Metal Complexes for Cancer Sonodynamic Therapy

Sonodynamic therapy (SDT) for cancer treatment is gaining attention owing to its non-invasive property and ultrasound‘s (US) deep tissue penetration ability. In SDT, US activates the sonosensitizer at the target deep-seated tumors to generate reactive oxygen species (ROS), which ultimately damage tumors. However, drawbacks such as insufficient ROS production, aggregation of sonosensitizer, off-target side effects, etc., of the current organic/nanomaterial-based sonosensitizers limit the effectiveness of cancer SDT. Very recently, metal complexes with tunable physiochemical properties (such as sonostability, HOMO to LUMO energy gap, ROS generation ability, aqueous solubility, emission, etc.) have been devised as effective sonosensitizers, which could overcome the limitations of organic/nanomaterial-based sonosensitizers. This concept introduces all the reported metal-based sonosensitizers and delineates the prospects of metal complexes in cancer sonodynamic therapy. This new concept of metal-based sonosensitizer can deliver next-generation cancer drugs.     

Coordination Complexes as a New Generation Photosensitizer for Photodynamic Anticancer Therapy

Photodynamic therapy (PDT) has become an alternative to standard cancer treatment methods such as surgery, chemotherapy and radiotherapy. The uniqueness of this method relies on the possibility of using various photosensitizers (PS) that absorb and convert light emission in radical oxygen-derived species (ROS). They can be present alone or in the presence of other compounds such as metal organic frameworks (MOFs), non-tubules or polymers. The interaction between DNA and metal-based complexes plays a key role in the development of new anti-cancer drugs. The use of coordination compounds in PDT has a significant impact on the amount ROS generated, quantum emission efficiency (Φem) and phototoxic index (PI). In this review, we will attempt to systematically review the recent literature and analyze the coordination complexes used as PS in PDT. Finally, we compared the anticancer activities of individual coordination complexes and discuss future perspectives. So far, only a few articles link so many transition metal ion coordination complexes of varying degrees of oxidation, which is why this review is needed by the scientific community to further expand this field worldwide. Additionally, it serves as a convenient collection of important, up-to-date information.     

Viral Nanoparticle System: An Effective Platform for Photodynamic Therapy

Photodynamic therapy (PDT) is a promising therapy due to its efficiency and accuracy. The photosensitizer is delivered to the target lesion and locally activated. Viral nanoparticles (VNPs) have been explored as delivery vehicles for PDT in recent years because of their favorable properties, including simple manufacture and good safety profile. They have great potential as drug delivery carriers in medicine. Here, we review the development of PDT photosensitizers and discuss applications of VNP-mediated photodynamic therapies and the performance of VNPs in the treatment of tumor cells and antimicrobial therapy. Furthermore, future perspectives are discussed for further developing novel viral nanocarriers or improving existing viral vectors.     

Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer

Colorectal cancer (CRC) involving a malignant tumour remains one of the greatest contributing causes of fatal mortality and has become the third globally ranked malignancy in terms of cancer-associated deaths. Conventional CRC treatment approaches such as surgery, radiation, and chemotherapy are the most utilized approaches to treat this disease. However, they are limited by low selectivity and systemic toxicity, so they cannot completely eradicate this disease. Photodynamic therapy (PDT) is an emerging therapeutic modality that exerts selective cytotoxicity to cancerous cells through the activation of photosensitizers (PSs) under light irradiation to produce cytotoxic reactive oxygen species (ROS), which then cause cancer cell death. Cumulative research findings have highlighted the significant role of traditional PDT in CRC treatment; however, the therapeutic efficacy of the classical PDT strategy is restricted due to skin photosensitivity, poor cancerous tissue specificity, and limited penetration of light. The application of nanoparticles in PDT can mitigate some of these shortcomings and enhance the targeting ability of PS in order to effectively use PDT against CRC as well as to reduce systemic side effects. Although 2D culture models are widely used in cancer research, they have some limitations. Therefore, 3D models in CRC PDT, particularly multicellular tumour spheroids (MCTS), have attracted researchers. This review summarizes several photosensitizers that are currently used in CRC PDT and gives an overview of recent advances in nanoparticle application for enhanced CRC PDT. In addition, the progress of 3D-model applications in CRC PDT is discussed.     

