Photodynamic therapy (PDT) is part of photochemotherapy and requires the presence of a photosensitive substance (drug, PS), oxygen, and a powerful light source in the area of absorption of the PS used.
The main requirements for activating the properties of a PS are its selective accumulation in tumor tissue, high intensity of absorption in the visible and near-infrared region of the spectrum, low level of dark toxicity, and absence of side-effects . Selective accumulation and retention of PS in tumor tissues rather than in the surrounding healthy tissue lead to selective destruction of the tumor in PDT, while the surrounding healthy tissue remains intact. Such selectivity is one of the biggest advantages of this method, which may be substituted in some cases for chemotherapy, radiotherapy, or surgery in the treatment of cancer. Due to drug excretion  and redistribution, the effective therapeutic dose entering tumor cells is only a fraction of the administered PS. Administration of increased amounts of therapeutics is not possible because they have cytotoxic effects, which could cause significant toxicity in healthy cells. It is very important therefore to find alternative approaches, which increase the efficacy of the drug dose in the tumor and decrease the dose in healthy tissue . Higher selectivity of PSs for tumor cells can be achieved by combining them with transport agents, which preferentially interact with tumor cells, ensure the selective accumulation of the drug within the diseased tissue, and deliver the desired therapeutic drug concentration to a targeted site in the patient’s body. Transport systems commonly used for photosensitizers are polymers, liposomes, oil emulsions, certain metals, some proteins, and carbon-based nanoparticles . Stable and biocompatible transport systems with a long half-life in the blood are ideal. Selective drug delivery to tumor tissue, transport of nanoparticles containing a PS, and a tumor cell with a receptor is the objectives for achieving high selectivity and low drug concentration . Several research groups have confirmed the hypothesis that one possible approach to achieving these goals is to prepare low-density lipoprotein (LDL)-based particles .
Physicochemical Mechanism of PDT
The photodynamic effect can be induced by two mechanisms called Type I and Type II (Figure 1—Step 4). After photon absorption, the PS molecule goes from the ground state (S0) to the singlet excited state (S1). From this excited state, the PS can be returned to the ground state by energy emission through non-radiative and/or radiant processes (fluorescence). In its excited state, the PS can also spontaneously move from the singlet state S1 to the excited triplet state (T1) by means of the intersystem conversion process. In this state, the transition to the ground state through a phosphorescence process can occur .
The type I mechanism involves electron transfer reactions between the PS molecule in the excited states of S1 and T1 and the substrate. This process results in the formation of ionic radicals, which tend to react immediately with oxygen to form a mixture of highly reactive oxygen radicals, such as superoxide radical (·O2), hydrogen peroxide (H2O2), and hydroxyl radical (·OH), which oxidize a wide range of biomacromolecules .
The type II mechanism is characterized by energy transfer reactions between PS in the excited triplet state T1 and molecular oxygen, which is also in the triplet ground state (T0). These reactions cause the formation of singlet oxygen (1O2), which is able to rapidly oxidize cellular structures such as proteins, lipids, nucleic acids , and organelles leading to tumor cell death . This also means that PDT may be a useful alternative treatment for cancer cells resistant to chemotherapy .
The reaction mechanism depends on the following conditions. First, the location of the PS is crucial because most of the ROS are highly reactive and cannot move far from the point of origin before disappearing. Second, the relative number of target biomolecules is important . Davies (2003) calculated the percentage of 1O2 responses in leukocytes: protein 68.5%, ascorbate 16.5%, RNA 6.9%, DNA 5.5%, beta-carotene 0.9%, NADH/NADPH 0.69%, tocopherols 0.5%, reduced glutathione 0.4%, lipids 0.2%, and cholesterol 0.1% . This means that the distribution of 1O2 may vary in different cell targets.
Both mechanisms can occur simultaneously. Their proportional representation is significantly influenced by the PS, the substrate, the oxygen concentration, and the binding of PS to the substrate. In addition, the type II mechanism appears to be more efficient as it has a higher rate constant than electron transfer reactions (type I mechanism). As a result, energy transfer to other compounds that can compete with oxygen is less important, so type II is more often dominant .
2. Plant-Derived Photosensitive Substances
Photoactive compounds occurring in medicinal plants with potential utilization in PDT have been found to be less toxic than synthetic agents. The reduction of side effects using natural PSs in cancer treatment is another advantage of this therapeutic approach. However, their clinical applications have been limited by several imperfections such as accumulation in tissues, a lack of chemical purity, or low penetration . Muniyandi et al.  have published a comprehensive review article about the role of photoactive phytocompounds in PDT. Phototoxic effects, potential applications in the PDT of cancer of the main natural PSs groups (furanocoumarins, thiophenes, alkaloids, curcumins, polyacetylenes, and anthraquinones) have been described . Our paper focuses on the four anthraquinones, of which hypericin is the most promising PS in the PDT of cancer. With regard to the hydrophobicity of studied anthraquinones, which is important for their penetration through membranes, the following types of PSs have been distinguished.
