Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.

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A low-cost, simple, and one-step synthesis of cellulose acetate nanoparticles (CANPs) has been invented using a continuous-flow advanced microfluidic reactor. For this purpose, the CANPs are self-organized inside a cross-junction microchannel by flowing cellulose acetate (CA) dissolved in N,N-dimethylformamide (DMF) through the axial inlet and the antisolvent water through the pair of side inlets. The preferential solubility (insolubility) of DMF (CA) to antisolvent water stimulates the in situ synthesis of CANPs at the DMF/water miscible interface following a phase-inversion process. Subsequently, nanofiltration, ultrafiltration, and microfiltration membranes of different porosities and permeabilities have been prepared from freshly synthesized CANPs. The porosity, thickness, transparency, and wettability of the membranes are tuned by varying the thickness of the membranes, size of the nanoparticles, and the porosity of the membranes. The as-synthesized CANPs show enhanced bactericidal properties with and without loading an external drug, curcumin, which has been validated against the Gram-negative Pseudomonas aeruginosa species. Importantly, enabling a pulsatile flow during the synthesis, the CANPs are embedded as nanofiltration membranes inside the microfluidic channel. Such microfluidic devices have been used to separate a corrosive dye from water. Concisely, the proposed in situ synthesis of CANPs in the continuous-flow microfluidic reactors, their usage for fabricating membranes with tunable wettability and transparency, and their subsequent integration into the microfluidic channel show the potential of the invention for a host of applications related to health care and environmental remediation.

Uveal melanoma (UM) originating in the eye and metastasizing to the liver is associated with poor prognosis. Here, we investigated whether the IGF-1/IGF-1R signaling axis is involved in UM growth and metastasis. TCGA dataset analysis reveals that UM has high IRS-1 expression, which is the first substrate of IGF-1R. Furthermore, IRS-1 is over-expressed in all UM cell lines tested (relative to non -cancer/normal cells) and in matched eye and liver UM tumors. Therefore, we targeted IRS-1/2 in UM cells as well as UM tumors developed on a chicken egg chorioallantoic membrane (CAM) model, and subcutaneous (subQ) UM tumors grown in mice using NT157, a small molecule inhibitor of IRS-1/2. NT157 treatment in UM cells resulted in reduced cell survival and cell migration, and increased apoptosis. NT157 treatment also significantly inhibited UM tumor growth in the in vivo chicken egg CAM and subQ mouse models, validating the in vitro effect. Moreover, NT157 appears more effective than a monoclonal antibody-based approach to block IGF-1R signaling. Mechanistically, through reverse phase protein array (RPPA) analysis, we identified significant proteomic changes in the PI3K/AKT pathway with NT157 treatment. Together, these results suggest that NT157 inhibits cell survival, migration in vitro and tumor growth in vivo via inhibiting IGF-1 signaling in UM cells.