Ir(III) and Ru(II) Complexes in Photoredox Catalysis and Photodynamic Therapy: A New Paradigm towards Anticancer Applications

Individually, photoredox catalysis (PC) and photodynamic therapy (PDT) are well-established concepts that have experienced a remarkable resurgence in recent years, leading to significant progress in organic synthesis for PC and clinical approval of anticancer drugs for PDT. But, very recently, new photoredox catalyst systems based on Ir(III) and Ru(II) complexes have garnered significant interest because they can simultaneously be used as PDT agents apart from their demonstrated PC activity. This highlight discusses the unique PC behavior of emerging Ir(III)- and Ru(II)-based systems while also examining their potential PDT activity in cancer treatment.     

Mechanism-Based Sonodynamic–Chemo Combinations against Triple-Negative Breast Cancer

Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.     

Towards Ruthenium(II)-Rhenium(I) Binuclear Complexes as Photosensitizers for Photodynamic Therapy

The search for new metal-based photosensitizers (PSs) for anticancer photodynamic therapy (PDT) is a fast-developing field of research. Knowing that polymetallic complexes bear a high potential as PDT PSs, in this study, we aimed at combining the known photophysical properties of a rhenium(I) tricarbonyl complex and a ruthenium(II) polypyridyl complex to prepare a ruthenium-rhenium binuclear complex that could act as a PS for anticancer PDT. Herein, we present the synthesis and characterization of such a system and discuss its stability in aqueous solution. In addition, one of our complexes prepared, which localized in mitochondria, was found to have some degree of selectivity towards two types of cancerous cells: human lung carcinoma A549 and human colon colorectal adenocarcinoma HT29, with interesting photo-index (PI) values of 135.1 and 256.4, respectively, compared to noncancerous retinal pigment epithelium RPE1 cells (22.4).     

Nanoparticle-Based Drug Delivery Systems for Photodynamic Therapy of Metastatic Melanoma: A Review

Metastatic melanoma (MM) is a skin malignancy arising from melanocytes, the incidence of which has been rising in recent years. It poses therapeutic challenges due to its resistance to chemotherapeutic drugs and radiation therapy. Photodynamic therapy (PDT) is an alternative non-invasive modality that requires a photosensitizer (PS), specific wavelength of light, and molecular oxygen. Several studies using conventional PSs have highlighted the need for improved PSs for PDT applications to achieve desired therapeutic outcomes. The incorporation of nanoparticles (NPs) and targeting moieties in PDT have appeared as a promising strategy to circumvent various drawbacks associated with non-specific toxicity, poor water solubility, and low bioavailability of the PSs at targeted tissues. Currently, most studies investigating new developments rely on two-dimensional (2-D) monocultures, which fail to accurately mimic tissue complexity. Therefore, three-dimensional (3-D) cell cultures are ideal models to resemble tumor tissue in terms of architectural and functional properties. This review examines various PS drugs, as well as passive and active targeted PS nanoparticle-mediated platforms for PDT treatment of MM on 2-D and 3-D models. The overall findings of this review concluded that very few PDT studies have been conducted within 3-D models using active PS nanoparticle-mediated platforms, and so require further investigation.     

Polypyridyl Ruthenium(II) Complexes with Red-Shifted Absorption: New Promises in Photodynamic Therapy

In the field of cancer photodynamic therapy (PDT) research, development of metal-based PDT drugs that can be used under red light exposure is the “holy grail” to achieve. This highlight highlighted few current literatures on polypyridyl-based Ru(II) complexes with significantly red-shifted absorption to achieve in-vitro and in-vivo PDT effect in 540–600 nm light. The enormous potential of judicial ligand choice and in-silico optimization to achieve the red light, metal-based PDT drugs are discussed.     

