International Journal of Molecular Sciences Review Photosensitizers Used in the Photodynamic Therapy of Rheumatoid Arthritis Manuel Gallardo-Villagrán 1,2 , David Yannick Leger 1,*, Bertrand Liagre 1,* and Bruno Therrien 2,* 1 Laboratoire PEIRENE, Faculté de Pharmacie, Université de Limoges, EA 7500, F-87025 Limoges, France 2 Institut de Chimie, Université de Neuchâtel, Avenue de Bellevaux 51, CH-2000 Neuchâtel, Switzerland * Correspondence: [email protected] (D.Y.L.); [email protected] (B.L.); [email protected] (B.T.) Received: 17 May 2019; Accepted: 4 July 2019; Published: 7 July 2019 Abstract: 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. Keywords: photodynamic therapy; rheumatoid arthritis; photosensitizers; porphyrins; tetrapyrroles; nanoparticles 1. Background 1.1. Photodynamic Therapy Principle Some compounds are known to absorb the energy they receive from light to reach higher excited states. This energy can be transferred to other substances or molecules, thus allowing the excited compound to return to its initial state of minimal energy [1]. Photodynamic therapy (PDT) is based on this principle, in which designed photoactive chemical compounds, known as photosensitizers (PSs), are injected into tissues and then irradiated at a certain wavelength to reach an excited energy level. The absorbed energy can then be transferred directly to neighboring molecules, such as O2, giving rise to singlet oxygen, which in turn gives rise to radical oxygen species (ROS). This phenomenon is associated with the type II mechanism (Figure1). The type I mechanism involves the transmission of the PS energy to a substrate or biomolecule, and, from this intermediate, the energy is forwarded to oxygen, giving rise again to ROS. In both cases, ROS induce cell death by apoptosis or necrosis, thus making PDT interesting for the treatment of several diseases [2–7]. Int. J. Mol. Sci. 2019, 20, 3339; doi:10.3390/ijms20133339 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 3339 2 of 21 Figure 1. Standard Photodynamic Therapy (PDT) process involving a photosensitizer (PS), oxygen, and light. 1.2. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic inflammatoryinflammatory autoimmune disease that can aaffectffect multiple organ systems. systems. It Itis isconsidered considered a disease a disease of ofthe the joints, joints, attacking attacking mainly mainly the thewrists wrists and andthe themetacarpophalangeal metacarpophalangeal and andproximal proximal interphalangeal interphalangeal joints joints of the of thehands. hands. RA RAis characterized is characterized by bysynovial synovial inflammation inflammation and andhyperplasia, hyperplasia, autoantibody autoantibody production production (particularly (particularly to rheumatoid to rheumatoid factor factorand citrullinated and citrullinated peptide), peptide), and andcartilage cartilage and andbone bone destruction destruction [8]. [8 ].The The etiology etiology of of RA RA remains mainly unknown,unknown, butbut the the clinical clinical features features of RA of seemsRA seems to be theto be consequence the consequence of interactions of interactions between environmentalbetween environmental factors, including factors, including smoking, smoking, diet, obesity, diet, infections obesity, infections and microbiota, and microbiota, as well as geneticas well predispositionas genetic predisposition (histocompatibility (histocompatibility complex, cytokines,complex, cytokines, chemokines, chemokines, and growth and factor growth genes) factor to autoimmunegenes) to autoimmune responses responses [9,10]. [9,10]. Many of the newly developed treatments and drugsdrugs for RA have focused on inducing the cell death ofof fibroblast-like fibroblast-like synoviocytes synoviocyt (FLS)es (FLS) by reducingby reducing and stoppingand stopping their proliferation. their proliferation. Studies suggestStudies thatsuggest this that proliferation this proliferation is linked tois thelinked activation to the acti of certainvation intracellularof certain intracellular signaling pathways signaling [8 pathways,11]. Such inflammation,[8,11]. Such inflammation, if not treated if in not time, treated leads in to time, the appearanceleads to the of appearance hyper-vascularization of hyper-vascularization and damage toand cartilage damage and to cartilage bones by and erosion, bones whichby erosion, causes which joint causes pain andjoint reduced pain and mobility. reduced Sincemobility. standard Since treatmentsstandard treatments against RA, against such as RA, synovectomy, such as synovect are invasive,omy, are destructive, invasive, anddestructive, involve longand rehabilitationinvolve long periods,rehabilitation in recent periods, decades, in recent less invasive decades, treatments less invasive have treatments been explored have been [12–14 explored]. [12–14]. To date,date, the the current current treatment treatment strategy strategy is to initiate is to aggressive initiate aggressive therapy by applyingtherapy antirheumaticby applying drugsantirheumatic (DMARDs) drugs and (DMARDs) to escalate theand therapy, to escalate guided the by therapy, an assessment guided of by the an disease’s assessment activity of [12the]. DMARDsdisease’s activity reduce the[12]. rate DMARDs of erosive reduce changes the and, rate therefore, of erosive have changes the potential and, totherefore, alter the have disease’s the coursepotential by to preventing alter the irreversibledisease’s course damage. by preven However,ting conventionalirreversible damage. and biologic However, disease conventional modifying therapiesand biologic sometimes disease failmodifying or produce therapies only partialsometimes responses fail or and, produce consequently, only partial clinical responses remission and, is rarelyconsequently, achieved. clinical remission is rarely achieved. In thisthis context,context, alternativealternative oror complementarycomplementary therapiestherapies couldcould bebe ofof interest.interest. PDT PDT is is a new therapy thatthat could could improve improve the the well-being well-being of patients of pati andents increase and increase the possibility the possibility of clinical of remission. clinical Therefore,remission. PDTTherefore, treatment, PDT regardlesstreatment,of regardless the photosensitizer of the photosensitizer used, aims to used, induce aims cell to death induce in cellscell involveddeath in cells in inflammation involved in inflammation and hyperplasia and inhyperp the joint.lasia Inin combinationthe joint. In combination with standard with treatments, standard PDTtreatments, would PDT enhance would the enhance control of the cartilage control and of cartilage bone destruction and bone in destruction the treated joint.in the Consequently, treated joint. theConsequently, constant development the constant of development new photosensitizers, of new andphotosensitizers, the improvement and ofthe cell improvement targeting, could, of cell in thetargeting, future, could, allow thein usethe offuture PDT, inallow the initiationthe use of RAPDT treatment. in the initiation The effectiveness of RA treatment. of PDT in The the treatmenteffectiveness of RAof PDT depends in the on multipletreatment factors, of RA mostdepe ofnds them on beingmultiple directly factors, related most to of the them type being of PS used.directly Solubility, related to retention the type time,of PS excitationused. Solubility, wavelength, retention elimination, time, excitation transport, wavelength, and cytotoxicity elimination, are sometransport, of the and factors cytotoxicity to consider are some when of choosing the factors a PS to for consider PDT. when choosing a PS for PDT. Therefore, in this review, wewe wantwant to gather allall the compounds used as a PS in the treatment of RA by PDT. An emphasis on the factors influencinginfluencing thethe eefficiencyfficiency of the PS is given, to illustrate the advantages andand limitationslimitations ofof eacheach of of them. them. Overall, Overall, we we want want to to provide provide to to researchers researchers in in the the fields fields of PDTof PDT and and RA RA an overviewan overview of theof the actual actual state state of the of art,the asart, well as well as new as new avenues avenues for designing for designing the next the generationnext generation of photosensitizers of photosensitizers for the for treatment the treatment of RA of by RA photodynamic