Forging Forward in Photodynamic Therapy.

In 1978, a Cancer Research article by Dougherty and colleagues reported the first large-scale clinical trial of photodynamic therapy (PDT) for treatment of 113 cutaneous or subcutaneous lesions associated with ten different kinds of malignancies. In classic applications, PDT depends on excitation of a tissue-localized photosensitizer with wavelengths of visible light to damage malignant or otherwise diseased tissues. Thus, in this landmark article, photosensitizer (hematoporphyrin derivative) dose, drug-light interval, and fractionation scheme were evaluated for their therapeutic efficacy and normal tissue damage. From their observations came early evidence of the mechanisms of PDT's antitumor action, and in the decades since this work, our knowledge of these mechanisms has grown to build an understanding of the multifaceted nature of PDT. These facets are comprised of multiple cell death pathways, together with antivascular and immune stimulatory actions that constitute a PDT reaction. Mechanism-informed PDT protocols support the contribution of PDT to multimodality treatment approaches. Moreover, guided by an understanding of its mechanisms, PDT can be applied to clinical needs in fields beyond oncology. Undoubtedly, there still remains more to learn; new modes of cell death continue to be elucidated with relevance to PDT, and factors that drive PDT innate and adaptive immune responses are not yet fully understood. As research continues to forge a path forward for PDT in the clinic, direction is provided by anchoring new applications in mechanistically grounded protocol design, as was first exemplified in the landmark work conducted by Dougherty and colleagues. See related article by Dougherty and colleagues, Cancer Res 1978;38:2628-35.

Photo-triggerable liposomes based on lipid-porphyrin conjugate and cholesterol combination: Formulation and mechanistic study on monolayers and bilayers.

Lipid-porphyrin conjugates are considered nowadays as promising building blocks for the conception of drug delivery systems with multifunctional properties such as photothermal therapy (PTT), photodynamic therapy (PDT), phototriggerable release, photoacoustic and fluorescence imaging. For this aim, we have recently synthesized a new lipid-porphyrin conjugate named PhLSM. This was obtained by coupling pheophorbide-a (Pheo-a), a photosensitizer derived from chlorophyll-a, to egg lyso-sphingomyelin. The pure PhLSMs were able to self-assemble into vesicle-like structures that were however not stable and formed aggregates with undefined structures due to the mismatch between the length of the alkyl chain in sn-1 position and the adjacent porphyrin. Herein, stable PhLSMs lipid bilayers were achieved by mixing PhLSMs with cholesterol which exhibits a complementary packing parameter. The interfacial behavior as well as the fine structures of their equimolar mixture was studied at the air/buffer interface by the mean of Langmuir balance and x-ray reflectomerty (XRR) respectively. Our XRR analysis unraveled the monolayer thickening and the increase in the lateral ordering of PhLSM molecules. Interestingly, we could prepare stable vesicles with this mixture that encapsulate hydrophilic fluorescent probe. The light-triggered release kinetics and the photothermal conversion were studied. Moreover, the obtained vesicles were photo-triggerable and allowed the release of an encapsulated cargo in an ON-OFF fashion.

Application of TD-DFT Theory to Studying Porphyrinoid-Based Photosensitizers for Photodynamic Therapy: A Review.

An important focus for innovation in photodynamic therapy (PDT) is theoretical investigations. They employ mostly methods based on Time-Dependent Density Functional Theory (TD-DFT) to study the photochemical properties of photosensitizers. In the current article we review the existing state-of-the-art TD-DFT methods (and beyond) which are employed to study the properties of porphyrinoid-based systems. The review is organized in such a way that each paragraph is devoted to a separate aspect of the PDT mechanism, e.g., correct prediction of the absorption spectra, determination of the singlet-triplet intersystem crossing, and interaction with molecular oxygen. Aspects of the calculation schemes are discussed, such as the choice of the most suitable functional and inclusion of a solvent. Finally, quantitative structure-activity relationship (QSAR) methods used to explore the photochemistry of porphyrinoid-based systems are discussed.

Progress of Phototherapy Applications in the Treatment of Bone Cancer.

Bone cancer including primary bone cancer and metastatic bone cancer, remains a challenge claiming millions of lives and affecting the life quality of survivors. Conventional treatments of bone cancer include wide surgical resection, radiotherapy, and chemotherapy. However, some bone cancer cells may remain or recur in the local area after resection, some are highly resistant to chemotherapy, and some are insensitive to radiotherapy. Phototherapy (PT) including photodynamic therapy (PDT) and photothermal therapy (PTT), is a clinically approved, minimally invasive, and highly selective treatment, and has been widely reported for cancer therapy. Under the irradiation of light of a specific wavelength, the photosensitizer (PS) in PDT can cause the increase of intracellular ROS and the photothermal agent (PTA) in PTT can induce photothermal conversion, leading to the tumoricidal effects. In this review, the progress of PT applications in the treatment of bone cancer has been outlined and summarized, and some envisioned challenges and future perspectives have been mentioned. This review provides the current state of the art regarding PDT and PTT in bone cancer and inspiration for future studies on PT.

