CC BY
4DOI 10.24412/cl-37136-2023-1-193-200
HOW IS PHOTONICS POTENTIATING COMBINATIONS OF PHOTODYNAMIC THERAPY WITH OTHER NON-INVASIVE THERAPEUTIC TECHNOLOGIES FOR ENHANCED
EFFICACY AND SELECTIVITY?
SANDILE SONGCA1 AND OLUWATOBI OLUWAFEMI2
'School of Chemistry and Physics, Pietermaritzburg, University of KwaZulu-Natal, South Africa 2Department of Chemical Sciences, University ofJohannesburg, Doornfontein,
Johannesburg, South Africa
songcas@ukzn.ac.za
ABSTRACT
Photodynamic therapy (PDT) utilizes light to activate special compounds known as photosensitizers (PSs) to produce reactive oxygen species (ROS) from oxygen that is present at the disease sites and cells. The penetration depth of human tissue by light is quite shallow. One of the photonics approaches in light delivery toward enhancing PDT includes using laser light sources and optic fiber delivery to reach deep-seated disease sites. Several innovations are available in the market for light distribution within the disease site at the end of the optic fiber. PDT has been enhanced by combination with other minimally invasive therapies such as photothermal therapy (PTT), sonodynamic therapy (SDT), magnetic hyperthermia therapy (MGH), radiotherapy (RT), cold atmospheric pressure plasma therapy (CAPP), and immunotherapy (IT), to name a few. Photonics often play well-defined roles in each of these combination therapies, resulting in synergistic enhancement against cancer and bacterial infections and an increasing scope of other applications. The current state of the art of PDT involves nanoconjugate systems that are loaded with copious amounts of the PS to improve the pharmacokinetics, delivery, targeting, and specificity of disease sites and cells. The purpose of the nanoconjugate approach is to induce very little or no immune response while the nanoconjugate is still in systemic circulation to selectively target the disease site and cells, where it is selectively taken up and retained by the disease cells. While an increasing number of modalities of the approach employ systems that respond to unique characteristics of the disease site and cell external and internal microenvironments to release the PS, an increasing number of nanoconjugates are stimulated by external stimuli to do so. The external stimuli reported in the literature include light, MGH, ultrasound (US), and X-rays. Therefore, photonics has a major role to play in stimulus-responsive PS release. Our research group has developed a number of nanoconjugate systems for PDT and combinations thereof with other minimally invasive technologies. For example, nanoconjugates combining PDT with PTT and those combining PDT with MGH have been prepared and are showing good results against cell lines in vitro. The appropriate literature update on photonics applications to potentiate PDT introduced in this paper focuses on three key applicators, namely basic, preclinical, and clinical research. The paper also introduces some of our research results of photonics applications in PDT, PTT, MGH, and combinations thereof. The paper concludes by highlighting state-of-the-art photonics devices in basic research and the clinic and recommendations on potential areas of further research and innovation. As part of these concluding remarks, the paper also comments on the future research directions in our research group based on the nanoconjugates we have developed and specific disease applications of national interest in South Africa.
INTRODUCTION
Light has been used in hospital physiotherapy and medicine for more than seven decades [1]. In contrast, according to Dr. Tomislav Mestrovic, the light therapy approach itself dates back more than three thousand years [2]. Nowadays, light has found more nuanced therapeutic applications. For example, in PDT, light is used to photosensitize the generation of ROS in the disease microenvironment. ROS are molecular species derived from molecular oxygen that are highly reactive and, therefore, toxic. They include singlet excited state oxygen,
hydroxyl anions, radical anions, peroxide, and superoxide radicals and anions, that are generated from the type I mechanism, shown in Figure 1 using a Jablonski diagram.
Photonics in Photodynamic Therapy
According to Algorri et al. (2021), photonics in PDT is composed mainly of three approaches, which include irradiation using halogen lamps, irradiation with LEDs, and laser irradiation used in the laboratory and the clinic [3]. To enhance selectivity for the disease over normal host tissue, it is necessary to align the distribution and dosimetry of the light energy with the morphology of the disease. While this is difficult to achieve with non-coherent light sources such as halogen lamps and LEDs, coherent laser light sources are often equipped with specialized optic fiber for transmitting the laser light energy to the disease site. More importantly, however, these laser light transmission optic fibers are equipped with devices that distribute the light energy evenly over the disease, depending on the location, histology, and anatomy [4]. The trouble with optic fiber laser light energy transmission and delivery is that it is quite invasive. Researchers have come up with a number of non-invasive and minimally invasive technologies for delivering light energy to activate PSs in deep-lying diseases. These include SDT, MGH, and RT. Additionally, a novel innovation involving miniature implantable devices that are wirelessly activated to emit the desired light frequency from within the disease site has been reported [5]. Furthermore, photochemical internalization (PCI) potentiates PDT by incorporating organic dye PSs into the bilayer of endocytic liposomes, followed by endocytosis. Once inside the disease cells, the PSs are released by light activation, which causes photodynamic disruption of the endocytosed liposomal vesicle membrane bilayer into the cytosol [6].
