Photodynamic Therapy (PDT) has become one of the most promising treatment against autoimmune diseases, such as rheumatoid arthritis (RA), as well as in the treatment of different types of cancer, since it is a non-invasive method and easy to carry out. The three main ingredients of PDT are light irradiation, oxygen, and a photosensitizer (PS). Light irradiation depends on the type of molecule or compound to be used as a PS. The concentration of O₂ fluctuates according to the medium where the target tissue is located and over time, although it is known that it is possible to provide oxygenated species to the treated area through the PS itself. Finally, each PS has its own characteristics, the efficacy of which depends on multiple factors, such as solubility, administration technique, retention time, stability, excitation wavelength, biocompatibility, and clearance, among others. Therefore, it is essential to have a thorough knowledge of the disease to select the best PS for a specific target, such as RA. In this review we will present the PSs used in the last three decades to treat RA under PDT protocol, as well as insights on the relevant strategies.

The effect of dimethyl sulfoxide (DMSO) in rheumatoid arthritis (RA) human fibroblast-like synoviocytes (FLSs) has been studied on five different samples harvested from the joints (fingers, hands and pelvis) of five women with RA. At high concentrations (>5%), the presence of DMSO induces the cleavage of caspase-3 and PARP-1, two phenomena associated with the cell death mechanism. Even at a 0.5% concentration of DMSO, MTT assays show a strong toxicity after 24 h exposure (≈25% cell death). Therefore, to ensure a minimum impact of DMSO on RA FLSs, our study shows that the concentration of DMSO has to be below 0.05% to be considered safe.

Ruthenium-based assemblies containing tetrapyridylporphyrins (TPyP) in their structure have been evaluated as photosensitizers (PS) to treat rheumatoid arthritis (RA) by photodynamic therapy (PDT). TPyP is useless by itself as a PS due to its low solubility in biological media, however, incorporated in metallacages it can be internalized in cells. The study shows a cellular antiproliferative activity in fibroblast-like synoviocyte (FLS) in the lower nanomolar range in the presence of light, and no dark toxicity at 1 μM concentration, thus having an excellent photoactivity index. The presence of diamagnetic (Zn²⁺) and paramagnetic (Co²⁺) metals in the center of TPyP impairs the effectiveness of PDT, showing no (Co) or reduced (Zn) photoactivity. A total of five metallacages with different structural characteristics have been evaluated, and our results suggest that the incorporation of PS in metalla-assemblies is not only an elegant method to increase solubility in biological media for TPyP but also appears to be an efficient hybrid system to treat RA by PDT.

For the first time, ruthenium-based assemblies have been used as carriers for photosensitizers in the treatment of rheumatoid arthritis by photodynamic therapy (PDT). These metallacages are totally soluble in physiological media and can transport photosensitizers (PS) in their cavity. After an incubation period, the PS is released in the cytoplasm and irradiation can take place. This strategy allows photosensitizers with low or null solubility in biological media to be evaluated as PDT agents in rheumatoid arthritis. The systems in which 21H,23H-porphine and 29H,31H-phthalocyanine are encapsulated show excellent photocytotoxicity and no toxicity in the dark. On the other hand, systems in which metalated derivatives such as Mg(II)-porphine and Zn(II)-phthalocyanine are used show good photocytotoxicity, but to a lesser extent than the previous two. Furthermore, the presence of Zn(II)-phthalocyanine significantly increases the toxicity of the system. Overall, fifteen different host–guest systems have been evaluated, and based on the results obtained, they show high potential for treating rheumatoid arthritis by PDT.

We report the synthesis and reactivity of Ru^II complexes with a new naphthyridinone-substituted phosphine ligand, 7-(diisopropylphosphinomethyl)-1,8-naphthyridin-2(1H)-one (L-H), which contains two reactive sites that can potentially be deprotonated by a strong base: an NH proton of naphthyridinone and a methylene arm attached to the phosphine. In the absence of a base, the stable bis-ligated complex Ru(L-H)₂Cl₂ (1) containing two NH groups in the secondary coordination sphere is formed. Upon further reaction with a base, a doubly deprotonated, dimeric complex is obtained, [Ru₂(L*-H)₂(L)₂] (2), in which two of the four ligands undergo deprotonation at the NH (L), while the other two ligands are deprotonated at the methylene groups (L*-H) as confirmed by an X-ray diffraction study; intramolecular hydrogen bonding is present between the NH group of one ligand and an O-atom of another ligand in the dimeric structure, which stabilizes the observed geometry of the complex. Complex 2 reacts with protic solvents such as water or methanol generating aqua Ru(L)₂(OH₂)₂ (3) or methanol complexes Ru(L)₂(MeOH)₂ (4), respectively, both exhibiting intramolecular H-bonded patterns with surrounding ligands at least in the solid state. These complexes react with benzyl alcohols to give aldehydes via base-free acceptorless dehydrogenation.

A family of stable and otherwise selectively unachievable 2,6-bisimino-4-R-1,4-dihydropyridinate aluminium (III) dialkyl complexes [AlR'₂(4-R-ⁱPrBIPH)] (R = Bn, Allyl; R′ = Me, Et, ⁱBu) have been synthesized, taking advantage of a method for the preparation of the corresponding 4-R-1,4-dihydropiridine precursors developed in our group. All the dihydropyrdinate(−1) dialkyl aluminium complexes have been fully characterized by ¹H- ¹³C-NMR, elemental analysis and in the case 2′a, also by X-ray diffraction studies. Upon heating in toluene solution at 110 °C, the dimethyl derivatives 2a and 2′a dimerize selectively through a double cycloaddition. This reaction leads to the formation of two new C–C bonds that involve the both meta positions of the two 4-R-1,4-dihydropyridinate fragments, resulting the binuclear aluminium species [Me₂Al(4-R-ⁱPrHBIP)]₂ (R = Bn (3a); allyl (3′a)). Experimental kinetics showed that the dimerization of 2′a obeys second order rate with negative activation entropy, which is consistent with a bimolecular rate-determining step. Controlled methanolysis of both 3a and 3′a release the metal-free dimeric bases, (4-Bn-ⁱPrHBIPH)₂ and (4-allyl-ⁱPrHBIPH)₂, providing a convenient route to these potentially useful ditopic ligands. When the R′ groups are bulkier than Me (2b, 2′b and 2′c), the dimerization is hindered or fully disabled, favoring the formation of paramagnetic NMR-silent species, which have been identified on the basis of a controlled methanolysis of the final organometallic products. Thus, when a toluene solution of [AlEt₂(4-Bn-ⁱPrBIPH)] (2b) was heated at 110 °C, followed by the addition of methanol in excess, it yields a mixture of the dimer (4-Bn-ⁱPrHBIPH)₂ and the aromatized base 4-Bn-ⁱPrBIP, in ca. 1 : 2 ratio, indicating that the dimerization of 2b competes with its spontaneous dehydrogenation, yielding a paramagnetic complex containing a AlEt₂ unit and a non-innocent (4-Bn-ⁱPrBIP)^˙− radical-anion ligand. Similar NMR monitoring experiments on the thermal behavior of [AlEt₂(4-allyl-ⁱPrBIPH)] (2′b) and [AlⁱBu₂(4-allyl-iPrBIPH)] (2′c) showed that these complexes do not dimerize, but afford exclusively NMR silent products. When such thermally treated samples were subjected to methanolysis, they resulted in mixtures of the alkylated 4-allyl-ⁱPrBIP and non-alkylated ⁱPrBIP ligand, suggesting that dehydrogenation and deallylation reactions take place competitively.