Self-luminescent photodynamic therapy and pathogen detection for infectious diseases.

The importance of detection and treatments of infectious diseases has been stressed to the world by the ongoing COVID-19 pandemic. As a substitution of an external light source, self-luminescent therapeutics featuring in situ light emission aims to address the lack of tissue penetration in conventional photodynamic therapy (PDT). Luminol-based self-luminescent systems are successfully incorporated in PDT and detection of pathogens in infectious diseases. In these systems, luminol/hydrogen peroxide is served as luminescence source which can be activated by horseradish peroxidase (HRP). As a supplement strategy to the HRP-based bioluminescence, electrochemiluminescence (ECL) provided an electric-driven therapeutic solution and demonstrated potential capabilities of wearable healthcare devices with properly constructed transparent flexible hydrogels. Besides the diagnosis of infection and detection of bacteria, fungi and virus in solution or powder samples have been achieved by ATP-derived self-luminescence as the light source. In this inspirational note, we provide an overview on latest progress in the PDT and microbial detection by self-luminescent systems with an emphasis on the bioluminescence and ECL.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

Actinic Keratoses: Reconciling the Biology of Field Cancerization with Treatment Paradigms.

This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies.

Growing tool-kit of photosensitizers for clinical and non-clinical applications.

Photosensitizers are photosensitive molecules utilized in clinical and non-clinical applications by taking advantage of light-mediated reactive oxygen generation, which triggers local and systemic cellular toxicity. Photosensitizers are used for diverse biological applications such as spatio-temporal inactivation of a protein in a living system by chromophore-assisted light inactivation, localized cell photoablation, photodynamic and immuno-photodynamic therapy, and correlative light-electron microscopy imaging. Substantial efforts have been made to develop several genetically encoded, chemically synthesized, and nanotechnologically driven photosensitizers for successful implementation in redox biology applications. Genetically encoded photosensitizers (GEPS) or reactive oxygen species (ROS) generating proteins have the advantage of using them in the living system since they can be manipulated by genetic engineering with a variety of target-specific genes for the precise spatio-temporal control of ROS generation. The GEPS variety is limited but is expanding with a variety of newly emerging GEPS proteins. Apart from GEPS, a large variety of chemically- and nanotechnologically-empowered photosensitizers have been developed with a major focus on photodynamic therapy-based cancer treatment alone or in combination with pre-existing treatment methods. Recently, immuno-photodynamic therapy has emerged as an effective cancer treatment method using smartly designed photosensitizers to initiate and engage the patient's immune system so as to empower the photosensitizing effect. In this review, we have discussed various types of photosensitizers, their clinical and non-clinical applications, and implementation toward intelligent efficacy, ROS efficiency, and target specificity in biological systems.

Versatile Nanoplatforms with enhanced Photodynamic Therapy: Designs and Applications.

As an emerging antitumor strategy, photodynamic therapy (PDT) has attracted intensive attention for the treatment of various malignant tumors owing to its noninvasive nature and high spatial selectivity in recent years. However, the therapeutic effect is unsatisfactory on some occasions due to the presence of some unfavorable factors including nonspecific accumulation of PS towards malignant tissues, the lack of endogenous oxygen in tumors, as well as the limited light penetration depth, further hampering practical application. To circumvent these limitations and improve real utilization efficiency, various enhanced strategies have been developed and explored during the past years. In this review, we give an overview of the state-of-the-art advances progress on versatile nanoplatforms for enhanced PDT considering the enhancement from targeting or responsive, chemical and physical effect. Specifically, these effects mainly include organelle-targeting function, tumor microenvironment responsive release photosensitizers (PS), self-sufficient O2 (affinity oxygen and generating oxygen), photocatalytic water splitting, X-rays light stimulate, surface plasmon resonance enhancement, and the improvement by resonance energy transfer. When utilizing these strategies to improve the therapeutic effect, the advantages and limitations are addressed. Finally, the challenges and prospective will be discussed and demonstrated for the future development of advanced PDT with enhanced efficacy.

Nano-Carriers of Combination Tumor Physical Stimuli-Responsive Therapies.

