Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.

The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

Biocompatible nanoparticles containing hydrophobic nickel-bis(dithiolene) complexes for NIR-mediated doxorubicin release and photothermal therapy.

Biocompatible nanoparticles (NPs) constituted by amphiphilic poly(ethylene glycol)-block-poly(benzyl malate), PEG-b-PMLABe, have been designed for site-specific PhotoThermal Controlled Release (PTCR) of drugs thanks to the presence of a near infra-red (NIR) photothermally active nickel-bis(dithiolene) complex in the inner core of the NPs, together with doxorubicin (Dox). A nanoprecipitation technique was used to prepare well-defined nickel-bis(dithiolene) and nickel-bis(dithiolene)/Dox loaded NPs, which were characterized by dynamic light scattering (DLS), zeta-potential measurements and Transmission Electron Microscopy (TEM). We have shown that the Dox release was effectively controlled by NIR irradiation (long or pulsed NIR laser irradiation). Cytotoxicity experiments on HeLa and MDA-MB-231 cells have shown that the incorporation of more than 10 w% of nickel-bis(dithiolene) complexes does not increase the intrinsic toxicity of the polymer nanoparticles. Finally, the viability of MDA-MB-231 cells was assessed after their incubation, for 24 hours, with empty NPs, Ni4C12 loaded NPs, Dox loaded NPs or Ni4C12/Dox loaded NPs, without or with NIR irradiation. Above all, the results have highlighted that the Ni4C12 loaded NPs after 5 min NIR laser irradiation can induce strong cell death up to 80% at 50 µg mL-1. These results demonstrate that these NPs are good candidates for photothermal therapy.

Fine and Clean Photothermally Controlled NIR Drug Delivery from Biocompatible Nickel-bis(dithiolene)-Containing Liposomes.

This work demonstrates that metal-bis(dithiolene) complexes can be efficiently incorporated inside organic nanocarriers and, that under near-infrared (NIR) irradiation, their high photothermal activity can be finely used to release encapsulated drugs on demand. In contrast to gold nanoparticles and other organic NIR dyes, nickel-bis(dithiolene) complexes do not produce singlet oxygen under irradiation, a highly desirable characteristic to preserve the chemical integrity and activity of the loaded drug during the NIR-triggered release from the nanocarriers. Finally, cytotoxicity experiments performed on various cell lines have shown that the incorporation of such metal complexes do not increase the toxicity of the final liposomal formulation. These results offer great promise for the development of innovative biocompatible drug nanocargos that are able to safely deliver their content on demand under NIR laser irradiation. Moreover, this work demonstrates that metal-bis(dithiolene) complexes, owing to their versatility of functionalization and metal complexation, are attractive photothermal agents for the development of original NIR-responsive materials for application not only in biotechnology but also in materials science.

High Photothermal Activity within Neutral Nickel Dithiolene Complexes Derived from Imidazolium-Based Ionic Liquids.

A new series of nickel N,N'-dialkylimidazolidine-2,4,5-trithione complexes ([Ni(R2timdt)2]) carrying linear or branched carbon chains (R = n-C4H9, n-C8H17, n-C12H25, n-C16H33, 2-ethylhexyl, 2-butyloctyl, phytanyl) have been obtained through an original synthetic pathway starting from easily available imidazolium-based ionic liquids. The chemical structures of these nickel complexes were confirmed by NMR and high-resolution mass spectroscopies as well as by X-ray analysis performed on single crystals. The complexes strongly absorb in the near-IR (NIR) region around 1000 nm, with high extinction coefficients reaching 80 000 M(-1) cm(-1). They are able to efficiently convert NIR light into heat under laser irradiation with very high photothermal conversion efficiencies (around 30%).

Molecular Alloys of Neutral Gold/Nickel Dithiolene Complexes in Single-Component Semiconductors.

Control of band filling or doping of molecular (semi)conductors can be performed by substitutional insertion of molecules with a similar shape but a different electron count, with one more or one less electron. This strategy has been explored here within the semiconducting, single-component, radical gold dithiolene complex [AuOC4] bearing para-butoxyphenyl substituents. Alloying with the corresponding neutral nickel dithiolene complex [NiOC4] lacking one electron afforded a complete isostructural series [NiOC4]1-x[AuOC4]x, spanning the whole composition range from x = 0 to x = 1 by 0.1 increments, further characterized by X-ray diffraction and EDX analyses. Magnetic susceptibility data confirm the antiferromagnetic interactions between neighboring radical gold dithiolene complexes. The electrical conductivity increases exponentially with the x gold fraction, while the activation energy remains constant in the more conducting, gold-rich samples. This behavior is tentatively assigned to the tunneling barriers of variable width (with x) but of constant height, separating more conducting gold-rich segments. Comparison of redox potentials for the 1e(-) oxidation and reduction of both [NiOC4] and [AuOC4] dithiolene complexes indicates that the [NiOC4] nickel complex does not act as a dopant for the radical [AuOC4] complex.

Water-soluble nickel-bis(dithiolene) complexes as photothermal agents.

The remarkable photothermal properties of pegylated nickel-bis(dithiolene) complexes in water can induce cell death under laser irradiation in the near infrared (NIR) region.

Photothermal control of the gelation properties of nickel bis(dithiolene) metallogelators under near-infrared irradiation.

The proper functionalization of nickel bis(dithiolene) complexes by pendant cholesteryl fragments allows for the formation of extended networks of intertwined fibers providing robust gels. Furthermore, such nickel bis(dithiolene) complexes are also efficient photothermal centers in solution in the near infrared (NIR), with a photothermal conversion efficiency comparable to that of gold nanoparticles. This unprecedented association in one single molecule, of the two properties, i.e., gelation ability and photothermal effect, gives a highly efficient handle to modulate the gel stability through light irradiation in the NIR region, providing a novel approach to photoresponsive gels.