Tin Carboxylate Complexes of Natural Bacteriochlorin for Combined Photodynamic and Chemotherapy of Cancer è

Photodynamic therapy (PDT) is currently one of the most promising methods of cancer treatment. However, this method has some limitations, including a small depth of penetration into biological tissues, the low selectivity of accumulation, and hypoxia of the tumor tissues. These disadvantages can be overcome by combining PDT with other methods of treatment, such as radiation therapy, neutron capture therapy, chemotherapy, etc. In this work, potential drugs were obtained for the first time, the molecules of which contain both photodynamic and chemotherapeutic pharmacophores. A derivative of natural bacteriochlorophyll a with a tin IV complex, which has chemotherapeutic activity, acts as an agent for PDT. This work presents an original method for obtaining agents of combined action, the structure of which is confirmed by various physicochemical methods of analysis. The method of molecular modeling was used to investigate the binding of the proposed drugs to DNA. In vitro biological tests were carried out on several lines of tumor cells: Hela, A549, S37, MCF7, and PC-3. It was shown that the proposed conjugates of binary action for some cell lines had a dark cytotoxicity that was significantly higher (8–10 times) than the corresponding metal complexes of amino acids, which was explained by the targeted chemotherapeutic action of the tin (IV) complex due to chlorin. The greatest increase in efficiency relative to the initial dipropoxy-BPI was found for the conjugate with lysine as a chelator of the tin cation relative to cell lines, with the following results: S-37 increased 3-fold, MCF-7 3-fold, and Hela 2.4-fold. The intracellular distribution of the obtained agents was also studied by confocal microscopy and showed a diffuse granular distribution with predominant accumulation in the near nuclear region.     

Conjugated Polymers with Aggregation-Induced Emission Characteristics for Fluorescence Imaging and Photodynamic Therapy

Accurate diagnosis and treatment have been extensively developed in the field of biomedicine, which put forward higher requirements for the development of biomedical materials with high efficiency and selectivity. Among them, conjugated polymers featuring aggregation-induced emission (AIE) characteristics (AIE conjugated polymers) have stood out in recent years owing to their unique properties, such as intense solid emission, high light-harvesting ability, efficient energy transfer, and high ¹O₂ generation ability, which empower them with effective biomedical functions in fluorescence imaging (FLI), photodynamic therapy (PDT), FLI-guided PDT, two-photon excited photodynamic therapy (2PE-PDT), etc. In this review, we highlight recent progress in AIE conjugated polymers and their applications in anticancer and antibacterial areas based on FLI and PDT, and summarize the mechanism of color-tuned fluorescence emission and efficient ¹O₂ generation ability. The challenges and perspectives for the future development of AIE conjugated polymers are also discussed.     

The effects of ultrasound and light on indocyanine-green-treated tumour cells and tissues

Photodynamic therapy (PDT) is emerging as a treatment modality for the management of neoplastic disease. Despite considerable clinical success, its application for the treatment of deep‐seated lesions is constrained by the inability of visible light to penetrate deeply into tissues. An emerging alternative approach exploits the fact that many photosensitisers respond to ultrasound, eliciting cytotoxic effects on target cells and tissues; this has become known as sonodynamic therapy (SDT). The objectives of this study were 1) to determine whether the IR‐absorbing dye, indocyanine green (ICG), can be employed as a sonosensitiser and 2) to determine whether ultrasound can be used to enhance ICG‐mediated PDT. Exposing ICG‐treated mouse fibrosarcoma cells to ultrasound at an energy density of 30 J cm^?2 decreased cell viability by 65 %. Prior exposure of ICG‐treated cells to light (λ 830 nm) and subsequent treatment with ultrasound led to a 90 % decrease in cell viability. In combination treatments a synergistic effect was observed at lower doses of ultrasound. Microscopic examination of cell populations treated with light or ultrasound demonstrated the production of intracellular reactive oxygen species (ROS). Using a mouse tumour model, treatment with light, ultrasound, or a combination thereof led to respective decreases in tumour growth of 42, 67, and 98 % at day 27 post‐treatment. These results could provide a means of circumventing light‐penetration issues that currently challenge the widespread use of PDT in the treatment of cancer.     

