Micellar formulations of Crizotinib and Dasatinib in the management of glioblastoma multiforme.

Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation.

Styrene maleic acid encapsulated raloxifene micelles for management of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) comprises a group of disorders that manifest through chronic inflammation of the colon and small intestine. Although the exact cause of IBD is still unclear, dysfunctional immunoregulation involving overproduction of inflammatory cytokines such as TNF-α, and IL-6 have been implicated in pathogenesis. Current therapy relies on immunosuppression, cytotoxic drugs, and monoclonal antibodies against TNF-α. These classes of drugs have severe side-effects, especially when used for long duration. Our previous work with raloxifene, a selective estrogen receptor modulator, has shown that the drug, and to a greater extent its micellar formulation, has a significant suppressive effect on NF-κB, an essential immune-regulator. This finding directed the current work towards testing the anti-inflammatory and immunomodulatory effects of raloxifene using cell lines, as well as testing the potential use of the styrene maleic acid (SMA) micelles loaded with raloxifene (SMA-Ral) against dextran sulfate sodium (DSS) induced colitis in an in vivo model of IBD. RESULTS: Treatment of MCF-7 cells with TNF-α was shown to protect the cells from the cytotoxic effect of raloxifene (42 vs. 10% cell death, with TNF-α. Treating CaCo-2 cells with both free and SMA-Ral improved cell survival after exposure to 2% DDS with significantly higher protection with SMA-Ral. Treatment of U-937 with SMA-Ral and free-Ral resulted in down-regulation of TNF-α, IL-1ß, IL-6, and MIP1α, with greater inhibition of the SMA-Ral, compared to free Ral. Balb/c mice treated with raloxifene and SMA-Ral showed weight gain at 14 days, compared to the control group (122, and 115% respectively). Treatment with raloxifene prevented DSS-induced diarrhea in 6/6 of free raloxifene treated mice and in 5/6 mice treated with SMA-Ral. Control group of DSS-treated mice showed average colon length of 7.4 cm compared to 13 cm in the control group. The average colon length was 12.3 and 11.5 cm for raloxifene and SMA-Ral treated groups, respectively. Furthermore, inflammatory cytokines such as IL-6 and TNF-α were reduced in serum of animals treated with free-Ral and SMA-Ral. CONCLUSIONS: Raloxifene and its micellar formulation warrants further studies to understand their effect on the treatment of colitis. Graphical abstract SMA-Raloxifene preparation and its in vivo and in vitro effect on colitis.