Polycyclodextrin (denoted PCD) composed of cyclodextrin monomer units and 1,3-diethoxypropan-2-ol containing many hydroxyl groups with lone pairs of electrons, easily coordinated with transition metals with empty orbitals. The CD unit can also provide host-guest binding sites for functional molecules. This article utilizes this feature of PCD for the first time as a "linker" to combine transition metal nanomaterials with synergistic functional molecules. We synthesized PCD with 50% CD monomer by epichlorohydrin cross-linking method. Utilizing the coordination effect of the hydroxyl group in PCD and the iron ion in photothermal nanoparticles (PB-Yb), the PCD is coated on its surface; simultaneously, CD in PCD can form a host-guest complex with adamantane-modified zinc phthalocyanine (Pc) photosensitizer. Using PCD as a "linker", PB-Yb and Pc (denoted PYPP) were combined to improve the solubility of PB-Yb, reduce the aggregation degree of Pc to increase their activity, and achieve photothermal and photodynamic synergistic tumor therapy.
Antineoplastic Agents/therapeutic use , Cyclodextrins/chemistry , Nanoparticles/chemistry , Neoplasms/drug therapy , Photosensitizing Agents/therapeutic use , Polymers/chemistry , Adamantane/radiation effects , Adamantane/therapeutic use , Animals , Cyclodextrins/toxicity , Female , Ferrocyanides/chemistry , Ferrocyanides/toxicity , HeLa Cells , Humans , Isoindoles/radiation effects , Isoindoles/therapeutic use , Light , Mice, Inbred BALB C , Nanomedicine/methods , Nanoparticles/toxicity , Neoplasms/metabolism , Organometallic Compounds/radiation effects , Organometallic Compounds/therapeutic use , Photosensitizing Agents/radiation effects , Polymers/toxicity , Reactive Oxygen Species/metabolism , Ytterbium/chemistry , Ytterbium/toxicity , Zinc Compounds/radiation effects , Zinc Compounds/therapeutic use
The discovery of salutary effects of low doses of carbon monoxide (CO) has spurred interest in designing exogenous molecules that can deliver CO to biological targets under controlled conditions. Herein we report a water-soluble photosensitive manganese carbonyl complex [MnBr(CO)3(pyTAm)] (2) (pyTAm = 2-(pyridyl)imino-triazaadamantane) that can be triggered to release CO upon exposure to visible light. Inclusion of a triazaadamantyl pharmacophore into the coligand of 2 improves its stability and solubility in water. Change in the coligand from 2-(pyridyl)imino-triazaadamantane to 2-(pyridyl)iminoadamantane (pyAm) or 2-(quinonyl)imino-triazaadamantane (qyTAm) dramatically alters these desired properties of the photoCORM. In addition to structures and CO-releasing properties of the three analogous complexes 1-3 from these three α-diimine ligands, theoretical calculations have been performed to determine the origin of Mn-CO bond labilization upon illumination. Rapid delivery of CO to myoglobin under physiological conditions attests the potential of 2 as a biocompatible photoCORM.
Adamantane/analogs & derivatives , Adamantane/chemistry , Carbon Monoxide/chemistry , Coordination Complexes/chemistry , Manganese/chemistry , Adamantane/radiation effects , Coordination Complexes/radiation effects , Ligands , Light , Manganese/radiation effects , Myoglobin , Solubility
Spiro[adamantane-2,2'-diazirine], which produces adamantyl carbene upon photolysis, binds tightly to P450 2B4 (KS = 3.2 microM), giving a normal substrate binding difference spectrum. Irradiation of 2-[3H]adamantane diazirine at 365 nm in the presence of native, ferric P450 2B4 resulted in first-order photolysis (t1/2 = 1.8 min). The main product was 2-[3H]adamantanol, with about 6% of the radioactivity covalently bound to P450 2B4. With the ferrous carbonyl form of P450 2B4, 2-adamantanol production decreased and protein labeling increased to 12%. When ferric cyanide 2B4 was used, 2-adamantanecarbonitrile was formed in addition to 2-adamantanol. The nitrile appears to have resulted from capture of the iron-bound cyanide ligand by the carbene. The use of multiple cycles of photolysis increased the percentage of protein labeling to 76%. Photolabeling was inhibited by known 2B4 substrates and inhibitors. Also, N-demethylation of benzphetamine and generation of a substrate binding difference spectrum by benzphetamine were both inhibited stoichiometrically with the fraction of radiolabeled protein. The labeled protein was permanently converted to the high-spin state, as indicated by the characteristic change in the absorbance spectrum, demonstrating irreversible occupation of the substrate binding site by the adamantyl residue. Mild acid hydrolysis of radiolabeled 2B4 at the five Asp-Pro bonds generated a 2-kDa peptide which carried 78% of the radioactivity. These results are interpreted as the result of the active site carbene reacting by three competing pathways: capture of the heme sixth ligand to yield either 2-adamantanol or 2-adamantanecarbonitrile, capture of an unbound active site water molecule to yield adamantanol, and covalent attachment to a protein residue. Thus, the P450 2B4 active site appears to contain at least one unbound water molecule in addition to the heme aquo sixth ligand, even when substrate is present.
Adamantane/analogs & derivatives , Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/metabolism , Steroid Hydroxylases/metabolism , Adamantane/metabolism , Adamantane/radiation effects , Affinity Labels , Alcohols/metabolism , Binding Sites , Heme/metabolism , Ligands , Models, Chemical , Photolysis , Spectrophotometry , Water/metabolism
