Open access peer-reviewed chapter
Abstract
Earlier applications of photodynamic therapy (PDT) were accomplished by direct or intravenous injection of the photosensitizer, followed by preferential accumulation in cancerous tissues after systemic circulation. Nowadays, nanoparticles are used as carriers and delivery systems, which also facilitate combinations of PDT with other non-invasive technologies. PDT has expanded to disease types other than cancers. Nanoparticle-mediated target specific PDT can reduce the emergence of resistance, and has introduced chemotherapy combinations with PDT, and potential repurposing of chemotherapy drugs that are being used less because of resistance. The novel discoveries of inorganic and organic dye nanoconjugate photosensitizers discussed in this chapter have enhancement PDT efficacy. This review describes the type I and II mechanisms of PDT, some of the first- and second-generation photosensitizers in the market, and the roles played by nanomaterials across the PDT clinical translation value chain. It discusses nanoparticles as delivery systems for photosensitizers, smart stimulus-responsive, and disease-targeting nanoparticles, focusing on folate, glycan-based, pH, and external stimulus-responsive targeting. Well-known in anticancer applications, folate targeting is now debuting in antibacterial applications. Other targeting technologies are discussed. Nanoparticles applications as agents for combining PDT with other therapies are discussed. The World Health Organization has identified PDT as a promising new technology.
Keywords
- antibacterial photodynamic therapy
- photodynamic antimicrobial chemotherapy
- nanoparticle-mediated photodynamic therapy
- bacterial resistance
- bacterial cell specificity
- selectivity
- drug carrier
- drug delivery
1. Introduction
From a clinical perspective, photodynamic therapy (PDT) may be defined as a treatment that involves the application of light energy in a disease-affected area where there is a sufficient concentration of the photosensitizer (PS). PDT destroys disease cells only upon activation by light, provided there is a sufficient oxygen concentration in the disease. PSs are generally activated using laser light of a wavelength that is absorbed by the PS. They are nontoxic compounds that become toxic upon light activation. Clinical PDT is widely used against psoriasis; cancers of the skin, lung, brain, bladder, pancreas, bile duct, esophagus, and head and neck; as well as other diseases such as acne and age-related macular degeneration. Additionally, antimicrobial photodynamic therapy (aPDT) is used to treat bacterial, fungal, and viral infections. It has been established from several studies that there is an immune response to PDT that can further enhance its efficacy. From a mechanistic point of view, PDT involves the excitation of the PS to its singlet excited state upon absorption of light of a frequency that matches the absorption spectrum of the PS, followed by intersystem crossing to the triplet state, which is the state in which the PS either transfers energy to normal triplet state oxygen to produce excited singlet state oxygen or reacts with biomolecules, causing damage to cells. Singlet oxygen production is the most effective PDT pathway. It takes place under conditions of oxygenation and is referred to as type II mechanism. In contrast, the direct reaction of the excited PS with biomolecules, referred to as type I mechanism, predominates under conditions of hypoxia, because there is not sufficient oxygen for type II mechanism.
In the aPDT approach, absorbed light energy is used to achieve the bactericidal or bacteriostatic effect through these two critical molecular PS-mediated mechanisms. Here the type I mechanism involves much radical formation through hydrogen transfer from the PS directly to biomolecules, and the type II mechanism proceeds via oxygen photosensitization to produce a series of oxygen-based molecular species known as reactive oxygen species (ROS), which includes singlet oxygen, oxygen radicals, and hydroxide radicals and radical anions. All ROS react with biomolecules, causing irreversible damage [1]. The Jablonski diagram shown in Figure 1 illustrates the two mechanisms. The irreversible chemical reactions that alter the functionality of biomolecules in bacterial cells and the extracellular polymeric substance (EPS) matrix [3], regardless of whether these biomolecules are cellular, EPS matrix components, or some other functional constituents of the biofilm [4], have been extensively studied. Many of these studies conclude that aPDT increases intracellular ROS and reduces the strength of the EPS matrix and the metabolic activity of the pathogen cells in the matrix [5].
Figure 1.
