pharmaceutics Review Potential of Cyanine Derived Dyes in Photodynamic Therapy Natalia Lange 1 , Wojciech Szlasa 1 , Jolanta Saczko 2 and Agnieszka Chwiłkowska 2,* 1 Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 5, 50-345 Wroclaw, Poland; [email protected] (N.L.); [email protected] (W.S.) 2 Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; [email protected] * Correspondence: [email protected] Abstract: Photodynamic therapy (PDT) is a method of cancer treatment that leads to the disinte- gration of cancer cells and has developed significantly in recent years. The clinically used photo- sensitizers are primarily porphyrin, which absorbs light in the red spectrum and their absorbance maxima are relatively short. This review presents group of compounds and their derivatives that are considered to be potential photosensitizers in PDT. Cyanine dyes are compounds that typically absorb light in the visible to near-infrared-I (NIR-I) spectrum range (750–900 nm). This meta-analysis comprises the current studies on cyanine dye derivatives, such as indocyanine green (so far used solely as a diagnostic agent), heptamethine and pentamethine dyes, squaraine dyes, merocyanines and phthalocyanines. The wide array of the cyanine derivatives arises from their structural mod- ifications (e.g., halogenation, incorporation of metal atoms or organic structures, or synthesis of lactosomes, emulsions or conjugation). All the following modifications aim to increase solubility in aqueous media, enhance phototoxicity, and decrease photobleaching. In addition, the changes Citation: Lange, N.; Szlasa, W.; introduce new features like pH-sensitivity. The cyanine dyes involved in photodynamic reactions Saczko, J.; Chwiłkowska, A. Potential could be incorporated into sets of PDT agents. of Cyanine Derived Dyes in Photodynamic Therapy. Keywords: cyanine dyes; photodynamic therapy; cancer therapy; irradiation Pharmaceutics 2021, 13, 818. https://doi.org/10.3390/ pharmaceutics13060818 Academic Editors: Udo Bakowsky, 1. Introduction Matthias Wojcik, Eduard Preis and 1.1. Basics of Photodynamic Therapy Gerhard Litscher Photodynamic therapy (PDT) is a low-invasive therapy, that destroys cancer cells through the generation of reactive oxygen species (ROSs). PDT involves a photosensitizer Received: 15 April 2021 (PS), administered topically or intravenously, a light source and oxygen in the targeted Accepted: 28 May 2021 tissue [1]. In the dark, the PS remains in its base energy state. However, the absorption of Published: 31 May 2021 light at the appropriate wavelength moves the PS to an excited state. An excess of absorbed energy leads to its release and reaction with the oxygen in the tissue, thus inducing the Publisher’s Note: MDPI stays neutral formation of ROS [2]. The photodynamic reaction might propagate in two main ways [3]. with regard to jurisdictional claims in The Type I mechanism of photodynamic reaction includes the production of highly reactive published maps and institutional affil- intermediates, mainly hydrogen peroxide H2O2 and •OH. Type II involves the formation of iations. 1 oxygen in the singlet state O2 (Figure1)[ 4]. The short half-life of free radicals determines the limited diffusion distance of these high cytotoxic molecules [5]. The dysregulation of the homeostasis free radicals induces irreversible oxidation of proteins, nucleic acids, fatty acids, cholesterol and organelles of the tumor cells. The process leads to loss of function Copyright: © 2021 by the authors. and eventually to the death of the irradiated cells depending on the conditions of the Licensee MDPI, Basel, Switzerland. therapy, especially the cellular localization of the photosensitizer [5]. Death might also arise This article is an open access article from an induced immune response as well as from the destruction of vessels supplying the distributed under the terms and tumor with nutrition [6]. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Pharmaceutics 2021, 13, 818. https://doi.org/10.3390/pharmaceutics13060818 https://www.mdpi.com/journal/pharmaceutics PharmaceuticsPharmaceutics 20212021, 13, 13, x, 818FOR PEER REVIEW 2 2of of 18 17 Figure 1. The mechanism of a photosensitizer action in photodynamic therapy. Figure 1. The mechanism of a photosensitizer action in photodynamic therapy. 