Aqueous-phase synthesis of upconversion metal-organic frameworks for ATP-responsive in situ imaging and targeted combinational cancer therapy

Herein,the nanoscaled ATP-responsive upconversion metal-organic frameworks(UCMOFs)are aqueousphase synthesized for co-delivery of therapeutic protein cytochrome c(Cyt c)and chemodrugs doxorubicin(DOX),achieving targeted combinational therapy of human cervical cancer.The UCMOFs are rationally fabricated by growing ZIF-90 on mesoporous silica-coated upconversion nanoparticles(UCNPs),in which the ZIF-90 layer attenuates the upconversion luminescence(UCL)and the rigid frameworks increase the stability of encapsulated proteins.Once the UCMOF@DOX/Cyt c are internalized into HeLa cells via specific recognition of sgc8 aptamers,the intracellular ATP triggers the dissolution of ZIF-90 into Zn^(2+),which facilitates not only the release of Cyt c and DOX but also the restoration of UCL for real-time monitoring of drug release.It has been demonstrated that the therapeutic efficacy is greatly improved by the combination of caspase-mediated apoptosis activated by Cyt c(protein therapeutics),DNA fragmentation induced by DOX(chemotherapy),and Zn;-promoted generation of reactive oxygen species(ROS)(oxidative stress).Overall,our proposed multifunctional UCMOFs provide an effective platform for targeted combinational cancer therapy and in situ imaging,which hold great promise in biomedical and clinical applications.

Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

More than 85%of patients with uveal melanoma(UM)carry a GNAQ or GNA11 mutation at a hotspot codon(Q209)that encodes G proteinαsubunit q/11 polypeptides(Gα_(q/11)).GNAQ/11 relies on palmitoylation for membrane association and signal transduction.Despite the palmitoylation of GNAQ/11 was discovered long before,its implication in UM remains unclear.Here,results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells.Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^(Q209L)-induced malignant transformation in NIH3T3 cells.Importantly,the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells,which are much more dependent on Gα_(q/11) signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations.Furthermore,the palmitoylation inhibitor,2-bromopalmitate,also specifically disrupted Gα_(q/11) downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor,ABT-199,in vitro.The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.