zn(ii)-phthalocyanine and 2-4-dinitrobenzenesulfonic-acid

A combined stimulus-responsive photosensitiser and drug release system based on mesoporous silica nanoparticles was prepared. This nanoplatform encapsulated molecules of zinc(ii) phthalocyanine substituted with a glutathione-cleavable 2,4-dinitrobenzenesulfonate quencher and doxorubicin linked via a singlet-oxygen-cleavable 9,10-dialkoxyanthracene linker. In the presence of glutathione (in mM range) and upon irradiation (λ > 610 nm), the phthalocyanine units were activated by detaching from the quenching component to emit fluorescence and generate singlet oxygen. The latter subsequently cleaved the 9,10-dialkoxyanthracene linker to trigger the release of a doxorubicin derivative. The glutathione- and light-controlled activation and drug-release processes on this nanoplatform were demonstrated in phosphate buffered saline. The activation in fluorescence emission by intracellular thiols was also shown inside HepG2 human hepatocellular carcinoma cells. Upon irradiation, the nanosystem exhibited high cytotoxicity due to the photodynamic effect of the activated phthalocyanine units, but the cytotoxic effect of the released Dox moieties was not notable probably due to their reduced cytotoxicity as a result of the pendant substituent and the low drug loading in the nanoparticles.

Topics: Antibiotics, Antineoplastic; Benzenesulfonates; Delayed-Action Preparations; Doxorubicin; Drug Liberation; Glutathione; Hep G2 Cells; Humans; Indoles; Isoindoles; Light; Nanoparticles; Organometallic Compounds; Porosity; Silicon Dioxide; Singlet Oxygen; Zinc Compounds

A novel molecular therapeutic agent was designed and synthesized, which contains three functional components, namely, a zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate (DNBS) group as a glutathione (GSH)-activated photosensitizer, a chemo-prodrug based on combretastatin A-4 (CA4) with a singlet oxygen-cleavable aminoacrylate linker, and a biotin moiety as a tumor-targeting ligand. The conjugate showed preferential uptake toward the biotin-receptor-positive HepG2 cells compared with the low biotin-receptor-expressed HCT-116 cells used as the negative control, resulting in the restoration of the fluorescence emission and singlet oxygen generation upon removal of the DNBS group by intracellular GSH. The singlet oxygen produced not only induced a significant photodynamic effect against HepG2 cells but also triggered the cascaded release of the chemocytotoxic CA4, leading to synergistic cytotoxicity as shown by the less-than-unity combination index.

Topics: Antineoplastic Agents; Benzenesulfonates; Bibenzyls; Drug Delivery Systems; Glutathione; HCT116 Cells; Hep G2 Cells; Humans; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Prodrugs; Zinc Compounds