With the development of nanotechnology, Tumor Physical Stimuli-Responsive Therapies (TPSRTs) have reached a new stage because of the remarkable characteristics of nanocarriers. The nanocarriers enable such therapies to overcome the drawbacks of traditional therapies, such as radiotherapy or chemotherapy. To further explore the possibility of the nanocarrier-assisted TPSRTs, scientists have combined different TPSRTs via; the platform of nanocarriers into combination TPSRTs, which include Photothermal Therapy (PTT) with Magnetic Hyperthermia Therapy (MHT), PTT with Sonodynamic Therapy (SDT), MHT with Photodynamic Therapy (PDT), and PDT with PTT. To achieve such therapies, it requires to fully utilize the versatile functions of a specific nanocarrier, which depend on a pellucid understanding of the traits of those nanocarriers. This review covers the principles of different TPSRTs and their combinations, summarizes various types of combination TPSRTs nanocarriers and their therapeutic effects on tumors, and discusses the current disadvantages and future developments of these nanocarriers in the application of combination TPSRTs.

Development of an ultrasound triggered nanomedicine-microbubble complex for chemo-photodynamic-gene therapy.

Recently, combination therapy has received much attention because of its highly therapeutic effect in various types of cancers. In particular, chemo-photodynamic combination therapy has been considered as an outstanding strategy. However, an abnormal increase in tumor angiogenesis caused by reactive oxygen species (ROS) generated during photodynamic therapy (PDT) has been reported. In this study, the complex of doxorubicin (DOX)-encapsulating anti-angiogenic small interfering RNA (siRNA) nanoparticle and chlorin e6 (Ce6)-encapsulating microbubble has been developed to suppress tumor angiogenesis. The first compartment, doxorubicin-encapsulating siRNA nanoparticle, was electrostatically coated using two biocompatible polymers to prevent the damage of genetic materials. The other part, Ce6-encapsulating microbubble, serves as an ultrasound-triggered local delivery system as well as a drug carrier. Both the in vitro and in vivo experimental results demonstrate successful inhibition of angiogenesis with a minimized damage of siRNAs caused by ROS as well as improved therapeutic effect by chemo-photodynamic-gene triple combination therapy using ultrasound-triggered local delivery.

Treatment and management strategies of onychomycosis.

Onychomycosis is one of the most prevalent and severe nail fungal infections, which is affecting a wide population across the globe. It leads to variations like nail thickening, disintegration and hardening. Oral and topical drug delivery systems are the most desirable in treating onychomycosis, but the efficacy of the results is low, resulting in a relapse rate of 25-30%. Due to systemic toxicity and various other disadvantages associated with oral therapy like gastrointestinal, hepatotoxicity, topical therapy is commonly used. Topical therapy improves patient compliance and reduces the cost of treatment. However, due to poor penetration of topical therapy across the nail plate, research is focused on different chemical, mechanical and physical methods to improve drug delivery. Penetration enhancers like Thioglycolic acid, Hydroxypropyl-ß-cyclodextrin (HP-ß-CD), Sodium lauryl sulfate (SLS), carbocysteine, N-acetylcysteine etc. have shown results enhancing the drug penetration across the nail plate. Results with physical techniques such as iontophoresis, laser and Photodynamic therapy are quite promising, but the long-term suitability of these devices is in need to be determined. In this article, a brief analysis of the treatment procedures, factors affecting drug permeation across nail plate, chemical, mechanical and physical devices used to increase the drug delivery through nails for the onychomycosis management has been achieved.

Aggregation-Induced Emission Photosensitizers: From Molecular Design to Photodynamic Therapy.

Photodynamic therapy (PDT) has emerged as a promising noninvasive treatment option for cancers and other diseases. The key factor that determines the effectiveness of PDT is the photosensitizers (PSs). Upon light irradiation, the PSs would be activated, produce reactive oxygen species (ROS), and induce cell death. One of the challenges is that traditional PSs adopt a large flat disc-like structure, which tend to interact with the adjacent molecules through strong π-π stacking that reduces their ROS generation ability. Aggregation-induced emission (AIE) molecules with a twisted configuration to suppress strong intermolecular interactions represent a new class of PSs for image-guided PDT. In this Miniperspective, we summarize the recent progress on the design rationale of AIE-PSs and the strategies to achieve desirable theranostic applications in cancers. Subsequently, approaches of combining AIE-PS with other imaging and treatment modalities, challenges, and future directions are addressed.

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress.

There have been many reports on the relationship between mitochondrial oxidative stress and various types of diseases. This review covers mitochondrial targeting photodynamic therapy and photothermal therapy as a therapeutic strategy for inducing mitochondrial oxidative stress. We also discuss other mitochondrial targeting phototherapeutic methods. In addition, we discuss anti-oxidant therapy by a mitochondrial drug delivery system (DDS) as a therapeutic strategy for suppressing oxidative stress. We also describe cell therapy for reducing oxidative stress in mitochondria. Finally, we discuss the possibilities and problems associated with clinical applications of mitochondrial DDS to regulate mitochondrial oxidative stress.