Jablonski diagram to illustrate the aPDT type I and II mechanisms. Reproduced from Songca and Adjei [
Nanoparticles may be defined as ultra-small particulate materials with one of the dimensions of the particles up to 100 nanometers. Metallic nanoparticles like metal chalcogenide and silica nanocomposites have been reported. Self-assembled phospho-lipid porphysome vesicles [6] and phthalocyanine-based porphysome-like nanostructures [7] are very common PSs for PDT. Organo-inorganic nanomaterials comprise organic and inorganic nucleated heterocyclic aromatic organic compounds in self-assembled nanoparticle (NP) formations. Recently, metal organic frameworks (MOFs) have emerged, in which the linking organic molecules are PS molecules such as phthalocyanines and porphyrins [8, 9]. Typical applications of these PS molecules in PDT include antiviral, antibacterial, antifungal, anticancer, pest control, and environmental sanitization [2]. Several combination therapies, gene therapies, immunotherapies, and checkpoint blockade immunotherapies, in which these molecules are used as integral parts of PS nanoconjugate systems, have been widely reported. These nanoconjugates are widely reported in pharmaceutical formulation; controlled, stimulus-responsive, and slow drug release; enhancement of bioavailability; combination therapies; and enhancement of therapeutic efficacy, using a range of techniques such as nano-crystallization and self-assembly. Nanomaterials are found at every node of the therapeutic value chain and drug development pipeline, from basic drug research and development, through 2D and 3D evaluations in vitro, finally arriving at the preclinical studies in vivo, pharmaceutical formulation, applications in clinical trials, and drug administration in clinical therapy.
The challenge of incorporating PS molecules that are used for PDT and other drug molecules that are used as antibacterial chemotherapeutic agents, into innovative nanoconjugate systems, in designing them to act as carriers and delivery vehicles of the PS and drug molecules, and act as systems that respond to internal or external stimuli, once they are internalized into disease cells, is an important preoccupation of scientists in nanomaterial-mediated PDT. The purpose of incorporating PS molecules and antibacterial chemotherapeutic drug molecules into innovative nanoconjugate systems is to ensure their inertness and non-toxicity while in systemic circulation. The purpose of building internal and external stimuli responsiveness is to ensure that they are released only when the nanoconjugate is inside the target disease cell or site, when the stimuli of the internal environment of these cells or sites trigger their release, or when an external stimulus is applied (Figure 2).
Figure 2.
Chemical structures of Foscan, Photofrin, Visudyne, Lutex, Pc4, Purlytin, HPPH, NPe6, Levulan, TLD1433, Hypocrellin a, and Hypocrellin B. The pharmaceutical companies are indicated in brackets.
Incorporating small molecules of antibacterial drugs as components of nanoconjugates presents many advantages in efficacy improvement. These include pharmacokinetic navigation of various physiological barriers and reduction of many of their side effects, including the development of bacterial resistance. Most of the self-assembly reactions used are conducted in aqueous media to form NPs composed of small, potent drug molecules. Most nanoconjugates are easy to fabricate; they can deliver high concentrations of their drug molecule cargo to the disease microenvironment and intracellular environment of the disease cells. Given the facile pharmacokinetic navigation of the systemic barriers by these drugs when capped or otherwise encapsulated in nanoconjugate form, they have great potential to reduce or eliminate their side effects because they are only released at the disease site and, in the most innovative designs, they are released only once they are inside the disease cells, and are not released inside normal host tissue cells.
Most PSs used in PDT are organic molecular chromophores that are capable of transferring electromagnetic radiation energy to oxygen to form ROS in situ [10]. However, the new inorganic NP PSs that have been discovered are showing good versatility because in addition to being used for transport and delivery of the PSs, they can also act as PDT PSs, photothermal therapy, and magnetothermal therapy agents in combination therapies with PDT. For example, an inorganic NP PS consisting of Fe2O3, and CuS, which also acts as a PS and therefore, possesses photothermal and magnetothermal conversion, in addition to PDT capabilities, as reported by Curcio et al. [11]. The nanoconjugate demonstrated its capabilities in a tri-therapeutic combination involving photothermal hyperthermia therapy (PTT), PDT and magnetic hyperthermia therapy (MH), in which the iron oxide shell is responsible for MH, and the copper sulfide multi-core is responsible for PTT and PDT. In their review, Zhang et al. [12] identified carbon-based inorganic nanomaterials such as dots, fullerenes, nanotubes, graphene oxide semiconductor nanomaterials such as zirconium and titanium oxides, and defective nanomaterials such as oxides of ruthenium and zinc, as some of the inorganic NPs that generate ROS upon photo irradiation. Conjugation of these nanomaterials with the organic dye type of PS results in efficacious nanoconjugates in combination therapies. For example, the conjugation of copper sulfide NPs with chlorin-e6 produced a potent PDT-and-PTT combination agent because both the core and shell materials produce ROS [13].
Examples of organic PSs that have clinical approval include Foscan from Scotia [14], Visudyne from QLT [15], Lutex from Pharmacyclics [16], Pc4 from Case Western Reserve [17], Purlytin from Miravant [18], NPe6 from Nippon [19], HPPH from Roswell Park Cancer Institute [20, 21], Amino Laevulinic Acid from DUSA [22], Hypocrellin Photosensitizer SL052 from Canadian Quest PharmaTech [23], and TLD1433 from Theralase [24]. Examples of inorganic PSs include sulfides of molybdenum, zinc, copper, iron, silver, and bismuth [25]. Nanostructured MOFs [26] and metal complexes with organic ligands [23], on the other hand, may therefore be considered among the wide and increasing variety of organic–inorganic hybrid nanostructured PDT PSs [27, 28, 29].
