title: Photoactivation of Diiodido-Pt(IV) Complexes Coupled to Upconverting Nanoparticles.
abstract: The preparation, characterization, and surface modification of upconverting lanthanide-doped hexagonal NaGdF4 nanocrystals attached to light sensitive diiodido-Pt(IV) complexes is presented. The evaluation for photoactivation and cytotoxicity of the novel carboxylated diiodido-Pt(IV) cytotoxic prodrugs by near-infrared (NIR) light (λ = 980 nm) is also reported. We attempted two different strategies for attachment of light-sensitive diiodido-Pt(IV) complexes to Yb,Er- and Yb,Tm-doped β-NaGdF4 upconverting nanoparticles (UCNPs) in order to provide nanohybrids, which offer unique opportunities for selective drug activation within the tumor cells and subsequent spatiotemporal controlled drug release by NIR-to-visible light-upconversion: (A) covalent attachment of the Pt(IV) complex via amide bond formation and (B) carboxylate exchange of oleate on the surface of the UCNPs with diiodido-Pt(IV) carboxylato complexes. Initial feasibility studies showed that NIR applied by a 980 nm laser had only a slight effect on the stability of the various diiodido-Pt(IV) complexes, but when UCNPs were present more rapid loss of the ligand-metal-charge transfer (LMCT) bands of the diiodido-Pt(IV) complexes was observed. Furthermore, Pt released from the Pt(IV) complexes platinated calf-thymus DNA (ct-DNA) more rapidly when NIR was applied compared to dark controls. Of the two attachment strategies, method A with the covalently attached diiodido-Pt(IV) carboxylates via amide bond formation proved to be the most effective method for generating UCNPs that release Pt when irradiated with NIR; the released Pt was also able to bind irreversibly to calf thymus DNA. Nonetheless, only ca. 20% of the Pt on the surface of the UCNPs was in the Pt(IV) oxidation state, the rest was Pt(II), indicating chemical reduction of the diiodido-Pt(IV) prodrug by the UCNPs. Cytotoxicity studies with the various UCNP-Pt conjugates and constructs, tested on human leukemia HL60 cells in culture, indicated a substantial increase in cytotoxicity when modified UCNPs were combined with five rounds of 30 min irradiation with NIR compared to dark controls, but NIR alone also had a significant cytotoxic effect at this duration.
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt University of Greifswald , 17487 Greifswald, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Perfahl
authors.affiliation: CNR-ICMATE, Department of Chemical Sciences, University of Padova , 35131 Padova, Italy.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Natile
authors.affiliation: Institute of Physics, Ernst-Moritz-Arndt University of Greifswald , 17487 Greifswald, Germany.
authors.forename: Heba S
authors.initials: HS
authors.lastname: Mohamad
authors.affiliation: Institute of Physics, Ernst-Moritz-Arndt University of Greifswald , 17487 Greifswald, Germany.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Helm
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt University of Greifswald , 17489 Greifswald, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Schulzke
authors.affiliation: Department of Chemistry, University of Bari , 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt University of Greifswald , 17487 Greifswald, Germany.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D006801:Humans; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry; D010777:Photochemistry / Q000379:methods*; D011355:Prodrugs / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011355:Prodrugs; D004247:DNA; C427203:calf thymus DNA
keywords: anticancer prodrug; photoactivatable Pt complexes; photoactivated chemotherapy; upconverting nanoparticles