Photodynamic therapy: Photosensitizers and nanostructures

3788 | Mater. Chem. Front., 2021, 5, 3788–3812 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Cite this: Mater. Chem. Front., 2021, 5, 3788 Photodynamic therapy: photosensitizers and nanostructures Alberto Escudero, * ab Carolina Carrillo-Carrio ´n, c M a Carmen Castillejos, b Elena Romero-Ben, b Christian Rosales-Barrios b and Noureddine Khiar * b The reactions of some structures to different external stimuli can be used for therapeutic purposes. In particular, in photodynamic therapy (PDT), a light-sensitive compound or structure, commonly named a photosensitizer (PS), is able to produce reactive oxygen species (ROS) after being irradiated with light in the presence of oxygen. Such ROS are effective in destroying cells and can be used as therapeutic agents to treat some skin and eye diseases, as well as certain types of cancer. This review will summarise the current state-of-the-art in PDT, with special focus on the different available photosensitizers, their chemistry, their incorporation into different nanostructures, and some of the current targeting strategies. 1. Introduction: fundamentals of photodynamic therapy and its physical mechanisms Photodynamic therapy (PDT), along with photothermal therapy (PTT) and magnetic hyperthermia, is one of a collection of techniques in medicine that uses the response of sensitive compounds or nanostructures to external stimuli. Under appropriate circumstances, some structures are able to produce reactive oxygen species (ROS) after being excited with light in a Departamento de Quı ´mica Inorga ´nica, Facultad de Quı ´mica, Universidad de Sevilla, Calle Profesor Garcı ´a Gonza ´lez 1, E-41012 Seville, Spain. E-mail: [email protected] b Instituto de Investigaciones Quı ´micas (IIQ), CSIC-Universidad de Sevilla, Avenida Ame ´rico Vespucio 49, E-41092 Seville, Spain c Departamento de Quı ´mica Orga ´nica, Universidad de Co ´rdoba, Campus de Rabanales, Edificio Marie Curie, Ctra Nnal IV-A Km. 396, E-14014, Cordoba, Spain Alberto Escudero Alberto Escudero obtained his PhD in Chemistry from the University of Seville in 2007. Afterwards, he was a postdoctoral researcher at the German universities of Jena, Bayreuth, and Marburg, and at the Materials Science Institute of Seville, Spain. He also worked as a researcher for the Leibniz Institute for New Materials in Saarbru ¨cken, Germany. Since 2019, he has been an assistant professor at the Department of Inorganic Chemistry of the University of Seville, Spain, and a researcher at the Institute for Chemical Research (CSIC, University of Seville). His research lines are focused on the synthesis, functionalization and applications of inorganic and hybrid nanomaterials. Carolina Carrillo-Carrio ´n Carolina Carrillo-Carrio ´n obtained her PhD from the University of Cordoba in 2011. Afterwards, she held postdoctoral postitions at the Philipps-Universita ¨t Marburg (Germany), CIC biomaGUNE (Spain) and CiQUS-University of Santiago de Compostela (Spain). In 2020, she joined the University of Cordoba as principal investigator of a project for young researchers. She will join the University of Seville and the Institute for Chemical Research (CSIC, University of Seville) as ‘‘Ramo ´n y Cajal’’ Researcher in April 2021. She has expertise in the synthesis and application of functional hybrid nanomaterials, and is currently working on metal–organic framework-based nanocomposites with applications in biomedicine and catalysis. Received 12th November 2020, Accepted 8th February 2021 DOI: 10.1039/d0qm00922a rsc.li/frontiers-materials MATERIALS CHEMISTRY FRONTIERS REVIEW Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Mater. Chem. Front., 2021, 5, 3788–3812 | 3789 the presence of oxygen. This can be used for the direct killing of cells, either by vascular damage or by activation of an immune response against them. 1–3 The term photosensitizer (PS) is usually used to refer to such species. Traditionally, some organic dyes 4 and aromatic hydrocarbons such as xanthene – derivative dyes (Rose Bengal 5 and eosin 6 ) as well as methylene blue 7 – have been used as PSs. The production of ROS is related to the electronic transitions among the different excited states of the dye, followed by an eventual electron or energy transfer to an oxygen species. The mechanisms of the production of ROS are closely related to those of luminescence, and are represented in Fig. 1. A photosensitive species can have at least two excited states: a singlet and a triplet. Typical electronic transitions in photosensitive species take place between the ground (S 0 ) and the singlet excited states (such as S 1 or S 2 ) after the appropriate absorption of radiation, but a further transition to the triplet excited state (T 1 ), in principle forbidden, may also occur. 8 The term intersystem crossing is used to refer to such a phenomenon. An appropriate energy difference between the excited states 9 and the presence of heavy atoms 10 in the PS favour this intersystem crossing. Once in the triplet state, two mechanisms may take place: (i) the excited electron may be transferred to other species yielding free radicals that can then react with oxygen to form ROS, such as superoxide radical anions (O 2   ), H 2 O 2 , and hydroxyl radicals (  OH), i.e., mechanism type 1; and (ii) this energy can be transferred to triplet oxygen ( 3 O 2 ) to form singlet oxygen ( 1 O 2 ), i.e.,mechanism type 2. 