2. Purpose statement
This paper presents the roles played by nanomaterials across the therapeutic value chain, from basic research to clinical applications, using examples from therapeutic technologies and their clinical applications against many bacterial and fungal diseases. The paper adopts an approach of considering therapeutic applications of nanotechnology in treating bacterial diseases and the nanomaterial-based therapeutic technologies applied in treating them, discussing the details of these applications and the technologies that define them. Using photosensitization type I and II mechanisms by which ROS are produced in the disease microenvironment, and the subsequent oxidative initiation of apoptosis and necrotic cell death, the purpose of this paper is pursued by discussing specific examples. The purpose of this approach is to provide the fundamental mechanistic basis of the technology and its combinations, an overview of its state-of-the-art from the current research and the historical viewpoint, the expansion of its scope, the enhancement of its efficacy and disease targeting, and the role of nanotechnology in these developments. This paper also aims to discuss potential areas of further research and innovation as indicated by gaps in the basic research and clinical translation literature.
3. Nanoparticles as carrier and delivery systems for photosensitizers
The use of NPs as carriers and delivery agents for PSs and other drugs has gained much attention [30, 31] and has demonstrated the enhancement of stability, solubility, administration, target delivery, specificity, selectivity, and toxicity reduction [32, 33]. Research on NPs as carriers of PSs has demonstrated that the enhancement of PDT is due to the enhancement of PS drug delivery and cellular uptake and retention [34, 35]. Due to the ultra-small size of NPs, they have large surface-to-volume ratios [36]. This allows them to absorb large quantities of the PS on their surface [37], which promotes the target tissue and cellular uptake [38] once they reach the target site and cells. In addition, this PS drug delivery mechanism can also enhance selectivity for the disease site and cells over host tissue sites or cells. The absorption of PSs on the surface of NPs increases NP stability while in systemic circulation [39]. This severely limits undesirable side effects of both the NP and PS, such as toxicity in the absence of light. PS-capped NPs generally have improved solubility in hydroxylic media, thus enhancing the administration of the nanoconjugate [40]. The foregoing discussion describes the encapsulation of NPs by PSs. It may be illustrated using the example of encapsulation of magnetic NPs with heparin-pheophorbide-A, as reported by Li et al. [41], shown in Figure 3, in which the aminopropyl triethoxysilane functionalized iron oxide NPs are encapsulated with heparin–pheophorbide-A by conjugation of the functionalized NPs. The encapsulation of NPs by PSs is one of the most effective and therefore most widely reported strategies for using NPs as carrier and delivery systems of PSs for use in PDT.
Figure 3.
Heparin–pheophorbide-a conjugation of aminopropyltriethoxysilane functionalized nanoparticles.
The PS may be covalently linked or adsorbed onto the surface of the NP. For example, a near-infrared absorbing and disulfide functionalized bacteriochlorophyll-a-based PS was covalently anchored onto the surface of gold NPs for anticancer PDT, using gold surface–sulfide dative covalent bonding of the disulphide functional group of the PS [42]. The researchers found that in comparison to the free bacteriochlorophyll-a-based PS, the gold-PS nanoconjugate remained in systemic circulation for longer and showed increased tumor accumulation, cancer cell uptake and retention. This nanoconjugate is illustrated in Figure 4.
Figure 4.
Covalent binding of bacteriochlorophyll-a-based PS onto the surface of gold nanoparticles.
In this case, the linker is a functional group of the PS. The covalent anchoring of Rose Bengal on the surface of silica NPs, however, was accomplished by functionalizing the NP surface with amino groups followed by covalent linking of the PS, via the formation of amide covalent bonds between the carboxylic acid functional group of Rose Bengal and the amino groups of the silica capping shell [43]. This is illustrated in Figure 5.
Figure 5.
Amide bond covalent binding via amino-functionalized silica nanoparticles.
The nanoconjugate inactivated gram-positive Methicillin-resistant
The encapsulation of PSs in the core of organic NPs such as liposomes and micelles has emerged as a powerful way of enhancing PS delivery [44]. This is a versatile approach because, while hydrophilic PSs are encapsulated in water-in-oil organic NPs, hydrophilic PSs are encapsulated in oil-in-water organic NPs [45, 46]. This is due to the respective structures of the oil-in-water and water-in-oil NPs. The constituent molecules of these organic NPs, known as micelles, are phospholipids, which self-assemble with the alignment of their hydrophilic heads and hydrophobic tails. Water-in-oil organic NPs align with hydrophilic heads in the interior of the NP, thus encapsulating hydrophilic PSs in an aqueous medium, while oil-in-water NPs align with hydrophobic tails in the interior of the NP, thus encapsulating hydrophobic PSs in an organic medium [47]. Unlike micelles, which have a single layer of phospholipids, liposomes have a double layer of phospholipids with an aqueous core, encapsulating hydrophilic PSs and a hydrophobic phospholipid bilayer that can accommodate large quantities of hydrophobic PSs [48]. The structures of liposomes are illustrated in Figure 6.