Types of Photosensitive Substances by Hydrophobicity
PDT either uses chemotherapeutics commonly applied in chemotherapy, which must also be photosensitive, or new PSs are proposed. All photosensitizers (except uroporphyrin and photophrin), which have been proposed as drugs for use in PDT, interact more or less with serum proteins after intravenous administration. From the point of view of PDT, however, the interaction of the drugs with DNA is also quite important, as it is necessary to disrupt and stop the division of tumor cells, and this can be achieved only through their interaction with DNA . In some cases, this interaction is not very significant (as these drugs have a greater affinity for proteins), so it is necessary to find a transporter that will help deliver the drug to the cell nucleus, thereby mediating the drug–DNA interaction . Success in the treatment of cancer requires sufficiently hydrophobic drugs to cross the lipid membrane. For this reason, the hydrophobicity of drugs plays an important role in their distribution, metabolism, and excretion from the patient´s body. Due to these facts, we distinguish four groups of drugs with the ability to localize and accumulate in the tumor. Moreover, there are no rigid boundaries between these groups of drugs, and there is some overlapping between them, in some cases a continuous transition.
Hydrophobic PSs—compounds requiring the presence of transporters, such as liposomes or Cremophor EL, or Tween 80. They have the ability to localize in the inner lipid part of lipoproteins, mainly in LDL and high-density lipoproteins (HDLs), but also in very-low-density lipoproteins (VLDLs). This group includes phthalocyanines (ZnPC, C1A1PC), naphthalocyanines (isoBOSINC), tin-etiopurpurine (SnET2) , and hypericin .
Amphiphilic PSs—asymmetric compounds, which can be incorporated into the outer phospholipid and apoprotein layer of lipoprotein particles, e.g., disulfonates (TPPS2a, C1A1PCS2a), lutetium teraphyrin (LuTex), and monoaspartyl chlorine (MACE), which forms a barrier between albumin and HDL . Emodin can be included in this group .
Hydrophilic PSs—drugs that predominantly bind to albumins and globulins, e.g., tetra-sulfone derivates of tetraphenylporfin (TPPS3 and TPPS4) and chloroaluminum phthalocyanine (C1A1PCS3 and C1A1PCS4) .
In this work, we focused in more detail on a very prospective PS in PDT of cancer hypericin. During a study of hypericin molecule incorporation into biomacromolecules (we focused on DNA) model compounds are using for simplification of the problem. Anthraquinones emodin, quinizarin, and danthron represent a significantly smaller part of the larger hypericin molecule with the same chemical groups. This fact facilitates the creation of a proper model for interaction between hypericin and biomacromolecules. Moreover, chosen hypericin derivatives themselves originate from medicinal plants, as the PS can be utilized in PDT and their anticancer effects are known. With respect to the above-mentioned sorting of PSs into groups, they can be representatives of highly hydrophobic (hypericin), mildly hydrophobic (emodin), and intercalating molecules (quinizarin and danthron).
Scientists and physicians are currently working on how to increase the effectiveness of cancer treatment. One option that has been shown to be very effective is a combination of therapies (PDT and chemotherapy), which involve the direct or mediated interaction of anticancer drugs with DNA and other bioactive macromolecules (serum albumins, lipoproteins) . Hypericin, emodin, quinizarin, and danthron are examples of anticancer drugs which are chemotherapeutics synthesized by medicinal plants and PSs, and which can be used, in PDT. The discovery of new natural drugs is very important because they have many benefits for the patients. Drugs derived from medicinal plants are less toxic to the body, their use poses less risk of adverse side effects, does not depends on them, they are suitable for all age groups of patients, and can be easily combined with conventional drugs, i.e., do not show contraindications.
The entry is from 10.3390/molecules25235666
- Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part one—photosensitizers, photochemistry and cellular localization. Photodiagnosis. Photodyn. Ther. 2004, 1, 279–293.
- Deda, D.K.; Araki, K. Nanotechnology, light and chemical action: An effective combination to kill cancer cells. J. Braz. Chem. Soc. 2015, 26, 2448–2470.
- Allen, T.M.; Hansen, C.B.; Demenzes, D.E.L. Pharmacokinetics of long circulating liposomes. Adv. Drug Deliv. Rev. 1995, 16, 267–284.
- Loomis, K.; McNeeley, K.; Bellamkonda, R.V. Nanoparticles with targeting triggered release and imaging functionality for cancer application. Soft. Matter. 2011, 7, 839–856.