11,12 For both mechanisms, the more probable the intersystem crossing, the more efficient the production of ROS. PSs are usually conjugated unsaturated organic molecules, often containing heavy atoms. Some transition metal complexes as well as some semiconductors 13 and other inorganic nanoparticles and nanostructures 14 have also been reported. Ideal PSs should possess high light absorption coefficients, ideally at long wavelength radiations (infrared or near-infrared M Carmen Castillejos M a Carmen Castillejos received her BSc in Pharmacy from the University of Seville, and her MSc in Health Science Current Research Trends from the University of Malaga, Spain. She is currently pursuing her PhD degree in selfassembled nanomaterials for biomedical applications at the Institute for Chemical Research (CSIC, University of Seville) under the supervision of Dr. Noureddine Khiar. Elena Romero-Ben Elena Romero-Ben received her BSc in Biology from the University of Seville, Spain, and her MSc in Health Biotechnology from the University Pablo de Olavide. She is currently pursuing her PhD degree in selfassembled nanomaterials for biomedical applications at the Institute for Chemical Research (CSIC, University of Seville) under the supervision of Dr. Noureddine Khiar. Christian Rosales-Barrios Christian Manuel Rosales- Barrios received his BSc in Biology from the University of Seville, Spain, and his MSc in Health Biotechnology from the University Pablo de Olavide. He is currently pursuing his PhD degree in self-assembled nanomaterials for biomedical applications at the Institute for Chemical Research (CSIC, University of Seville) under the supervision of Dr. Noureddine Khiar. Noureddine Khiar Noureddine Khiar received a PhD in Organic Chemistry from the University of Strasbourg, France. After several post-doctoral positions in the USA and Europe, in 1997 he joined the newly created Institute of Chemical Research (IIQ, CSIC, University of Seville). He is currently the Director of the IIQ, Senior Research Scientist of the CSIC, Principal Investigator of the group ‘‘Asymmetric Synthesis and Functional Nanosystems’’, and is responsible for the research group of the Junta de Andalucı ´a ‘‘Organic Synthesis and Molecular Recognition’’. His main scientific interests are the rational design of bionanomaterials and their applications in medicine, and the development of new asymmetric transformations for the synthesis of biologically relevant products. Review Materials Chemistry Frontiers Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 3790 | Mater. Chem. Front., 2021, 5, 3788–3812 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 (NIR)), to ensure better tissue penetration, 15 low photobleaching quantum yields, high intersystem crossing efficiencies, as well as low toxicity in the absence of light, and in principle, an appropriate hydrophilic and hydrophobic balance itself to favour selective accumulation in tumours. 16 Different structures have been used as PSs. 14 Porphyrins, with special attention to the hematoporphyrin derivative (HpD), constitute the first-generation PSs, which were started to be used in the 1970s. They are naturally occurring compounds that usually show high quantum yields for the production of ROS, although they might suffer from photobleaching. Other structures such as derivatives of hematoporphyrin and chlorins were designed to overcome some of the limitations of the previously used compounds, such as their lack of solubility, given that most of them are hydrophobic, or to improve their optical properties. They are the second-generation of PSs. As in many other cases, the development of nanotechnology offered new possibilities and implementations. Nanostructures possess the size of 1–100 nm in which most of the biomolecular interactions take place. 17,18 In particular, the conjugation or incorporation of PSs into nanostructures paved the way for their use in nanomedicine. The possibility of multifunctionality, including targeting to selectively treat tumour tissues, as well as possible improvements in intracellular delivery in terms of efficiency and selectivity are some of the advantages of the so-called third-generation of PSs. 19 Different nanostructures such as inorganic nanoparticles (NPs), micelles, and vesicles, especially liposomes, with already developed commercial formulations, have recently been used for the conjugation with PSs. The fourth-generation PSs are related to the use of porous carriers, which include mesoporous silica and metal–organic frameworks (MOFs). These structures can incorporate a large number of sensitizer molecules. From the pharmaceutical point of view, the term pharmaceutical formulation of PSs is also used to refer to both third- and fourth-generation PSs. This review will summarise the different PS structures that have been proposed to be used for PDT, with a description of their chemistry and physical properties, as well as their incorporation into nanostructures and porous nanomaterials. 2. Photosensitizers 2a. Porphyrins, chlorines, purpurins, and phthalocyanines Porphyrins are compounds based on a ring of four interconnected modified pyrrole subunits, and are usually hydrophobic. Due to their high level of conjugation, they are well known for absorbing visible light. In some cases, they might also have a metallic atom in the center, resulting in a naturally occurring group of chromoproteins, including hemoglobin and chlorophyll. The most important advantage of such compounds is their relatively high quantum yields (F) for the production of ROS, and their rich chemistry. In fact, the original porphyrin structure can be modified, affecting its optical properties such as the absorbance spectrum. Photobleaching, low absorption in the IR or NIR spectral window and poor selectivity 20 are their main drawbacks. Hematoporphyrin derivative (HpD, Fig. 2a) and photofrin II (a purified version of HpD) are good examples of these types of PSs, and can be considered as first-generation PSs. In fact, they are nowadays widely used as PSs. 21 Both structures absorb radiation at around 630 nm, and show a relatively high quantum yield for the production of singlet molecular oxygen (F= 0.64 in the case of HpD, in methanol 22 ). Both compounds have been used to treat brain, laryngeal, lung, skin, gastric, colorectal, and esophageal carcinomas. 23,24 Modifications of the structure of porphyrins constitute the so-called second-generation PSs. For example, chlorines are Fig. 1 Electronic states and possible transitions in a photosensitizer, and mechanisms for the formation of radical oxygen species (ROS). Taken from ref. 11, published by Frontiers. Materials Chemistry Frontiers Review Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Mater. Chem. Front., 2021, 5, 3788–3812 | 3791 formed after the saturation of one or two double bonds of the porphyrin structure. This shifts the absorbance spectra to longer wavelengths and thus toward the therapeutic window. 