1.2. Advantages and Disadvantages of PDT 1.2. AdvantagesSeveral advantages and Disadvantages of PDT makeof PDT it a promising treatment against malignancies. Selec- tivitySeveral of the advantages PS towards cancerof PDT cells make makes it a it promising applicable treatment for curative against treatment, malignancies. early-stage Selectivitytumors, and of the reducing PS towards the size cancer of inoperable cells makes tumors. it applicable Additionally, for curative as a local treatment, low-invasive ear- ly-stageprocedure, tumors, PDT hasand minimalreducing systemic the size side of effectsinoperable compared tumors. with Additionally, standard chemotherapy as a local low-invasiveor radiotherapy. procedure, PDT can PDT also has lead minimal to the eradicationsystemic side of effects the tumor compared vasculature with [standard5], which chemotherapywill be described or radiotherapy. in Section 1.5 .PDT can also lead to the eradication of the tumor vascu- lature Another[5], which point will be in described its favor is in that Section PDT 1.5. may trigger various immune responses to cancerousAnother cells point [7]. Primarily,in its favor if theis that irradiated PDT may cells undergotrigger various necrosis, immune an acute responses inflammatory to cancerousresponse mediatescells [7]. Primarily, the removal if ofthe the irradiated dead tissue cells [8 undergo]. Then, dendriticnecrosis, cellsan acute (DCs) inflam- absorb matorythe cancer-related response mediates antigens the through removal phagocytosis of the dead tissue and present [8]. Then, it to dendritic the immune-system cells (DCs) absorbcells, thusthe triggeringcancer-related the systemic antigens inhibitory through responsephagocytosis to cancer and cells present [9]. it to the im- mune-systemThe penetration cells, thus of triggering light at an the appropriate systemic wavelengthinhibitory response to activate to cancer the FDA-approved cells [9]. PSsThe (Porfimer penetration sodium, of light Temoporfin, at an appropriate Verteporfin wavelength [10]) can be to suppressed activate the by FDA-approved the tissue, thus PSsputting (Porfimer deep-seated sodium, tumors Temoporfin, out of reach. Verteporfi To overcomen [10]) can this problem,be suppressed PSs, that by absorbthe tissue, light from the NIR-I could be applied. Another obstacle is the low oxygenation of the tumor thus putting deep-seated tumors out of reach. To overcome this problem, PSs, that absorb microenvironment. Namely, when cancer cells are in hypoxia [11], PDT may be rendered light from the NIR-I could be applied. Another obstacle is the low oxygenation of the ineffective due to the lack of substrate for ROS generation. The main advantages and tumor microenvironment. Namely, when cancer cells are in hypoxia [11], PDT may be disadvantages of PDT are shown in Figure2, whereas a broad reference to the efficacy and rendered ineffective due to the lack of substrate for ROS generation. The main ad- application of the PDT is reviewed by Agostinis et al. [12]. vantages and disadvantages of PDT are shown in Figure 2, whereas a broad reference to the efficacy and application of the PDT is reviewed by Agostinis et al. [12]. Pharmaceutics 2021, 13, x FOR PEER REVIEW 3 of 18 Pharmaceutics 2021, 13, 818 3 of 17 Figure 2. Summary of the main advantages and disadvantages of photodynamic therapy. Figure 2. Summary of the main advantages and disadvantages of photodynamic therapy. 1.3. Desired Characteristics of the Photosensitizer 1.3. DesiredA PS shouldCharacteristics be characterized of the Photosensitizer by low dark toxicity and selective accumulation in the tumorA PS cells. should The be compound characterized should by below highly dark toxicity susceptible and toselective irradiation accumulation and generate in the as tumormany cells. ROS asThe possible compound in the should tumor environmentbe highly susceptible [13]. Also, to an irradiation ideal PS should and generate localize out-as manyside theROS nucleus as possible to avoid in the pro-canceroustumor environmen mutationst [13]. inAlso, the DNAan ideal [1]. PS Preferably, should localize an ROS outsideshould the be generatednucleus to in avoid the mitochondria the pro-cancerou or lysosomes,s mutations but in an the especially DNA [1]. effective Preferably, targeting an ROScombination should be involves generated both in ofthe them mitochondria [14]. Photodamage or lysosomes, to the but organelles an especially would effective result in targetinga controlled combination cell death, involves like apoptosis both of or them paraptosis [14]. Photodamage [15], rather than to the a mutagenicorganelles processwould resultin the in nuclei. a controlled Controlled cell death, cell death like apoptosis results in or the paraptosis lack of tissue [15], rather necrosis, than which, a mutagenic despite processits assets, in risksthe nuclei. an uncontrolled Controlled inflammation cell death results response in the [16 lack]. Moreover, of tissue thenecrosis, dye should which, be despitecharacterized