gran-MVs) from SS patients display a heterogeneous PGC profile driven by the uPA (urokinase)/uPAR system. In vitro, these MVs lyse a thrombus according to their MV-PGC levels in a uPA/uPAR-dependent manner, as shown in a fluorescent clot lysis test and a lysis front retraction assay. Fibrinolytic activators conveyed by MVs contribute to approximately 30% of the plasma plasminogenolytic capacity of SS patients. In a murine model of SS, the injection of high PGC Gran-MVs significantly improved mouse survival and reduced the number of thrombi in vital organs. This was associated with a modification of the mouse coagulation and fibrinolysis properties toward a more fibrinolytic profile. Interestingly, mouse survival was not improved when soluble uPA was injected. Finally, using a multiplex array on plasma from SS patients, we found that neutrophil elastase correlates with the effect of high-PGC-capacity plasma and modulates the Gran-MV plasmin generation capacity by cleaving uPA-PAI-1 complexes. In conclusion, we show that the high PGC level displayed by Gran-MVs reduces thrombus formation and improves survival, conferring to Gran-MVs a protective role in a murine model of sepsis