25 Chlorin e6 (Ce6) and its derivatives (hydrophobic, Fig. 2b) 26 have been used for the treatment of bile duct carcinoma, 27 as well as breast and hypopharyngeal cancer cells. 28 A chlorin-based compound, termoporfin (m-THPC, hydrophobic, with an absorption maximum at 650 nm), is in fact a clinically used PS, 29 some formulations of which are commercially available. Protoporphyrin IX (PpIX, hydrophobic, Fig. 2c) 30 and the 5-aminolevulinic acid (ALA, hydrophilic, the biological precursor of PpIX) 31 (Fig. 2d) are also examples of this generation of PSs, and have been applied, for example, in malignant glioma surgery. 32,33 In fact, the use of ALA to drive the production of intracellular PpIX is in common clinical use. 34 Some studies regarding both dark cytotoxicity and toxicity under light irradiation of different PSs can be found in the literature. For example, for human epidermoid carcinoma cells, ALA-induced PpIX showed both dark toxicity and phototoxicity of 2–3 orders of magnitude lower than those of photofrin, and a higher dark toxicity:phototoxicity ratio, whereas formulations based on m-THPC showed much more toxicity under light irradiation and a much higher dark toxicity : phototoxicity ratio. 35 Within this PS generation, naphthalocyanines, which bear a second benzene ring, 36 and purpurins, 37 based on a chlorophyll derivative, have also been proposed. Most of these PSs are hydrophobic, even when in some cases chemical modifications can be designed to yield hydrophilic derivatives. In general terms, even when their commercial formulations are used to treat different cancers, the synthesis of these PSs as well as the required structural modifications are difficult. For this reason, non-porphyrin photosensitizers that can be made more easily, thus becoming more synthetically accessible, have started to receive research interest. 2b. BODIPY and derivatives BODIPY dyes, based on the 4,4-difluoro-4-bora-3a,4a-diaza-s- indacene core, have also been suggested to be used as PSs for PDT. In general terms, such compounds show high absorption Fig. 2 Examples of some compounds used as photosensitizers for PDT: (a) hematoporphyrin, (b) chlorin e6, (c) protoporphyrin IX, (d) 5-aminolevulinic acid (AVA), (e) iodine-substituted BODIPY, (f) aza-BODIPY derivative, (g) Ru[(dmb) 2 (IP-3T)]Cl 2 , and (h) AIEgen-based photosensitizer containing a tetraphenylethylene moiety. Review Materials Chemistry Frontiers Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 3792 | Mater. Chem. Front., 2021, 5, 3788–3812 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 coefficients, low photobleaching, relatively low toxicity in the absence of light, and low influence of the chemical environment on their properties. 16 However, they possess high luminescence efficiency, meaning that the intersystem crossing transitions generally have a low probability. The consequence of this is that they produce a low level of ROS. This can be improved by modifying their structure, in most of the cases by incorporating heavy atoms. For example, the ROS quantum yield improves up to 50 times when two iodine atoms are introduced in the core structure. 38 Further modifications of the BODIPY core with the introduction of up to four iodine atoms and a p-tolyl hydrocarbon substituent give rise to structures with high absorption coefficients. These species can be excited from 548 to 581 nm and show quantum yields higher than 0.83 for the production of ROS 39 (Fig. 2e). Absorptions shifted to the NIR region can be obtained by using aza-BODIPY derivatives, as is the case of dibromo-aza-BODIPY (known as ADPM06, Fig. 2f), at expenses of slight changes in their absorption coefficients and the ROS quantum yield generation, as well as some aqueous solubility issues. 8,40 Aza-BODIPY derivatives have been suggested to be closer to clinical development than any other subcategory in their category, and although they are less synthetically accessible, 16 they currently attract wide research attention. 41 In general terms, BODIPY-based PSs are hydrophobic, but as in the previously commented species, hydrophilic derivatives can be obtained after appropriate chemical modifications. 42 2c. Transition metal complexes, aggregation-induced emission species, nanoparticles, and other structures Similar quantum yields for the production of ROS than those shown by traditionally used organic dyes have also been reported for some transition metal complexes, as occurs with [Ru(bpy) 3 ] 2+ (excitable at 452 nm) 43 and rac-Ru[(dmb) 2 (IP-3T)]Cl 2 (known as TLD1433, Fig. 2g, excitable at 525 nm, and used for the treatment of nonmuscle-invasive bladder cancer). In general terms, transition metal complexes show rich photochemistry, given their variety of excited-state electronic configurations accessible with visible and near-infrared light, which can be designed to enhance both energy- and electrontransfer processes. Other metal complexes of Pt(IV), Ru(II), Rh(III), Ir(III) and Os(II)havealsobeenproposed. 44 Rhenium(I) carbonyl complexes with ligands such as bpy, phen, pyridazine derivatives and BODIPY have also been reported and used, reaching high quantum yields for the production of ROS. 45 Aggregation-induced emission (AIE) species, also known as AIE luminogens or AIEgens, have recently emerged as a new class of luminescent materials with applications in biosensing. Such species show an enhanced luminescence upon aggregate formation, contrary to what usually happens with conventional organic dyes, in which the fluorescence is weakened or quenched in concentrated solution or in the aggregated state, 46 and might suffer from attenuated fluorescence and insufficient ROS generation. 