FRET in a Polymeric Nanocarrier: IR-780 and IR-780-PDMS.

We introduce a method to monitor the integrity of micellar nanocarriers using a novel fluorescent dye, IR-780-PDMS and Förster resonance energy transfer (FRET) as a readout. In addition, these dye-loaded nanocarriers can be used as a phototoxic agent in vitro. Mainly, a nanocarrier was designed, based on a previously described amphiphilic ABA-copolymer (Pip-PMOXA-PDMS-PMOXA-Pip) scaffold that incorporates the fluorescent FRET dye partners IR-780-PDMS (donor) and IR-780 (acceptor). The confirmation of FRET (that only occurs when donor and acceptor are in the required close proximity of less than ∼10 nm) in the nanocarriers is used to prove that the acceptor dye (IR-780) is still contained in its hydrophobic core. We measured such FRET signals of the nanocarriers also upon cellular uptake into HeLa cells using fluorescence-lifetime imaging microscopy (FLIM). Confocal laser scanning microscopy after incubation with nanocarriers demonstrated the intracellular uptake of the particles and their localization in an intracellular granular pattern. To demonstrate the intactness of the nanocarriers by detection of FRET we measured the fluorescence lifetime (FLIM) of the donor dye. FLIM showed that both types of lifetimes, that of the quenched donor, and that of the unquenched donor were present, in a granular pattern and homogeneously in the cytosol, respectively, indicating the presence of intracellular intact and disintegrated micellar nanocarriers. These data show that the herewith-described FRET method allows monitoring the intactness of nanocarriers while en route to the target, and also that the cargo is delivered and released within a potential target cell. In addition, near-infrared (NIR) irradiation of IR-780-loaded micellar nanocarriers leads to photocytotoxicity, which we demonstrated in in vitro experiments. Our findings open potential avenues in photodynamic therapy (PDT) of cancer.

Trends and targets in antiviral phototherapy.

Photodynamic therapy (PDT) is a well-established treatment option in the treatment of certain cancerous and pre-cancerous lesions. Though best-known for its application in tumor therapy, historically the photodynamic effect was first demonstrated against bacteria at the beginning of the 20th century. Today, in light of spreading antibiotic resistance and the rise of new infections, this photodynamic inactivation (PDI) of microbes, such as bacteria, fungi, and viruses, is gaining considerable attention. This review focuses on the PDI of viruses as an alternative treatment in antiviral therapy, but also as a means of viral decontamination, covering mainly the literature of the last decade. The PDI of viruses shares the general action mechanism of photodynamic applications: the irradiation of a dye with light and the subsequent generation of reactive oxygen species (ROS) which are the effective phototoxic agents damaging virus targets by reacting with viral nucleic acids, lipids and proteins. Interestingly, a light-independent antiviral activity has also been found for some of these dyes. This review covers the compound classes employed in the PDI of viruses and their various areas of use. In the medical area, currently two fields stand out in which the PDI of viruses has found broader application: the purification of blood products and the treatment of human papilloma virus manifestations. However, the PDI of viruses has also found interest in such diverse areas as water and surface decontamination, and biosafety.

Photodynamic therapy of cancer with liposomal photosensitizers.

The photodynamic reaction involves the light-induced generation of an excited state in a photosensitizer molecule (PS), which then results in the formation of reactive oxygen species in the presence of oxygen, or a direct modification of a cellular molecule. Most PSs are porphyrinoids, which are highly lipophilic, and are administered usually in liposomes to facilitate their effective delivery to target cells. The currently available liposomal formulations are Visudyne® and Fospeg®. Novel PSs were developed and tested for their photodynamic activity against cancer cells. Several compounds were highly phototoxic to oral cancer cells both in free and liposome-encapsulated form, with nanomolar IC50 values. The lowest IC50s (7-13 nM) were obtained with a PS encapsulated in cationic liposomes.

Photodynamic Therapy in the Treatment of Bladder Cancer: Past Challenges and Current Innovations.

There are limited treatment options for patients with recurrent non-muscle-invasive bladder cancer. In this report, we will talk about the history of photodynamic therapy; although it showed encouraging therapeutic results, it was largely abandoned due to toxicity or bystander effects on normal cells. Monoclonal antibody-conjugates represent an emerging therapeutic approach for malignancies that improves upon tumor specificity. The use of a monoclonal antibody-photosensitizer conjugate is a more selective method of delivering light therapy and has been termed "photoimmunotherapy", which we will discuss in the last part of this report.