Figure 6.
Liposome with hydrophilic core hydrophobic bilayer, two partitions for hydrophilic and hydrophobic PSs respectively.
To overcome the lipophilicity of porphyrins that limits their water solubility, protoporphyrin IX was conjugated with oleylamine to enhance its solubility in the liposomal bilayer [49]. Figure 6b and 7 illustrate the liposomal bilayer incorporation of the hydrophobic PS. The in vitro anticancer studies of the liposome incorporated PS showed that it significantly reduced the viability of HeLa and AGS cancer cell lines. Bilayer incorporation of the PS was also observed with temoporphyrin [50].
Figure 7.
Liposomal bilayer incorporation of the oleylamine conjugated protoporphyrin IX.
In contrast, the water-soluble PSs like Methylene Blue, Neutral Red, and Rose Bengal are encapsulated into the inner aqueous core of the liposome [51]. The liposomal encapsulation of these PSs, which was evaluated by gel filtration chromatography using Sephadex 100, is illustrated in Figure 6a.
Unlike the encapsulation of NPs discussed above, mesoporous NPs (Figure 8) have micro-pores that are large enough to absorb large quantities of PSs, permeating through their entire nanostructures. Mesoporous silica [53] and MOFs [54] are among the most widely studied mesoporous NPs. The advantage of using mesoporous silica NPs as PS carriers and delivery systems is that they are biocompatible and safe to use [55]. Mesoporous silica NPs are fabricated to assume several 3D structures, which enable loading and the control of NP release at the target site, and surface functionalization, depending on the synthetic methodology [56]. Dendritic mesoporous silica nanostructures have now emerged with highly porous nanostructures and high loading capacity due to their large pore sizes [57]. MOFs can absorb large quantities of PSs in their large pore sizes that can be hydrophobic or hydrophilic depending on the organic molecule linkers and the linked metal cations. As a result, they can absorb hydrophilic PSs in hydrophilic pore sites and hydrophobic PSs in hydrophobic pore sites [58]. Although most MOF pores tend to be hydrophobic due to the hydrophobic organic molecule linkers, the design and self-assembly of hydrophilic MOFs have been reported for the absorption of hydrophilic molecules such as glycol peptides [59]. Although, in theory, such MOFs can also be used to absorb hydrophilic PSs, to the best of our literature search, such research has yet to be reported.
Figure 8.
Mesoporous silica nanoparticles and metal-organic-frameworks are highly porous nanomaterials. Copied from Zhang and Chang [
A new type of MOF consisting of porphyrins or phthalocyanines as the organic linkers has been reported to absorb large quantities of oxygen, thus alleviating hypoxia in PDT and acting as PSs by ROS generation [60]. Furthermore, to ameliorate the tissue penetration challenge of normal light energy used in PDT, porphyrin-based MOFs have been reported, which absorb X-rays and transfer the energy to the porphyrin linkers for oxygen sensitization to generate ROS [61]. Other mesoporous nanomaterials developed for use in PDT include mesoporous carbon and titanium NPs. For example, oxygenated perfluoro hexane was loaded onto the mesoporous carbon NP channels for antibacterial applications in combining PTT and PDT [62]. Mesoporous titanium oxide NPs have been developed for overcoming drug resistance in a combination therapeutic approach involving disease targeting and drug delivery in PDT [63].
4. Smart targeting nanoparticles in antimicrobial photodynamic therapy
Microbial infectious diseases, especially those due to bacterial and fungal infections, initially affect specific areas and may subsequently spread throughout the entire organism [64]. Therefore, in order to arrest bacterial pathogenesis, treatment modalities that identify and target affected areas, sites, and cells are preferred. The importance of using smart targeting NPs in aPDT emanates from the desire to direct such treatment to disease-affected areas, sites, and cells, with minimal or no negative effects on normal host tissue cells [65]. When the disease-infected site is external, and the aPDT treatment is topical rather than systemic, the purpose of smart NP-mediated targeting is to enhance selectivity for the infective microbial cells and their supporting EPS matrix over normal host tissue cells. In cases of deep tissue or systemic infection, however, such targeting has a general purpose of selectivity for disease cells [66]. Several methods have been reported to enhance selectivity for the disease cells over normal host tissue cells.