- Reddi, E. Role of delivery vehicles for photosensitizers in the photodynamic therapy of tumors. J. Photochem. Photobiol. B 1997, 37, 189–195.
- Huntošová, V.; Buzová, D.; Petrovajová, D.; Kasak, P.; Naďová, Z.; Jancura, D.; Sureau, F.; Miškovský, P. Development of a new LDL-based transport system for hydrophobic/amphiphilic drug delivery to cancer cells. Int. J. Pharm. 2012, 436, 463–471.
- Hally, C.; Delcanale, P.; Nonell, S.; Viappiani, C.; Abbruzzetti, S. Photosensitizing proteins for antibacterial photodynamic inactivation. Transl. Biophotonics 2020, e201900031.
- Ghorbani, J.; Rahban, D.; Aghamiri, S.; Teymouri, A.; Bahador, A. Photosensitizers in antibacterial photodynamic therapy: An overview. Laser Ther. 2018, 27, 293–302.
- Buriankova, L.; Buzova, D.; Chorvat, D.; Sureau, F.; Brault, D.; Miskovsky, P.; Jancura, D. Kinetics of hypericin association with low-density lipoproteins. Photochem. Photobiol. 2011, 87, 56–63.
- Lenkavska, L.; Blascakova, L.; Jurasekova, Z.; Macajova, M.; Bilcik, B.; Cavarga, I.; Miskovsky, P.; Huntosova, V. Benefits of hypericin transport and delivery by low- and high-density lipoproteins to cancer cells: From in vitro to ex ovo. Photodiagnosis Photodyn. Ther. 2019, 25, 214–224.
- Konan, Y.N.; Gurny, R.; Allemann, E. State of the art in the delivery of photosensitizers for photodynamic therapy. J. Photochem. Photobiol. B Biol. 2002, 66, 89–106.
- Firestone, R.A. Low-density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells. Bioconjugate Chem. 1994, 5, 105–113.
- Versluis, A.J.; van Geel, P.J.; Oppellar, H.; van Berkel, T.J.; Bijsterbosch, M.K. Receptor-mediated uptake of low-density lipoprotein by B16 melanoma cells in vitro and in vivo in mice. Br. J. Cancer 1996, 4, 525–532.
- Rensen, P.C.; de Vrueh, R.L.; Kuiper, J.; Bijsterbosch, M.K.; Biessen, E.A.; van Berkel, T.J. Recombinant lipoproteins: Lipoprotein-like lipid particles for drug targeting. Adv. Drug Deliv. Rev. 2001, 47, 251–276.
- Kader, A.; Pater., A. Loading anticancer drugs into HDL as well as LDL has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cells. J. Control. Release 2002, 80, 29–44.
- Zheng, G.; Chen, J.; Li, H.; Glickson, J.D. Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. Proc. Natl. Acad. Sci. USA 2005, 102, 17757–17762.
- Song, L.; Li, H.; Sunar, U.; Chen, J.; Corbin, I.; Yodh, A.G.; Zheng, G. Naphthalocyanine-reconstituted LDL nanoparticles for in vivo cancer imaging and treatment. Int. J. Nanomed. 2007, 2, 767–774.
- Allison, R.R.; Bagnato, V.S.; Sibata, C.H. Future of oncologic photodynamic therapy. Future Oncol. 2010, 6, 929–940.
- Boegheim, J.P.; Scholte, H.; Dubbehman, T.M.; Beems, E.; Raap, A.K.; van Steveninck, J. Photodynamic effects of hematoporphyrin-derivative on enzyme activities of murine L929 fibroblasts. J. Photochem. Photobiol. B 1987, 1, 61–73.
- Gibson, S.L.; Hilf, R. Interdependence of fluence, drug, dose and oxygen on hematoporphyrin derivate induced photosensitization of tumor mitochondria. Photochem. Photobiol. 1985, 42, 367–373.
- Dolmans, D.E.; Fukumura, D.; Jain, R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387.
- Ochsner, M. Photophysical and photobiological processes in the photodynamic therapy of tumors. J. Photochem. Photobiol. B 1997, 39, 1–18.
- Canti, G.; Lattuada, D.; Morelli, S.; Nicolin, A.; Cubeddu, R.; Taroni, P.; Valentini, G. Efficacy of photodynamic therapy against doxorubicin-resistant murine tumors. Cancer Lett. 1995, 93, 255–259.
- Lofgren, L.A.; Hallgren, S.; Nilsson, E.; Westerborn, A.; Nilsson, C.; Reizenstein, J. photodynamic therapy for recurrent nasopharyngeal cancer. Arch. Otolaryngol. Head Neck Surg. 1995, 121, 997–1002.
