Light-Sensitive Phenacyl Crosslinked Dextran Hydrogels for Controlled Delivery.

Stimuli-responsive soft materials enable controlled release of loaded drug molecules and biomolecules. Controlled release of potent chemotherapeutic or immunotherapeutic agents is crucial to reduce unwanted side effects. In an effort to develop controlled release strategies that can be triggered by using Cerenkov luminescence, we have developed polymer hydrogels that can release bovine serum albumin and immunoglobulin G by using light (254 nm-375 nm) as a trigger. We describe the synthesis and photochemical characterization of two light sensitive phenacyl bis-azide crosslinkers that are used to prepare transparent self-supporting hydrogel patches. One crosslinker was designed to optimize the overlap with the Cerenkov luminescence emission window, bearing an π-extended phenacyl core, resulting in a high quantum yield (14 %) of photocleavage when irradiated with 375 nm light. We used the extended phenacyl crosslinker for the preparation of protein-loaded dextran hydrogel patches, which showed efficient and selective dosed release of bovine serum albumin or immunoglobulin G after irradiation with 375 nm light. Cerenkov-triggered release is as yet inconclusive due to unexpected side-reactivity. Based on the high quantum yield, efficient release and large overlap with the Cerenkov window, we envision application of these photosensitive soft materials in radiation targeted drug release.

Photo cleavable thioacetal block copolymers for controlled release.

We present a new light cleavable polymer containing o-nitrobenzene thioacetal groups in the main chain. By conjugation to a PEG block, we synthesized block copolymers capable of forming nanoparticles in aqueous solution. We studied drug encapsulation and release using the model drug Nile Red. Irradiation with UV-A light (365 nm) leads to efficient degradation of the polymers and associated burst release of the payload. Unlike other thioacetal and thioketal polymers, these polymers are stable to reactive oxygen species (ROS), preventing non-triggered release. Moreover, the nanocarriers showed low cytotoxicity in cell viability experiments.

Tuneable Control of Organocatalytic Activity through Host-Guest Chemistry.

Dynamic regulation of chemical reactivity is important in many complex chemical reaction networks, such as cascade reactions and signal transduction processes. Signal responsive catalysts could play a crucial role in regulating these reaction pathways. Recently, supramolecular encapsulation was reported to regulate the activities of artificial catalysts. We present a host-guest chemistry strategy to modulate the activity of commercially available synthetic organocatalysts. The molecular container cucurbit[7]uril was successfully applied to change the activity of four different organocatalysts and one initiator, enabling up- or down-regulation of the reaction rates of four different classes of chemical reactions. In most cases CB[7] encapsulation results in catalyst inhibition, however in one case catalyst activation by binding to CB[7] was observed. The mechanism behind this unexpected behavior was explored by NMR binding studies and pKa measurements. The catalytic activity can be instantaneously switched during operation, by addition of either supramolecular host or competitive binding molecules, and the reaction rate can be predicted with a kinetic model. Overall, this signal responsive system proves a promising tool to control catalytic activity.

Conditional Copper-Catalyzed Azide-Alkyne Cycloaddition by Catalyst Encapsulation.

Supramolecular encapsulation is known to alter chemical properties of guest molecules. We have applied this strategy of molecular encapsulation to temporally control the catalytic activity of a stable copper(I)-carbene catalyst. Encapsulation of the copper(I)-carbene catalyst by the supramolecular host cucurbit[7]uril (CB[7]) resulted in the complete inactivation of a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The addition of a chemical signal achieved the near instantaneous activation of the catalyst, by releasing the catalyst from the inhibited CB[7] catalyst complex. To broaden the scope of our on-demand CuAAC reaction, we demonstrated the protein labeling of vinculin with the copper(I)-carbene catalyst, to inhibit its activity by encapsulation with CB[7] and to initiate labeling at any moment by adding a specific signal molecule. Ultimately, this strategy allows for temporal control over copper-catalyzed click chemistry, on small molecules as well as protein targets.

Effects of the Bidentate Ligand on the Photophysical Properties, Cellular Uptake, and (Photo)cytotoxicity of Glycoconjugates Based on the [Ru(tpy)(NN)(L)]2+ Scaffold.