5. Aptamer-based targeting
Nanoconjugates functionalized with disease cell-specific aptamers have been reported to enhance specificity for microbial pathogens. Aptamers are single strands of intact sequences of nucleic or xeno nucleic acids. Because of their high affinity, selectivity, and specificity for specific microorganism targets, aptamers are selected and prepared, typically using the SELEX procedure [67] and used for NP functionalization [68]. The use of aptamers for the targeted delivery of anticancer drugs and PSs has been ubiquitously studied [69]. However, the use of aptamers for the targeted delivery of antibacterial drugs and PSs in aPDT has recently attracted attention [70]. Disease cell targeting aPDT applications may be illustrated with the studies of a DNA-aptamer-functionalized nanographene oxide as a targeted nanomaterial-mediated bio-theragnostic approach against
6. Glycan-based targeting
Evidence that the carbohydrate-based polysaccharide polymers found on bacterial cells, also known as glycans, can form the basis for bacterial targeting has been presented [77]. There are glycan-recognizing and binding proteins on bacterial target host cell surfaces, known as lectins. These protein molecules are recognized by the glycan structures on bacterial target host cell surfaces where the bacteria attach for host cell invasion [78]. The antibacterial macrophage strategy involves the initial attachment to the bacterial cell surface, followed by the delivery of depolymerases and lysins to degrade the bacterial cell wall-based glycans [79]. Similarly, the bacterial glycan cell targeting technology is based on extensively lectin-functionalized nanoconjugate systems that attract and selectively bind to bacteria with high binding affinity, delivering their antibacterial cargo, such as antibiotic chemotherapy drugs and PDT PSs, yet maintaining host microenvironment biocompatibility [80, 81].
7. Smart stimulus-responsive nanoparticles in antimicrobial photodynamic therapy
Further enhancement of selectivity for the disease over host tissue cells can be achieved if the aPDT toxicity of the drug and PS molecules is controlled in such a way that they are only toxic on target and are benign elsewhere. As a result, substantial research has been dedicated to developing stimulus-responsive aPDT. Two approaches have emerged to achieve this. In the one approach, nanoconjugate systems have been cleverly designed and fabricated to respond to the pH and redox potential difference between normal host tissue cells and the extracellular environment, on the one hand, and the intracellular environment of bacterial disease cells, on the other hand. In bacterial cells and the extracellular bacterial microenvironment, the pH drops by nearly 2–3 compared to normal host tissue cells and the usual host tissue extracellular microenvironment [82]. Therefore, systems have been cleverly designed in which the drug and PS molecules are covalently bound by functional groups that are cleaved upon the pH drop as they enter the disease cells. Due to the pH differential, this stimulus responsiveness selects only disease cells to deliver their drug and PS cargo and withholds it anywhere else.
Utilizing the pH differential, the PS curcumin was incorporated into the zeolitic imidazolate framework-8, ZIF-8, which disassembles at low pH, releasing the PS. The zinc ions released from the MOF increased the porousness of the bacterial cell membrane, causing the enhanced production of ROS in the extracellular environment, which resulted in bacterial cell membrane disruption and damaged appearance of the bacteria under the electron microscope [83]. Therefore, the authors concluded that pH-sensitive MOF-mediated bacterial cell targeting might be a promising aPDT strategy. A similar study showed pH-responsive delivery of ammonium methylbenzene blue incorporated into the ZIF-8 [82]. Clearly, the MOF strategy is an important approach to pH-sensitive drugs and PS release in aPDT. The technology of encapsulation of the PS in organic NPs has also been studied in pH-responsive targeting. For example, Chlorin e6-encapsulated pH-sensitive charge-conversion polymeric NPs were used to target
Nanoconjugate systems have also been designed that respond to externally applied physical stimuli, such as MH, PTT, and US. The high preference for MH and ultrasound (US) is due to their unlimited tissue penetration depth compared to the limited tissue penetration depth of light, even in the therapeutic window. Utilizing external stimuli may be illustrated with the combination of MH with PDT by encapsulating magnetic iron oxide NPs in the liposome aqueous core and organic PSs in the hydrophobic liposomal bilayer (Figure 9a). The PS is released upon applying a high frequency alternating magnetic field (Figure 9b), which elevates the temperature to 42–45°C, disassembling the liposome and releasing the PS (Figure 9c) from the liposomal bilayer [86]. Encapsulating plasmonic and photo-responsive NPs also achieves the release of the PS in the same way, upon the application of light to elevate the temperature by the photothermal mechanism. Used to target cancer cells in experimental studies, this approach eradicated all cancer cells in an
Figure 9.
Magnetic hyperthermia-triggered release of the PS from the liposome bilayer.
