Heavy atom effect and configuration are important for BODIPY derivatives to generate singlet oxygen (O) for photodynamic therapy. Herein, a series of BODIPY derivatives with different halogens were synthesized. O quantum yields (QYs) and MTT assay confirm that incorporation of more heavy atoms onto dimeric BODIPY cannot effectively enhance the O QYs. Rather, the dark toxicity increases. This phenomenon can be attributed to the competition of heavy atom effect and configuration of dimeric BODIPY. In addition the BODIPY derivative with two iodine atoms (BDPI) owns the highest O QYs (73%) and the lowest phototoxicity IC (1 μM). Furthermore, an in vivo study demonstrates that BDPI NPs can effectively inhibit tumor growth and can be used as a promising threanostic agent for photodynamic therapy in clinic.
NF-κB signaling plays a critical role in tumor growth and treatment resistance in GBM as in many other cancers. However, the molecular mechanisms underlying high, constitutive NF-κB activity in GBM remains to be elucidated. Here, we screened a panel of tripartite motif (TRIM) family proteins and identified TRIM22 as a potential activator of NF-κB using an NF-κB driven luciferase reporter construct in GBM cell lines. Knockout of TRIM22 using Cas9-sgRNAs led to reduced GBM cell proliferation, while TRIM22 overexpression enhanced proliferation of cell populations, in vitro and in an orthotopic xenograft model. However, two TRIM22 mutants, one with a critical RING-finger domain deletion and the other with amino acid changes at two active sites of RING E3 ligase (C15/18A), were both unable to promote GBM cell proliferation over controls, thus implicating E3 ligase activity in the growth-promoting properties of TRIM22. Co-immunoprecipitations demonstrated that TRIM22 bound a negative regulator of NF-κB, NF-κB inhibitor alpha (IκBα), and accelerated its degradation by inducing K48-linked ubiquitination. TRIM22 also formed a complex with the NF-κB upstream regulator IKKγ and promoted K63linked ubiquitination, which led to the phosphorylation of both IKKα/β and IκBα. Expression of a non-phosphorylation mutant, srIκBα, inhibited the growth-promoting properties of TRIM22 in GBM cell lines. Finally, TRIM22 was increased in a cohort of primary GBM samples on a tissue microarray, and high expression of TRIM22 correlated with other clinical parameters associated with progressive gliomas, such as wild-type IDH1 status. In summary, our study revealed that TRIM22 activated NF-κB signaling through posttranslational modification of two critical regulators of NF-κB signaling in GBM cells.
A novel NIR absorbing aza-BODIPY photosensitizer with high 1O2 quantum yield and excellent photothermal conversion efficiency was designed for synergistic phototherapy.
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