Ruthenium polypyridyl complexes have received widespread attention as potential chemotherapeutics in photodynamic therapy (PDT) and in photochemotherapy (PACT). Here, we investigate a series of sixteen ruthenium polypyridyl complexes with general formula [Ru(tpy)(N-N)(L)]+/2+ (tpy=2,2':6',2''-terpyridine, N-N=bpy (2,2'-bipyridine), phen (1,10-phenanthroline), dpq (pyrazino[2,3-f][1,10]phenanthroline), dppz (dipyrido[3,2-a:2',3'-c]phenazine, dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine), pmip (2-(4-methylphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), pymi ((E)-N-phenyl-1-(pyridin-2-yl)methanimine), or azpy (2-(phenylazo)pyridine), L=Cl- or 2-(2-(2-(methylthio)ethoxy)ethoxy)ethyl-ß-d-glucopyranoside) and their potential for either PDT or PACT. We demonstrate that although increased lipophilicity is generally related to increased uptake of these complexes, it does not necessarily lead to increased (photo)cytotoxicity. However, the non-toxic complexes are excellent candidates as PACT carriers.

Extremely bulky copper(i) complexes of [HB(3,5-{1-naphthyl}2pz)3]- and [HB(3,5-{2-naphthyl}2pz)3]- and their self-assembly on graphene.

The synthesis and characterization, using NMR (1H and 13C), infrared spectroscopy, and X-ray crystallography, of the ethene and carbon monoxide copper(i) complexes of hydridotris(3,5-diphenylpyrazol-1-yl)borate ([TpPh2]-) and the two new ligands hydridotris(3,5-bis(1-naphthyl)pyrazol-1-yl)borate ([Tp(1Nt)2]-) and hydridotris(3,5-bis-(2-naphthyl)pyrazol-1-yl)borate ([Tp(2Nt)2]-) are described. X-ray crystal structures are presented of [Cu(TpPh2)(C2H4)] and [Cu(Tp(2Nt)2)(C2H4)]. The compound [Cu(TpPh2)(C2H4)] features interactions between the protons of the ethene ligand and the π-electron clouds of the phenyl substituents that make up the binding pocket surrounding the copper(i) center. These dipolar interactions result in strongly upfield shifted signals of the ethene protons in 1H-NMR. [Cu(Tp(1Nt)2)(CO)] and [Cu(Tp(2Nt)2)(CO)] were examined using infrared spectroscopy and were found to have CO stretching vibrations at 2076 and 2080 cm-1 respectively. The copper(i) carbonyl complexes form self-assembled monolayers when drop cast onto HOPG and thin multilayers of a few nanometers thickness when dip coated onto graphene. General macroscopic trends such as the different tendencies to crystallize observed in the complexes of the two naphthyl-substituted ligands appear to extend well to the nanoscale where a well-organized monolayer could be observed of [Cu(Tp(2Nt)2)(CO)].

d- Versus l-Glucose Conjugation: Mitochondrial Targeting of a Light-Activated Dual-Mode-of-Action Ruthenium-Based Anticancer Prodrug.

Light-activated ruthenium polypyridyl anticancer prodrugs often suffer from poor water solubility, poor selectivity, and/or ill-defined intracellular targets. Coordination of the d- or l-glucose thioether ligand 3 (2-(2-(2-(methylthio)ethoxy)ethoxy)ethyl-ß-glucopyranoside) to the highly lipophilic ruthenium complex [Ru(tpy)(dppn)(H2 O)]2+ ([1]2+ ; dppn=benzo[i]dipyrido-[3,2-a:2',3'-c]phenazine, tpy=2,2':6',2''-terpyridine) solved all these problems at once. The two enantiomers of [Ru(tpy)(dppn)(3)][PF6 ]2 , [d-2][PF6 ]2 and [l-2][PF6 ]2 , were soluble in water, which allowed the influence of the chirality of the glucose moiety on uptake, toxicity, and intracellular localization of the prodrug to be probed without changing any other physicochemical properties. Both compounds showed mild, but different, cytotoxicity in A549 (human lung carcinoma) and MCF-7 (human breast adenocarcinoma) cancer cells in the dark, whereas following low doses of visible light irradiation (3.1 J cm-2 at λ = 454 nm), a similar, but high cytotoxicity (EC50 < 1 µm), was observed. Irrespective of the chirality, both slightly emissive Ru complexes were found in the mitochondria, and two modes of action may contribute to light-induced cell death: 1) the glucose thioether ligand is photosubstituted by water, thus [1]2+ , which interacts with DNA at an exceptionally high 400:1 base pair/Ru ratio, is released; 2) both [1]2+ and [2]2+ produce massive amounts of singlet oxygen, which leads to very efficient photodynamic DNA cleavage.