Reversing cold tumors to hot: An immunoadjuvant-functionalized metalorganic framework for multimodal imaging-guided synergistic photoimmunotherapy

Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity.Herein,we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF(MIL101-NH2)as the core carrier;the MOF was dual-dressed with photoacoustic and fluorescent signal donors(indocyanine green,ICG)and immune adjuvants(cytosine-phosphate-guanine sequence,CpG)and named ICGCpG@MOF.This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging(fluorescence,photoacoustic,photothermal and magnetic resonance imaging)of the tumor.Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation.ICG-CpG@MOF achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment.Furthermore,the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system,which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects.This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.

Effect of Fluorine Atoms and Piperazine Rings on Biotoxicity of Norfloxacin Analogues:Combined Experimental and Theoretical Study

To clarify the effect of the fluorine atom and piperazine ring on norfloxacin(NOR),NOR degradation products(NOR-DPs,P1−P8)were generated via UV combined with hydrogen peroxide(UV/H2O2)technology.NOR degradation did not significantly affect cytotoxicity of NOR against BV2,A549,HepG2,and Vero E6 cells.Compared with that of NOR,mutagenicity and median lethal concentration of P1−P8 in fathead minnow were increased,and bioaccumulation factor and oral median lethal dose of P1−P8 in rats were decreased.Molecular docking was used to evaluate the inhibitory effect of DNA gyrase A(gyrA)on NOR-DPs to determine the molecular-level mechanism and establish the structure−activity relationship.Results indicated that the most common amino acid residues were Ile13,Ser27,Val28,Gly31,Asp36,Arg46,Arg47,Asp157,and Gly340;hydrogen bonds and hydrophobic interactions played key roles in the inhibitory effect.Binding area(BA)decreased from 350.80Å2(NOR)to 346.21Å2(P1),and the absolute value of binding energy(|BE|)changed from 2.53 kcal/mol(NOR)to 2.54 kcal/mol(P1),indicating that the fluorine atom mainly affects BA.The piperazine ring clearly influenced BA and|BE|.“Yang ChuanXi Rules”were used to explain effects of molecular weight(MW),BA,|BE|,and sum ofη1+η2(η1:normalization of BA,η2:normalization of|BE|)and predict biotoxicity of NOR-DPs based on half-maximum inhibitory concentration(IC50),half-minimal inhibitory concentration(MIC50),and half-minimal bactericidal concentration(MBC50)values.