Interestingly, to the best of our literature search, studies of MH in combination with PDT have not been reported, although studies on the antibacterial effects of static magnetic fields have been conducted. For example, applying an external magnetic field caused magnetic NPs to move deep into the biofilm [88]. Yet no studies have been found on the application of MH in combination with PDT to eradicate bacteria. Liposomal encapsulation of plasmonic NPs and PSs as a basis for antibacterial photothermal and aPDT combination, on the other hand, has been reported. The encapsulation of gold nanorods in the liposome core and the PS curcumin in the liposome bilayer, for example, was reported for treating recurrent acne with the combination of PTT and aPDT [89]. In this research, the curcumin PS is activated by blue light for PDT, while the gold nanorods were activated by near infrared (NIR) light for PTT, resulting in heat and ROS-based inhibition of bacterial growth.
8. Antibacterial photodynamic therapy folate targeting
A recent research report has found that folate receptor expression is significantly higher in animal tissues infected with Methicillin-resistant Staphylococcus aureus (MRSA) compared to in uninfected control tissues. The researchers exploited this finding by incorporating vancomycin in folate-decorated liposomes for folate over-expression targeting of the MRSA-infected tissue. They found that the bactericidal and biofilm inhibition effects of the folate-decorated liposomes incorporating vancomycin was higher compared to direct vancomycin application, suggesting superior MRSA targeting and delivery of the drug [90]. The targeting potential of folate functionalization was also confirmed by the superior targeting and antibacterial enhancement of the efficacy of folate-functionalized cerium NPs [91]. This has been widely exploited in PDT studies. Recently, for example, titanium dioxide NPs have been conjugated with folic acid and a phthalocyanine PS for targeted anticancer PDT [92].
The folate over-expression disease cell-targeting mechanism is illustrated in Figure 10. It involves the functionalization of the PS-carrier NPs with folic acid. These NPs will bind to the folate receptors followed by enhanced endocytosis by the disease cells because there is enhanced expression of the folate receptors on the disease cells. Once inside the disease cells, the NPs are induced by the disease cell internal microenvironment to release their PS cargo, thus initiating the PDT cell death pathways.
Figure 10.
The folate over-expression disease cell-targeting mechanism.
Therefore, in addition to their well-known folate over-expression-enabled cancer-cell targeting, folate-functionalized NPs incorporating PDT PSs could be used to target bacterial infection for enhanced antibacterial PDT. It is therefore quite surprising that this potential of folate targeting bacterial infection has hardly been investigated as a bacterial targeting strategy in antibacterial PDT. In this regard, the potential of the findings of the folate receptor over-expression of MRSA by Vanamala et al. [90] could be the groundbreaking research that will lead to folate-targeting applications in antibacterial PDT. Therefore, studies are required to determine the microbial infection universality of the higher folate receptor expression found in MRSA-infected tissues compared to in uninfected control tissues.
9. Nanoparticles as agents for photodynamic therapy combination therapies
Nanotechnology has taken a prime position in PDT combination therapeutics research where NPs, due to their small size and huge volume-to-surface area ratio, can absorb and otherwise load large quantities of PSs and the therapeutic agents required for the PDT combination therapy. In combining PDT with antibacterial chemotherapy, for example, NPs are loaded with antibacterial PDT PSs and antibiotic drugs. In this combination therapy, the NPs can act not only as drug and PS carriers and delivery agents but also as bacterial infection-targeting agents [93]. Nanoconjugates that are either inherently cationic or rendered cationic by virtue of cationic PS capping agents have shown selectivity for bacterial pathogens and bacterial infection. For example, polymeric chlorin-e6-incorporating nanoconjugate systems that become cationic at slightly acidic pH were reported to show pH-dependent bacterial selectivity and efficacy variation [94], while a zeolite-based inorganic NP, capped with the cationic tetravalent silicon phthalocyanine PS, showed a positive zeta potential, selectivity for bacterial infection, and enhanced efficacy [95]. However, the primary purpose of multifunctional nanoconjugate systems is to incorporate functionalities that enable the desired combination therapy into nanoconjugate systems. For example, to enable the combination of antibiotic chemotherapy with PDT, a nanoconjugate system consisting of a core of gold and a shell of silver was passivated with 4-mercaptobenzoic acid. Subsequently, the mercaptobenzoic acid shell of the gold NPs was modified by conjugation with vancomycin and loaded with the phthalocyanine PS to enable vancomycin-mediated antibiotic chemotherapy in combination with phthalocyanine-mediated PDT [96].
10. Antibacterial photodynamic therapy in combination with chemotherapy
The urgent response to the fast development of bacterial resistance to antibiotics is probably the single most compelling reason for the current rising interest in nanomaterial-mediated PDT, specifically the ability of nanomaterials to carry multiple drug and PS payloads and to deliver them only in the infection site or upon stimulation by an external source, which is the basis for combination therapies involving PDT. The reason for this is that although mechanisms of resistance against antibacterial PDT have been described, including hypoxia, the repair of DNA damage, efflux of the PS, upregulation of the heat shock protein, and inhibition of apoptosis [97], very little resistance has been observed [98, 99, 100]. Antibiotic therapy and PDT have been the subject of much interest [101, 102, 103, 104].