47 This phenomenon was first observed in molecules with twisted structures and freely rotatable peripheral aromatic moieties, as is the case of hexaphenylsilole, 48 tetraphenylethene, diphenylfumaronitrile and distyreneanthracene, 49 and it has been associated with the restriction of intramolecular motions, rotations and vibrations within the molecule when they areinanaggregatedstate. 50 AIEgens are used in the development of fluorescent biosensors with superior sensitivity, but in some cases, their molecular structures can be designed to show both high fluorescence and efficient ROS generation upon aggregation. 51 Taking into account that most of the PSs show a hydrophobic character, and they thus tend to aggregate in aqueous media, AIEgens are currently attractive PSs, receiving research attention and having been proposed for image-guided PDT. 52–54 An AIEgen-based PS containing a tetraphenylethylene moiety is shown in Fig. 2h. Nanoparticles (NPs) can also be used in PDT, not only as a functional carrier, as will be discussed in the following section, but also as a ROS source or for the modulation of the production of other species. 55,56 In general terms, they offer a wider possibility of excitation, ranging from ultraviolet to visible, infra-red and even X-rays, as well as higher chemical stability, when compared to that of their molecular counterparts. Nanoparticles with uses in PDT can be classified into three categories, as follows: (1) NPs capable of producing ROS by themselves. This is the case of fullerenes and their derivatives. Such structures have an extended p-conjugation which allows them to absorb visible light, and also show a high triplet yield that can thus generate reactive oxygen species upon illumination. 57 Their main drawback is that they are highly hydrophobic and consequently are prone to aggregates, thus requiring appropriate functionalization or encapsulation strategies for their use. 58 (2) NPs consisting of an absorbing semiconducting polymer,whichcanactasaPS,asisthecaseofPCPDTBT, 59 and other polymer-based structures. 60 (3) Nanostructures composed of well-known photoactive materials such as titanium dioxide (TiO 2 ) have also been suggested, 61 although the fact that they absorb in the UV region of the spectra limits their use in the treatment of superficial tumours. 62 Core–shell nanostructures based on titaniacoated upconversion nanoparticles (UCNPs) have been recently proposed to overcome the limitation of the UV excitation requirements of TiO 2 -based structures. 63,64 UCNPs are able to absorb NIR radiations and emit visible and UV light, which excite TiO 2 . A similar strategy has been used for graphene quantum dots decorated with UCNPs. 65 This concept introduces the second group of NP-based PSs, in which the inorganic NPs absorb radiations and transfer them to the active PS species, including possible FRET processes. 66,67 CdSe/CdS/ZnS quantum dots conjugated with organic dyes such as Rose Bengal or chlorin e6 68 are representative examples of nanostructures also belonging to this category. Some inorganic silicate-based NPs have also been proposed as X-ray excitable nanosensitizers, combining the advantages of both radiotherapy and PDT. 69 Finally, some nanostructures can also act as quenchers of the luminescence of active PSs, thus enhancing the possibilities of non-radiative relaxation and then the efficiency of the production of ROS. This is the case, for example, of carbon nanotubes, which have been used to improve the ROS efficiency production in chlorin by quenching its luminescence. 70 Materials Chemistry Frontiers Review Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Mater. Chem. Front., 2021, 5, 3788–3812 | 3793 3. Incorporation into nanostructures The third- and fourth-generation PSs are those in which the active optical species is incorporated into a nano or porous structure. This is a key point for the eventual biomedical applications of such structures, given that nanostructures possess the size in which most of the biological interactions take place. 17 Specifically, to prevent fast renal clearance from the circulation and non-specific permeation across fenestrated sinusoids of the lymphoid, liver, bone marrow or spleen, the size of the NP carriers must be 420 nm. 71 However, NPs of about 100–200 nm may pass through the pores of the vessels in the tumor microenvironment. 72 Thus, NPs within a size range of 20–50 nm would be a better choice. Moreover, in terms of delivery, it should be noted that many drugs suffer from poor solubility and stability, 73 especially most of the PSs. Thus, their incorporation into nanostructured carriers usually improves the delivery efficiency, 74,75 and can also allow a spatiotemporally controlled release of the drug in response to specific stimuli. 76 Gold, silica, iron oxide and upconverting nanoparticles (UCNPs) are inorganic NPs widely used in biomedicine, and many examples of the incorporation of PSs into such structures can be found in the literature. Polymer-based NPs have also been described, with a special interest in natural biodegradable polymers such as alginate and chitosan, and other carbohydrate and protein derivatives. Amphiphilic structures forming micelles and vesicles are also widely used as carriers for PDT, as well as nanosized metal–organic frameworks (MOFs), which have been proposed to carry diverse PSs, either by encapsulation of the PSs into the pores of the MOFs or by the integration of the PSs as building units of the framework structure. Depending on the PS nature, different strategies for the attachment/conjugation to the carriers have been reported, including encapsulation, covalent conjugation, physical adsorption, and hydrophobic interactions, among others. 55 The advantages and disadvantages of the incorporation of PSs into both inorganic and organic nanostructures are related to the properties or characteristics of the nanostructures themselves. On one hand, inorganic nanostructures can provide the systems with additional functionalities, as is the case of magnetism and luminescence. Moreover, their physicochemical properties are more dependent on the nature and size of the material, which are easily modified in most of the NP types, providing a better control of their properties. 