Figure 1: Jablonski diagram showing the mechanism of photodynamic therapy.
Mechanism of Photodynamic Therapy
Upon light absorption, the PS is excited from its singlet ground state to the singlet excited states (:PS0^:PSi, :PS0^:PSn, n = 1, 2, ...). Excitation to higher singlet excited states is almost always followed by non-radiative relaxation back to the first singlet excited state (:PSn^:PSi), enhancing the population of the first singlet excited state (1PS1). Due to the enhanced population, the first singlet excited state relaxes by multiple mechanisms, including non-radiative intersystem crossing, fluorescence, and other non-radiative relaxations. The critical transition for PDT is the intersystem crossing (1PS1^3PS1) because it involves a spin state change that takes the PS to an excited triplet state from which radiative relaxation to the singlet ground state is forbidden. Because the excitation of molecular oxygen from its triplet ground state to its singlet excited state (3O2—^ O2), which requires change from the triplet to the singlet state, has an equal energy differential and reverse spin state change, the energy transfer between the triplet state of the PS (3PS1) and molecular oxygen in its triplet ground state (3O2) occurs when the molecules collide, in a process known as photosensitization. The photosensitization of molecular oxygen from its triplet ground state to the singlet excited state (3PS1 +3O2—>3PS0+1O2) is an essential initial step in ROS production. Excited singlet state oxygen leads to other
ROS, such as hydroxyl and peroxide radicals and anions. Therefore, this process is made possible by two critical photonics factors. The first factor is the energy differential between the singlet excited state of molecular oxygen and its triplet ground state AEq2 = [E(1O2) - E(3O2)] and the energy differential between the triplet excited state of the PS and its singlet ground state AEPS = [E(3PS1) - E(1PS0)]. The energy differential between the PS species, AEPS, must be equal to or marginally greater than the energy differential between the molecular oxygen species, AEO2, which is equal to 94.5 kJ/mol (AEPS > AEO2 = 94.5 kJ/mol). The second is the spin state differential between the ground and excited states. This renders the electronic transitions untenable for both the PS and molecular oxygen because a forbidden change between triplet and singlet spin states is required for each of these transitions. However, when the 3PS1 and 3O2 molecules collide, simultaneous energy transfer and triplet/singlet spin state change occurs.
(a) spherical resonance (b) longitudinal resonance (c) transverse resonance
Figure 2: illustration of (a) the resonance mechanism for spherical nanostructures, (b) the tudinal surface plasmon resonance, and (c) transverse surface plasmon resonance. Reproduced from er et al. (2015) [7] and Jiang et al. (2014) [11] under the appropriate creative commons attribution
licenses.
Mechanism of Photothermal Therapy
Light is also used to generate therapeutic localized hyperthermia. For example, due to the local surface plasmonic resonance (LSPR) of their surface electrons, some nanoparticles absorb light and transform the light energy into heat. Therefore, when such nanoparticles are irradiated after they are embedded in the disease site or selectively taken up by the disease cells, they can generate heat there. The disease cells will therefore be killed provided the generated heat exceeds the threshold for the disease cells enough to overwhelm the biological response of heat shock proteins. The LSPR mechanism of these nanoparticles is shown in Figure 2. Light comprises perpendicularly orientated synchronous electric and magnetic field components with sinusoidal intensity variation. The sinusoidally changing electric and magnetic fields cause a coupled resonance of the nanoparticle surface electrons, thus absorbing the energy and converting it to heat. This energy conversion occurs mainly by hysteresis [8]. Theoretical analytical research [9,10] and empirical evaluation [11,12] have shown that the LSPR is more intense with longitudinal nanostructures than non-longitudinal ones. Hence the LSPR absorption band arising from longitudinal surface electron resonance is more intense compared to the absorption band arising from transverse surface electron resonance, which is arguably of the same magnitude as that of non-longitudinal nanostructures of similar diameter. Longitudinal nanostructured materials known for applications in photothermal hyperthermia include nanorods of gold, silver, iron oxide, and carbon nanotubes. Others include nanosheets of several chalcogenides, including manganese, molybdenum, and copper. The range of non-longitudinal structures includes metal nanostructures such as silver and gold, carbon structures such as graphene dots and fullerenes, and nanostructures of oxides of many metals.
(a) light penetration through the (b) therapeutic window (c) deepest penetrating
skin frequencies
Figure 3: illustrations of the therapeutic window showing the deepest penetrating light frequencies and light propagation through the skin according to Rugguiero et al. (2013) [13].