Incorporating a porphyrin PS, the immunosuppressant methotrexate, and silver in one nanoconjugate may be used as an example of the nanomaterial-mediated combination of PDT with an antibiotic material [105]. While demonstrating biocompatibility and release of silver and the porphyrin PS, the nanoconjugate also showed excellent antibacterial activity in excess of that shown by the antibiotic and the porphyrin PS each acting alone. This type of combination of antibiotic silver with PDT was also shown by the eradication of
11. Anticancer photodynamic therapy in combination with chemotherapy
Given the history of PDT and chemotherapy as anticancer therapeutic technologies, it is not surprising that the combination of PDT and anticancer chemotherapy is among the most widely reported. A study of the combination of the aluminum phthalocyanine chloride complex as the PS and doxorubicin as the chemotherapy drug agent, both encapsulated in nano-emulsions, was reported to reduce the induction of breast cancer in mice, to reduce the expression of the vascular endothelial growth factor, and to increase the expression of the apoptosis-indicating Caspase-3 protein as well as tissue death by necrosis. There was a large reduction in cancer cell proliferation [109]. The combination of PDT with anticancer chemotherapy was also studied using chlorin-e6 as the PS and cisplatin as the chemotherapy drug while ameliorating hypoxia using perfluorocarbon-mediated molecular oxygen self-supply. These three key elements were incorporated in pH- and ROS-responsive micelles made of polyethylene glycol and polyglycolic acid. This remarkable innovation showed enhanced activity against SKOV3 ovarian cancer cell lines [110]. This was attributed to the pH responsiveness, which ensured that the nano-micelles released their cargo only when they were inside the ovarian cancer cells. The perfluoro hydrocarbon-mediated oxygen encapsulation in the micelles ensured oxygenation to overcome hypoxia. Figure 11 shows a similar nanoconjugate formed by the self-assembly of polyethylene glycol after conjugation of the PS IR780 with a perfluoro hydrocarbon, along with loading with doxorubicin, achieving similar results against MCF-7 cancer cell lines [111].
Figure 11.
Self-assembly of polyethylene glycol after conjugation with the perfluoro hydrocarbon and IR780 was loaded with doxorubicin.
12. Photodynamic therapy in combination with photothermal hyperthermia
Plasmonic NPs that possess high photothermal conversion, such as those of graphene oxide, are required to enable the combination of PDT and PTT against cancer and other diseases. For example, the conjugation of graphene oxide NPs with folic acid to enable the folate over-expression cancer cell-targeting mechanism and chlorin-e6 to enable PDT was reported to enhance the cancer cell uptake and retention and to selectively kill cancer cells
Gold NPs are well-known for their photoacoustic and photothermal properties, which enable light absorption and the production of heat due to their localized plasmon surface resonance [113]. Marketed as Temoporfin or Foscan over the past decade or so, the PS meso-tetrakis(3-hydroxyphenyl)chlorin is approved by the Food and Drug Administration (FDA) for PDT [114]. Therefore, a therapeutic modality that combines meso-tetrakis(3-hydroxyphenyl)chlorin-mediated PDT with gold NP-mediated PTT, based on a nanoconjugate made of NPs of gold and a capping shell of meso-tetrakis(3-hydroxyphenyl)chlorin, was reported to have a twofold synergistic enhancement of efficacy against the neuroblastoma-derived SH-SY5Y cells
Figure 12.
A nanoconjugate made of nanoparticles of gold with a capping shell of temoporfin.
13. Photodynamic therapy in combination with sonodynamic therapy
The exploratory clinical study of PDT combined with sonodynamic therapy (SDT) against cholangiocarcinoma in which hematoporphyrin was used as the sono-photosensitizer provides a clear indication of the state of this technology in the clinical translation trajectory [117]. This is supported by the clinical pilot studies [118] and case reports [119] that are starting to appear in the literature. Nanotechnology is ubiquitous not only as a platform for the PDT and SDT agents [120, 121], but also for other purposes of the innovation, such as hypoxia amelioration, disease targeting, imaging-guided therapy, and stimulus-responsive release. For example, reducing human serum albumin to cleave the disulfide linkages and produce free thiol groups, followed by conjugation with hemoglobin, was used to produce a nanoplatform capable of carrying oxygen. The innovative nanoplatform was used to encapsulate manganese (II) phthalocyanine as the PS and to absorb copious amount of oxygen before administration as a sono-photosensitizer that responds to light and ultrasonic activation to produce ROS, even from the insufficiently oxygenated tumor microenvironments of 4 T1 breast cancer xenografts in mice. It also enabled magnetic resonance and photoacoustic imaging [122]. Additionally, although notoriously difficult to reach by PDT, brain cancer can be reached with SDT. The PS 3-(1′-Hexyloxy)ethyl-3-devinylpyropheophorbide-a, delivered using cationic polyacrylamide NPs functionalized with tetramethyl ammonium groups, improved the kill rate of the combination of PDT and SDT relative to the individual technologies, against the U87 human glioblastoma cell line, considered to be the best model for brain cancer [123].