77 On the other hand, organic self-assembled nanostructures such as liposomes are especially appropriate for the encapsulation of hydrophobic cargos, and thus for drug delivery applications. 78 The upscaling and the large-scale production of organic nanostructures are much more developed, which also explain the commercial availability of many liposome-based formulations. Another important point to consider is the toxicity. In general terms, inorganic nanostructures usually show higher toxicity levels than their organic counterparts, which in many cases can also be biodegradable. This can somehow limit their uses for in vivo applications. 79 3a. Inorganic nanostructures Gold nanoparticles have been widely studied in the last few decades, and are probably the most widely used inorganic nanoparticles in nanomedicine, being of special interest for delivery applications, among others. 80 This is in fact the most important role played by Au NPs within PDT, which in most of the cases act as a passive carrier and are used to deliver photosensitizer agents for the PDT of cancer. In some cases, the production of ROS with gold nanostructures themselves has been reported, even when the mechanisms are not fully understood and are currently an open topic. 81–83 PSs can be incorporated into gold nanostructures either by non-covalent interactions (based on ionic, electrostatic or hydrophobic forces) or by forming covalent bonds with the Au surface, usually using thiolated linkers. The formation of N-bonds with the Au surface has also been described. 84 One of the strategies reported in the literature consists of a previous modification of the PS by adding thiol groups to its structure. Given the high affinity of sulfur for metallic gold, Au NPs can be easily functionalised with such species. This is the case of Au NPs functionalised with Zn(II)-phthalocyanine, in which the Au NPs are synthesised by following a relatively standard strategy consisting of the reduction of gold precursor in THF in the presence of Zn(II)-phthalocyanine disulfide (C11Pc), which is eventually linked to the gold surface NPs by forming an Au–S bond. The presence of PEG-containing thiol groups, which also link to the Au NPs, has been shown to enhance the solubility of the nanostructure and also to improve the efficiency of the PDT 85 (Fig. 3a). This strategy has also been reported for PSs such as thiolated palladium tetrapyrrole complexes. 86 Although much weaker, the incorporation of PSs through the formation of an Au–N bond has also been reported. As an example, the terminal amine of a silicon phthalocyanine 4 (Pc4) can be entrapped into PEG-functionalised Au NPs, giving rise to a kind of entrapped structure which the authors define as a ‘‘cage-type structure’’, that can be used to encapsulate hydrophobic PSs. 87 However, given the weak Au–N bond, other stabilising ligands, such as PEG derivatives, are usually demanded. Typical functionalization of the already synthesised Au NPs has also been reported, as is the case of the conjugation of thiolated PEG–Au nanostars with chlorin e6 through the widely used EDC chemistry. 88 The same strategy can be used with other linkers or gold nanoparticle shapes, as occurs with glutathione-functionalised Au nanostars further linked with chlorin e6, by using a similar chemistry. 89 Other PSs such as indocyanine green (ICG) can be electrostatically bonded to gold-bearing nanostructures, for example, Au nanorods/MoS 2 nanoagents, 90 or porous Au@Rh nanostructures. The latter constitutes one example of the fourth-generation PSs 91 (Fig. 3b). Zn porphyrins can also be electrostatically attached to Au NPs functionalised with amphiphile pyridinium salts by following a similar strategy. 92 Under appropriate circumstances, Au NPs can play a relatively active role in PDT, even when in some cases, as previously commented, they have been claimed to produce ROS without a PS. Au NPs themselves can, in some cases, modify the ROS Review Materials Chemistry Frontiers Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 3794 | Mater. Chem. Front., 2021, 5, 3788–3812 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 production efficiency of active species, given that their fluorescence can be enhanced or quenched due to their proximity to the Au NP surface. The metal-enhanced fluorescence (MEF) usually occurs for fluorophores located at ca. 5–30 nm from the metal surface, while quenching effects in PS-functionalised Au NPs in which the fluorophore is on or very close to the metal surface give rise to metal-enhanced singlet oxygen production (ME 1 O 2 ). 93 The latter leads to an enhanced PDT effect. This is, for example, the case of Au NPs functionalised with short carbon chain zinc phthalocyanines, which showed higher ROS efficiency production when compared with that of their long carbon chain counterparts. 94 Another advantage of the use of PS-functionalised Au NPs is their possible applications in multimodal therapies, given that under appropriate conditions, Au NPs themselves can also be employed for PTT, and thus produce heat for killing cancer cells. This has been reported, for example, for an Au nanoechinus structure, which can be used to treat tumours in mice by both PDT and PTT under NIR irradiation, 81 and in porphyrin-coated gold nanoshells deposited on silica spheres. 95 A double chemo- and photodynamic therapy has also been proposed for doxorubicin- and chlorin e6-functionalised gold nanoclusters. 96 The use of other inorganic nanostructures has also been reported in the literature. Silica derivative-based nanostructures are also used for PDT. 97 In general terms, silica nanostructures are well known for their biocompatibility and the possibility of subsequent functionalization, as well as for the usually high colloidal stability of the final products. 