Biomedical Light Sources
For PDT and PTT, halogen lamps and light-emitting diode (LED) light sources are widely used. PDT and PTT irradiation was also accomplished using laser light sources, most of which generate low-intensity lasers for direct application or via transmission through optic fibers. For example, while we used an LED light source, the laser light source used for some of our PDT and PTT experiments was a tunable intensity dual-output frequency laser light source with optic fiber transmission and an output distribution device that delivered spherically shaped equal distribution. The first category of biomedical light sources and devices are those used in basic experimental research. Three important parameters are the intensity and frequency of the light and the portability of these devices. The frequency depends on the application, including the biomedical agents such as the PS nanoconjugate and plasmonic nanoparticles used. In cases of direct application to superficial and shallow disease, the frequency depends on the penetration depth of the tissue. As a result, near-infrared light sources are preferred because the maximum penetration depth is achieved in the near-infrared therapeutic window. The therapeutic window may be illustrated using Fig. 3, showing the variation of human tissue penetration with frequency. The second category of light sources are those used in clinical settings, referred to as medical lasers. The characteristics of medical lasers depend on specific clinical applications. Whereas some are used for light therapy, the characteristics of those used for PDT, and PTT, and combinations thereof also depend on the PS and the plasmonic nanoparticles used.
(a) microlens tipped optic fiber
(b) spherical diffusor-tipped optic fiber delivery
(c) the cylindrical diffusor-tipped delivery
m
(d) balloon-tipped delivery system
Figure 4: schematic illustration of microlens-tipped optic fiber, spherical diffusor-tipped optic fiber delivery, cylindrical diffusor-tipped delivery system, and balloon-tipped delivery
system
Laser Light Distribution Devices
Delivery of light to clinical disease or disease models in-vitro and in-vivo depends on the shape and size of the disease model container or disease site. Several light delivery devices are available in the market. While
overcoming the shallow depth of light penetration through human tissue to reach the disease site, optic fibers are tipped with lenses that distribute the energy of light evenly over a 2-dimensional plane (Fig. 4a). They are also tipped with a spherical diffusor to distribute the light over a spherical disease morphology (Fig. 4b). Cylindrical diffusor-tipped devices are useful for treating disease in tubular organs such as blood vessels and the gastrointestinal tract (Fig. 4c). The balloon-tipped diffusor is used for distributing light from within the internal cavities of organs such as the stomach and the bladder (Fig. 4d).
METHODS
Samples were irradiated using one of three light sources; a halogen lamp (tungsten halogen GE Quartzline lamp; 500 W, 560-780 nm), a light emitting diode array (164.51 J/cm2, 660 nm), and laser light source (continuous-wave NdYVO4 air-cooled NIR laser (2.5 ± 0.5 W/cm2, 1064 nm).
Irradiation Using a Halogen Lamp
Initially, rudimentary photonics arrangements were used to irradiate our samples. For example, to evaluate the effect of protoporphyrin-IX and methylene blue-mediated aPDT against biofilm-forming multidrug-resistant A. baumannii, we irradiated the samples using a halogen lamp, filtering the heat from the lamp using a water bath, as shown in Fig. 5a [14]. This arrangement was also used to evaluate the aPDT effect of cationic porphyrin encapsulated gold nanorods on bacterial cell lines [15]. Samples were placed on an opaque surface at the bottom drawer of the device shown in Figure 5a, and the front lid was closed. The samples were irradiated from the rectangular irradiation hole at the top of the device. After irradiation, the hole was closed, and the samples were transferred to an incubator. Despite low power density and low light fluence, the use of the halogen lamp as a light source for PDT and PTT has been reported widely in the literature [16].
Irradiation Using a Light-Emitting Diode
Due to reduced excess heat, LED and laser light sources were also employed. For example, to overcome the cytotoxicity of common passivating agents, gold nanorods were passivated with gelatin. The as synthesized nanoconjugates were then irradiated with an LED in the PTT experiment [17]. Additionally, to overcome the poor water solubility of porphyrin dye PS molecules and their non-specific binding, ZnCuInS/ZnS quantum dots were conjugated with the PS meso-tetrakis(3-hydroxyphenyl)porphyrin. In the PDT experiment, the resulting nanoconjugate was irradiated with an LED light source, as shown in Figure 5a [18]. While the LED was effective and reproducible, irradiation quantification was still challenging.
(a) rudimentary photonics arrangements (b) schematic showing the continuous-wave Nd:YVO4 air-illy used to irradiate our samples for PDT ed NIR laser [19]. Reproduced from Wang et al. (2019) under the in-vitro measurements. creative commons attribution license.
Figure 5: halogen lamp, LED, and Laser irradiation techniques.