14. Photodynamic therapy in combination with magnetic hyperthermia
Enabled by a whole-body applicator, MH is used to treat cancerous tumors that are difficult to reach, such as tumors in the brain and those located in dark tissues, such as the liver, spleen, pancreas, and bones [124]. Recently, however, the development of a handheld MH device has been reported for more focused treatments [125]. Nanoconjugate platforms for the combination of PDT with MH need to incorporate the PS and magnetic NPs ideally in the same nanoconjugate [87]. For example, using nanoemulsions loaded with magnetic iron oxide NPs and an aluminum phthalocyanine PS, the combination of MH and PDT was reported to achieve 66% reduction in the viability of the human bone marrow mesenchymal stem cell line [126]. In addition, there are examples of multifunctional nanotechnology platforms aimed at combining PDT with MH that are selective for cancer cells. For example, a nanoconjugate of Janus nanobulets with magnetic manganese oxide heads and chlorin-e6 PS-laden mesoporous silica bodies was cloaked with the breast cancer cell membrane. Following rapid cancer cell endocytosis, the disulfide anchor of the PS onto the mesoporous silica side of the Janus nanobulet was easily cleaved upon the pH drop of the breast cancer cell internal microenvironment, thus releasing the PS [127].
15. Conclusion
The development of resistance against antibacterial drugs is the rising challenge of the century, because it was nearly one century ago that bacterial infections were dealt a lethal blow by the discovery of antibiotics, which are now facing a drastic decline in efficacy against bacterial and fungal infections, due to the development of resistance. Generally, nanomaterial-mediated targeted drug delivery is a major thrust against antibacterial drug resistance. It has been noted that the development of resistance against PDT is a difficult feat for microbial pathogens to mount. It follows therefore that nanomaterial-mediated targeted PS delivery further diminishes the likelihood of the development of resistance. The boundaries may be pushed even further by the combination of nanomaterial-mediated delivery of antibiotic drugs and PDT PS, contained in multifunctional nanoconjugate systems used in photodynamic-antibiotic chemotherapy drug combination therapies because such systems would dramatically reduce systemic release of the antibiotic chemotherapy drug and PS. It is for these reasons that the ruthenium polypyridyl complexes, which are potent generators of ROS upon photo-irradiation as antibacterial PDT PSs, have been developed with the purpose of pursuing the capability of combating antibiotic resistance [128]. In the same way as combining different antibiotic drugs is effective in repurposing older drugs rendered unusable by the development of resistance, so is combining antibiotic drugs with PDT [129].
Future benefits of combination therapies include enhancement of the combating of cancer and bacterial infections. However, the current rapid expansion of the scope of these combination therapies has left a few gaps. For example, the applications of the combination of MH with PDT, which appears to have been thwarted by the requirements for onerous investments in equipment and infrastructure, could benefit in the future from the development of handheld MH devices, subject to the advances in availability of such devices [125]. Therefore, this paper is a timeous addition to the advocacy for the development of such handheld devices. Additionally, other combinations with PDT hold great promise for the future, which are still being explored in experimental research. For example, the combination of PDT with cold atmospheric pressure plasma therapy has been shown by researchers at the Universität Greifswald in Germany, to eradicate bacterial infections of common skin and wound pathogens
Glossary of acronyms
Photodynamic therapy | |
Antimicrobial photodynamic therapy | |
Magnetic hyperthermia therapy | |
Photothermal hyperthermia therapy | |
Reactive oxygen species | |
Extracellular polymeric substance | |
Metal-organic frameworks | |
Nanoparticles | |
Methicillin-resistant | |
Sonodynamic therapy | |
Zeolitic imidazolate metal-organic-framework-8 | |
Ultrasound | |
Photosensitizer | |
Near infrared | |
Methicillin-resistant | |
Food and Drug Administration | |
Singlet spin state photosensitizer in the ground state | |
Singlet spin state photosensitizer in the first excited state | |
Singlet spin state photosensitizer in the second excited state | |
Triplet spin state photosensitizer in the first excited state | |
Triplet spin state molecular oxygen in the ground state | |
Singlet spin state molecular oxygen in the excited state |
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