98 Two main groups of nanostructures can be mostly found in the literature. On one hand, the incorporation of PSs into mesoporous silica-based materials is of special interest, and this constitutes one type of the so-called fourth-generation PSs. On the other hand, silicaderived structures are often used as a coating material of other nanostructures. One example of the first case is silica particles loaded with the photosensitizer Ce6. The most important advantage of such structures is the possibility to incorporate other active species, such as radionuclides, to activate the PS. 99 The rich chemistry of these materials, including the possibility of layer-by-layer deposition of different compounds, can also be used to design multifunctional carriers that can be used for both PDT and chemotherapy. These structures can also show luminescence properties due to the incorporation of rare-earth cations 100 or lanthanide upconversion nanoparticles. 101 Examples of silica particles functionalised with polymers containing the active PS can also be found in the literature. 102 Examples of the use of silica as a coating material of other nanostructures are the porphyrin-containing silica coating of Au nanorods, 103 and upconverting nanoparticles coated with mesoporous silica, where PSs can be loaded in the porous matrix, as well as targeting moieties and other functional inorganic NPs can be attached to the silica surface 104,105 (Fig.3c).Othermesoporousnanostructures with uses in PDT have also been reported. Some recent examples include X-ray induced deep-penetrating PDT mesoporous silicate nanosensitizers, 69 mesoporous Ag-embedded ZnO nanocomposites, 106 mesoporous ruthenium 107 and gadolinium orthoniobate 108 NPs, and mesoporous cerium oxide-coated upconversion nanoparticles. 109 Thesenanoplatformsareoften used for both chemo- and photodynamic therapies, and in some cases also for bioimaging. Iron oxide nanoparticles (IONPs) are also often used in nanomedicine given their ability to reach the desired site of treatment upon application of an external magnetic field, also known as magnetic targeting, and their relatively good biocompatibility. Moreover, their possibility of generating heat upon alternating magnetic field stimulation makes them suitable for multiple therapies of tumours, including magnetic hyperthermia. 110 Different examples of IONPs functionalised with PSs can be found in the literature. 111–114 Iron oxide NPs can also be incorporated into different nanostructures to couple photodynamic therapy (PDT) to magnetic hyperthermia (MHT) and thus to obtain multifunctionality. One example is liposomes that combine both such magnetic nanoparticles and a photosensitizer, in which the IONPs are introduced into the liposome cavity via a water-in-oil emulsion strategy, and the hydrophobic photosensitizer m-THPC is eventually enclosed in the lipid bilayer. 115 Combination with other materials such as Fig. 3 (a) A phthalocyanine derivative (blue ligand) incorporated into PEG-functionalised Au NPs. Taken from ref. 85. Reproduced with permission from the Royal Society of Chemistry, Copyrightr2016; (b) pyridinium-stabilised gold nanoparticles with an incorporated anionic Zn(II) porphyrin (blue stars). Taken from ref. 92. Reproduced with permission from Elsevier, Copyright r2017; (c) silica-coated UCNP. The PSs zinc phthalocyanine (ZnPC) and merocyanine 540 are incorporated into the mesoporous silica coating. An additional coating with a stem-cell membrane provides the nanostructure with long circulation and tumour-targeting capability. Taken from ref. 105. Reproduced with permission from the American Chemical Society, Copyrightr2016. Materials Chemistry Frontiers Review Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Mater. Chem. Front., 2021, 5, 3788–3812 | 3795 SiO 2 and rare earth-based NPs to create more complex nanostructures has also been reported in the literature. 116 3b. Organic nanostructures Capsules, micelles and vesicles are structures widely used for the delivery of many drugs and molecules of biomedical interest, and also have applications in PDT. Polyelectrolyte-based capsules have also been used for the encapsulation of PSs. These structures are usually synthesised by following the layer-by-layer (LbL) strategy, which involves the alternate deposition of layers of polyelectrolytes of opposite charge on an inorganic core, which is eventually dissolved. 117 Given that in most of the cases the PSs are relatively small molecules, they are usually incorporated by incubation with previously synthesised polyelectrolyte-based capsules (postloading strategy), as in the case of a water-soluble PS zinc phthalocyanine choline derivative, which can be incorporated into polyelectrolyte capsules by incubation at both room temperature and at 80 1C. 118 Hydrophilic PSs can also be incorporated into the capsule wall during the layer-by-layer process, as in the case of silicon(IV) phthalocyanine. 119 However, hydrophobic PSs are preferably incorporated into polyelectrolytebased capsules during the inorganic core precipitation (preloading strategy). One example of this is Hypocrellin B (HB)-loaded polyelectrolyte capsules. 120 Micelles are spherical, ellipsoid, cylindrical, or unilamellar nanostructures, mostly formed by amphiphilic molecules in an aqueous solution that self-assemble into a structure containing a hydrophobic core and a hydrophilic corona. The size of a typical micelle ranges from 5 to 100 nm. 121 Polymeric micelles are emerging as attractive drug delivery systems 122 and are usually used to carry hydrophobic drugs, which are contained in their hydrophobic inner core. Micelles and other selfassembled structures based on low molecular weight amphiphiles are also attracting research interest due to the possibility of a more controlled supramolecular structural design, 123–125 at the cost of possible stability issues, 126 for example, toward dilution. 127 Additional polymerization processes 128 on such self-assembled nanosystems provide them with enhanced stability, thus making them suitable for delivery applications. 129,130 Given that many PSs are hydrophobic, micelles are ideal carriers to be used for PDT. 131–133 Micelles can also be functionalised with additional moieties providing them with new functionalities, especially with targeting molecules. However, the biggest disadvantage of these nanostructures is their lack of stability in the physiological environment, given that they may dissociate and thus provoke premature drug release, thus limiting their efficacy as a drug carrier. 