Irradiation Using a Continuous-Wave Optic Fiber-Transmitted Laser
In evaluating their effect against cancer metastasis in the proper axillary lymph nodes in mice, however, mPEG-passivated gold nanorods were irradiated with a continuous-wave optic fiber-transmitted laser, tipped
with a spherical diffuser (Fig. 4b) with a focusing diameter of up to 6 mm from a neodymium air-cooled NIR laser source [20]. Another advantage of using a tunable laser light source is that the desired output is set on the laser-generating device. These output settings may be reproducibly repeated many times. In addition, the laser light source is calibrated to a desired narrow monochromatic bandwidth to enable irradiation at specific absorption bands of the chromophores. This is important to isolate the absorption of the PS from the absorption of the nanoconjugate and vice versa, thus isolating the PDT from the PTT effect.
RESULTS
In the initial rudimentary irradiation using a halogen lamp, heat from the lamp was absorbed by the water bath at room temperature, with a depth of at least 120 mm. Therefore, the temperature of the medium-filled control samples was constant within ±2 oC. In the arrangement shown in Figure 5a, initially used with the halogen lamp, the water bath soon became of little value when the LED was used because the LED produced significantly less heat. Nevertheless, the water bath was retained to remove any heat from the lamp. In each case, the light energy was monitored using a light meter, adjusting the distance of the lamp from the samples as needed. The temperature was also monitored using a thermometer by continuously measuring the temperature of an identical control sample among the sample cell lines. This arrangement was not needed when using laser light. Additionally, the laser light source delivered reproducible energy with the same settings (power = 2.5 ± 0.5 W/cm2, ^max = 1064 nm, and beam diameter = 0.6 mm) with a laser focus diameter of up to 0.6 cm) [Ошибка! Закладка не определена.].
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(a) Q-bands of 5,10,15,20- (b) TSPR and LSPR absorption (c) Q-bands of 5,10,15,20-;rakis(4-aminophenyl)porphyrin bands of the gold nanorods tetrakis(4-4-pyridyl)porphyrin
Figure 6: different absorption of the PSs (a) TAP and (b) TPyP, and gold (c) nanorods. Reproduced from Hlapisi et al. (2021) [15] under the creative commons attribution license 4.0.
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CONCLUSION
Photonics has enabled several combinations of PDT, for example, with PTT, thus potentiating the technology. In all our experiments, irradiation with a halogen lamp and subsequently with an LED served their purpose well. However, the reproducibility of the laser light source and variable power settings presented significant advantages for PDT and PTT. Laser light power calibration curves were completed in minutes. There was no need for the filtration of heat from the light source. It is possible to isolate the PTT effect from the PDT effect by irradiating at the plasmonic resonance band because it is well separated from the PS Q bands. For example, it was possible to isolate the PTT response from the PDT response by irradiating at 800 nm, the longitudinal nanorod absorption where the porphyrin has no absorption. Similarly, irradiating at any of the Q bands (Q1 ~ 510 nm, Q2 ~ 550 nm, Q3 ~ 580, and Q4 ~ 655 nm) isolated the PDT response from the PTT response because the PS Q band absorptions are well separated from the nanorod longitudinal absorption (Fig. 6). To overcome the tissue penetration depth challenge, our group has embarked on studies of the combination of MHT with PDT. We first demonstrated the capping of iron oxide nanoparticles with a meso-tetra(4-hydroxyphenyl)porphyrin [21,22] and a porphyrin-capped layer of gold [23,24]. These materials exhibited aPDT and anticancer PDT against cell lines in-vitro. In-vivo studies using mouse models against cancer and bacterial infection have been initiated. A benchtop magnetic hyperthermia equipment was procured for
applications in the planned preclinical studies. Additionally, a dual-frequency tunable laser has been made available to be used for topical aPDT studies in-vivo using mouse models. Our group has plans to test the SDT ROS generation of the nanoconjugate systems thus far developed as we commence our debut into SDT. The current focus includes breast cancers and various bacteria, such as multidrug-resistant S. Aureus and A. baumannii, because they make a significant contribution to the South African national burden of disease. While located, arguably, at the tail end of the clinical PDT and PTT translation, the development of photonics devices offers avenues for novel innovations to support the clinical lobby in ways that can be anticipated from the photonics support for basic PDT and PTT research. One example of current device innovation already showing promise is the combination of PDT and PTT against superficial cancer, and possibly multidrug-resistant bacterial and fungal strains, is the microneedle technology [25].
Acknowledgments
The research was made possible by several grants from the National Research Foundation South Africa (105262, 149191, 129808, 129806, 129736, 114313, 118774, 129391) and the Council for Scientific and Industrial Research, South Africa (LREPA26, LREQA26, LRERA23, LRESA24, LRETA24).
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