- Vatansever, F.; de Melo, W.C.M.A.; Avci, P.; Vecchio, D.; Sadasivam, M.; Gupta, A.; Chandran, R.; Karimi, M.; Parizotto, N.A.; Yin, R.; et al. Antimicrobial strategies centered around reactive oxygen species—bactericidal antibiotics, photodynamic therapy, and beyond. Microbiol. Rev. 2013, 37, 955–989.
- Davies, M.J. Singlet oxygen-mediated damage to proteins and its consequences. Biochem. Biophys. Res. Commun. 2003, 305, 761–770.
- Bicalho, L.S.; Longo, J.P.F.; Pereira, L.O.; Santos, M.F.M.A.; Azevedo, R.B. Photodynamic therapy, a new approach in the treatment of oral cancer. Rev. Univ. Ind. Santander. Salud. 2010, 42, 167–174.
- Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in photodynamic therapy: Part three—Photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. Photodiagnosis Photodyn. Ther. 2005, 2, 91–106.
- Muniyandi, K.; George, B.; Parimelazhagan, T.; Abrahamse, H. Role of photoactive phytocompounds in photodynamic therapy of cancer. Molecules 2020, 25, 4102.
- Doherty, R.E.; Sazanovich, I.V.; McKenzie, L.K.; Stasheuski, A.S.; Coyle, R.; Baggaley, E.; Bottomley, S.; Weinstein, J.A.; Bryant, H.E. Photodynamic killing of cancer cells by a platinum(II) complex with cyclometallating ligand. Sci. Rep. 2016, 6, 22668.
- Pouton, C.W.; Wagstaff, K.M.; Roth, D.M.; Moseley, G.W.; Jans, D.A. Targeted delivery to the nucleus. Adv. Drug Deliv. Rev. 2007, 59, 698–717.
- Sobolev, A.S. Novel modular transporters delivering anticancer drugs and foreign DNA to the nuclei of target cancer cells. J. Buon. 2009, 14 (Suppl. 1), S33–S42.
- de Melo, W.C.M.A.; Lee, A.N.; Perussi, J.R.; Hamblin, M.R. Electroporation enhances antimicrobial photodynamic therapy mediated by the hydrophobic photosensitizer, hypericin. Photodiagnosis Photodyn. Ther. 2013, 10, 647–650.
- Alves, D.S.; Pérez-Fons, L.; Estepa, A.; Micol, V. Membrane-related effects underlying the biological activity of the anthraquinones emodin and barbaloin. Biochem. Pharmacol. 2004, 68, 549–561.
- Du, K.; Xia, Q.; Heng, H.; Feng, F. Temozolomide-doxorubicin conjugate as a double intercalating agent and delivery by apoferritin for glioblastoma chemotherapy. ACS Mater. Interfaces 2020, 12, 34599–34609.
- Mandelli, F.; Vignetti, M.; Suciu, S.; Stasi, R.; Petti, M.C.; Meloni, G.; Muus, P.; Marmont, F.; Marie, J.P.; Labar, B.; et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: The EORTC and GIMEMA groups study AML-10. J. Clin. Oncol. 2009, 27, 5397–5403.
- Wójcik, K.; Zarebski, M.; Cossarizza, A.; Dobrucki, J.W. Daunomycin, an antitumor DNA intercalator, influences histone-DNA interactions. Cancer Biol. Ther. 2013, 14, 823–832.
- Hu, X.; Cao, Y.; Yin, X.; Zhu, L.; Chen, Y.; Wang, W.; Hu, J. Design and synthesis of various quinizarin derivatives as potential anticancer agents in acute T lymphoblastic leukemia. Bioorganic Med. Chem. 2019, 27, 1362–1369.
- Chen, H.; Zhao, C.; He, R.; Zhou, M.; Liu, Y.; Guo, X.; Wang, M.; Zhu, F.; Qin, R.; Li, X. Danthron suppresses autophagy and sensitizers pancreatic cancer cells to doxorubicin. Toxicol. In Vitro 2019, 54, 345–353.
- Wang, Y.; Yang, M.; Qian, J.; Xu, W.; Wang, J.; Hou, G.; Ji, L.; Suo, A. Sequentially self-assembled polysaccharide-based nanocomplexes for combined chemotherapy and photodynamic therapy of breast cancer. Carbohydr. Polym. 2019, 203, 203–213.
- Lee, H.; Han, J.; Shin, H.; Han, H.; Na, K.; Kim, H. Combination of chemotherapy and photodynamic therapy for cancer treatment with sonoporation effects. J. Control. Release 2018, 283, 190–199.
- He, C.; Liu, D.; Lin, W. self-assembled core-shell nanoparticles for combined chemotherapy and photodynamic therapy of resistant head and neck cancers. ACS Nano 2015, 9, 991–1003.