134 Several strategies such as the use of cross-linking structures, production of polymeric prodrug micelles, and design of micelles with lower critical micelle concentration (CMC) or even unimolecular micelles have been proposed to overcome such limitations. 130 Two main strategies to introduce the PS into micelles can be found in the literature. On one hand, the PS can be incorporated into the amphiphile, and eventually form the micelles after self-assembly. On the other hand, the micelles can be first prepared by following standard methods, and the PS can be later incorporated or loaded into the structure. Regarding the first group of examples, a common protocol is to use a hydrophobic PS such as porphyrin as the hydrophobic block of the amphiphile, and conjugate it with hydrophilic polymers, yielding PS-containing micelles after their self-assembly in water. 133 This strategy can be used with other PSs, as in the case of hydrophobic iridium(III) complexes that are conjugated to hydrophilic PEG, giving rise to an amphiphilic block copolymer, and eventually to micelles. 135 A slight variation of this strategy is the conjugation of the hydrophobic PS with large dendritic wedgets that are supposed to sterically prevent or weaken the aggregation of the center dye molecules, and a subsequent conjugation with hydrophilic polymers such as PEG to eventually form micelles after self-assembly. 136 Hydrophobic PSs can also be linked to the hydrophobic tail of amphiphilic block copolymers. This has been reported for a porphyrin, which was linked to the polycaprolactone (PCL) part of a PCL–PEG copolymer via an acetal group. This type of porphyrin-based micelles can also be loaded with anti-cancer drugs such as hydrophobic doxorubicin (DOX) (Fig. 4). For such nanostructures, PDT reinforces the delivery of anticancer drugs, given that the formed ROS under irradiation induces the breakdown of endosome and lysosome membranes, and this improves the drug release and facilitates the drug translocation into the cell nucleus. 137 These multifunctional systems combine chemotherapy with PDT and are proposed as a potential vehicle for overcoming drug resistance in chemotherapy. Examples for loading with more than one anticancer drug can also be found in the literature. 138 In some cases, the PSs can also be linked to the hydrophilic part of an amphiphilic molecule by following the appropriate chemistry. For example, the porphyrin derivative monoaminoporphyrin can be linked to the hydrophilic segment of the poly(2-aminoethyl methacrylate) (PAEMA)–PCL diblock copolymer. In this case, given that the porphyrin moiety was connected to the hydrophilic part of the polymer, its aggregation in aqueous media could be avoided, and thus the quantum yield and effective energy absorption could be improved, which resulted in the improved photodynamic efficacy. 139 In other Fig. 4 Example of a micelle formed from an amphiphilic molecule, in which a porphyrin has been linked to the hydrophobic tail (PCL) of an amphiphilic block copolymer. The anticancer drug DOX has also been incorporated. Taken from ref. 137. Reproduced with permission from the American Chemical Society, Copyrightr2017. Review Materials Chemistry Frontiers Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 3796 | Mater. Chem. Front., 2021, 5, 3788–3812 This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 cases, porphyrins can act as a crosslinker within an amphiphilic block copolymer, increasing the stability of the formed micelles. 140 Structures related to micelles and based on the self-assembly of hydrophobic polymers with hydrophilic carbohydrate derivatives have also been reported, as in the case of poly(3-hexylthiophene-2,5- diyl) (P3HT)–poly(styrene-co-maleic anhydride) (PSMA) core glycoshell nanodots decorated with poly(styrene-co-maleic anhydride) (PSMA), in which the sugars are used as targeting moieties, and the P3HT is responsible for producing ROS species under irradiation. 141 The second group of strategies consists of the incorporation of the PS into already formed micelles. In these cases, the result is the photosensitizer is encapsulated and stabilised in aqueous media inside the micelle. 142,143 In other studies, the photosensitizer can be encapsulated in the micelles during the same micelle formation process. 144 Liposomes are quite biocompatible round bubbles consisting of an aqueous core encapsulated by natural or synthetic phospholipids. They are one of the most advanced delivery vehicles currently used in nanomedicine, with several formulations approved by the U.S. Food and Drug Administration (FDA). 145 This is reflected in the high number of studies and formulations that can be found in the literature. Their structure makes them suitable for the encapsulation of both hydrophilic and hydrophobic drugs, which can be incorporated into the core or within the lipid bilayers, respectively. Liposomes are quite advantageous in terms of biocompatibility and biodegradability, although the first-generation liposomes usually suffered from high-cost production, stability in different media, relatively low encapsulation efficiency, and short plasma half-life. 146 Physicochemical parameters such as the liposome size, surface charge, steric stabilization, membrane lipid packing or route administration can play a key role in the pharmacokinetics of the liposomes. 147 Given that liposomes are especially suitable for the encapsulation of hydrophobic drugs and that porphyrin-related PSs are usually highly lipophilic, 148 examples of the encapsulation of PSs for PDT in liposomes have been reported since the last few decades of the last century. 149–151 Some of these formulations are even currently available as commercial products. For the loading of liposomes, two main loading strategies can be found in the literature. In most of the cases, the typical general synthesis consists of the mixing of the desired phospholipids in the presence of the hydrophobic cargo or PS (passive loading), and a subsequent drying step to form a lipid film. The hydrophobic PS is then entrapped into the lipid bilayer. Liposomes are eventually formed after treatments with aqueous suspensions, which may also contain hydrophilic cargos. 152 One example of this kind of strategy is the encapsulation of the protoporphyrin IX. In this case, an oleylamine-conjugated protoporphyrin is dissolved in chloroform in the presence of a phospholipid, obtaining the liposomes with the PS entrapped into the lipid bilayer after drying and hydration (Fig. 5A). For this system, the conjugation of the PS with oleylamine moieties enhanced the cell membrane interactions of the porphyrin macrocycles, caused more apoptotic effects, and helped load the porphyrin into the liposome lipid bilayer. 153 Similar strategies have been used to encapsulate BODIPY-based PSs in lipidic structures. 154 However, the PSs can also be incorporated after incubation with already formed liposomes, as it happens with the hydrophilic 5-aminolevulinic acid (ALA), 155 and also with methylene blue (Fig. 5B). 156 This second strategy is known as active loading. In some cases, highly hydrophobic and nonionizable cargos can be previously encapsulated into cyclodextrins, and later be incorporated into the liposomes (Fig. 5C). 157,158 Liposomes are well-known drug carriers, and in fact, some PSs are commercially available as liposomal formulations. Visudyne s was one of the first nanoformulations of photosensitizers. It consists of a liposomal formulation of verteporfin, a semisynthetic porphyrin derived from protoporphyrin, and it was approved by the FDA in 2000 for the treatment of age-related macular degeneration (AMD), and in 2001, for the treatment of pathological myopia. 159 Foslip s is a more recently developed third-generation PS based on a liposomal formulation of Fig. 5 (A) Encapsulation of a hydrophobic protoporphyrin IX derivative into the lipid bilayer of a liposome. Taken from ref. 153. Reproduced with permission from Elsevier, Copyrightr2014; (B) encapsulation of the hydrophilic methylene blue into a liposome core. Taken from ref. 156. Published by MDPI; (C) previous encapsulation of a hydrophobic cargo into cyclodextrins, and incorporation into a liposome. Taken from ref. 157. Reproduced with permission from the National Academic of Sciences, Copyrightr2014. Materials Chemistry Frontiers Review Open Access Article. Published on 26 February 2021. Downloaded on 10/24/2022 4:44:41 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry and the Chinese Chemical Society 2021 Mater. Chem. Front., 2021, 5, 3788–3812 | 3803 nonapeptide is conjugated with PEG, which serves as a tumourtargeting ligand for medullary thyroid cancers. Such nanostructures combine chemotherapy, NIR-activated PDT and fluorescence imaging, and also allow controlled drug release, based on a hydrophobic to hydrophilic transition in the polymer shell under irradiation (Fig. 10). 229 Another interesting example of multimodal therapeutic nanoplatforms based on nMOFs has been discussed above (Fig. 6B), 200 where chemotherapy and PDT are combined. Similar nanoplatforms have also been designed for the combination of PDT and chemodynamic therapy (CDT), which is an emerging nanocatalyst-based therapeutic modality based on Fenton or Fenton-like reactions. For example, Lin and co-workers have recently constructed a core–shell nanostructure, O 2 -Cu/ZIF- 8@Ce6/ZIF-8@F127 (OCZCF), to enhance the PDT and CDT efficacy by relieving hypoxia and consuming GSH. 199 ZIF-8 can be decomposed in the acidic tumour microenvironment and release O 2 , Ce6, and Cu 2+ simultaneously. The released O 2 could be converted into 1 O 2 by Ce6 under irradiation of a 650 nm laser. Moreover, the released Cu 2+ can act as a smart reactive oxygen species protector by consuming intracellular GSH via oxidation, and thereby producing GSSG and Cu + . The byproduct Cu + can further catalyse the decomposition of H 2 O 2 to generate OH Fenton-like reactions for enhancing CDT. The in vitro and in vivo experimental data indicated that OCZCF could cause remarkable tumour inhibition through enhanced synergetic PDT and CDT. These works clearly highlight that multifunctional nanoplatforms may open up a new way for engineering highly efficient multimodal therapeutic approaches for clinical tumour treatment. Last but not least, biosafety is a major concern for the clinical applications of nanostructures. The possible dark toxicity (toxicity before irradiating with light) of the nanostructure for PDT is a key point that has still to be better understood; therefore, more systematic in vitro and in vivo studies for investigating the toxicity of PDT-based nanostructures are mandatory. One critical issue is the difficulty to compare the performance (both toxicity and efficiency) of the reported nanosystems because studies are performed under quite different conditions. In this direction, the developmentofstandardizedprotocolsforcharacterizingthe relevant features of the nanosystems for PDT would mean a huge step toward their further successful clinical translation. Additionally, to minimize side effects, the nanostructures should be removed from the body after completing their therapeutic functions. Unfortunately, most current NPs used in PDT are non-biodegradable and they may accumulate in the body if their excretion is not completed, which limits their clinical applications. Future research should be directed toward developing biodegradable nanostructures with high phototherapeutic properties. Conflicts of interest There are no conflicts to declare. Acknowledgements The authors want to thank the Sixth Research and Technology Transfer Plan of the University of Seville (VI PPIT-US, to A.E.) and the projects CTQ2016-78580-C2-1-R of the Spanish Ministry of Economy and Competitiveness, COST action CA-18132 ‘‘Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe’’, and CSIC PIE 202080E157 (to N. K.). 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