Recent Advances in the Design of Targeted Iridium(III) Photosensitizers for Photodynamic Therapy

Photodynamic therapy (PDT) is a noninvasive treatment for certain types of cancer, bacterial, fungal and viral infections, and skin diseases. In recent years, adaptation of this treatment so as to achieve more specific targeted cancer therapy in particular has attracted significant attention. We focus herein on the design of novel iridium‐based photosensitizers (PSs) with tunable photophysical and photobiological properties as efficient PDT agents. We highlight the ability of some Ir^III photosensitizers to target specific cellular components, including their activation by one‐ and two‐photon irradiation.     

Critical PDT Theory III: Events at the Molecular and Cellular Level

Photodynamic therapy (PDT) is capable of eradicating neoplastic cells that are accessible to sufficient light and oxygen. There is adequate information now available for assessing conditions where PDT might be the therapy of choice, but limited access to clinical facilities and impediments to regulatory approval of new agents have limited clinical usage. Early reports mainly involved clinical data with few thoughts towards finding death pathways. In 2022, there is a clear understanding of the determinants of successful tumor eradication. While PDT may be the optimal method for many clinical indications, support for this approach has lagged. This report provides a commentary on some elements of recent progress in PDT at the molecular and cellular levels, along with a discussion of some of the limitations in current research efforts.     

Photodynamic Therapy of Up-Conversion Nanomaterial Doped with Gold Nanoparticles

Two key concerns exist in contemporary cancer chemotherapy: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating the revolutionary cancer treatment techniques of photodynamic therapy (PDT) and photothermal therapy (PTT) proposed by many scholars. A photothermal treatment of cancer was synthesized using the hydrothermal method which has high photothermal conversion efficiency and can generate reactive oxygen species (ROS) in cells. Photothermal treatment of tumors has a good short-term effect and photodynamic therapy lasts longer. However, both PTT and PDT have their inevitable shortcomings and it is difficult to completely eradicate a tumor using a single mode of treatment. PTT and PDT synergistic treatment not only inherits the advantages of low toxicity and side effects of phototherapy but also enables the two treatment methods to complement each other. It is an effective strategy to improve curative effects and reduce toxic and side effects. Furthermore, gold doped UCNPs have an exceptionally high target recognition for tumor cells. The gold doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy and exceptionally low side effects. These findings may encourage the creation of fresh, effective imaging-guided approaches to meet the goal of photothermal cancer therapy.     

Porphylipoprotein Accumulation and Porphylipoprotein Photodynamic Therapy Effects Involving Cancer Cell-Specific Cytotoxicity

In photodynamic therapy (PDT) for neoplasms, photosensitizers selectively accumulate in cancer tissue. Upon excitation with light of an optimal wavelength, the photosensitizer and surrounding molecules generate reactive oxygen species, resulting in cancer cell-specific cytotoxicity. Porphylipoprotein (PLP) has a porphyrin-based nanostructure. The porphyrin moiety of PLP is quenched because of its structure. When PLP is disrupted, the stacked porphyrins are separated into single molecules and act as photosensitizers. Unless PLP is disrupted, there is no photosensitive disorder in normal tissues. PLP can attenuate the photosensitive disorder compared with other photosensitizers and is ideal for use as a photosensitizer. However, the efficacy of PLP has not yet been evaluated. In this study, the mechanism of cancer cell-specific accumulation of PLP and its cytotoxic effect on cholangiocarcinoma cells were evaluated. The effects were investigated on normal and cancer-like mutant cells. The cytotoxicity effect of PLP PDT in cancer cells was significantly stronger than in normal cells. In addition, reactive oxygen species regulated intracellular PLP accumulation. The cytotoxic effects were also investigated using a cholangiocarcinoma cell line. The cytotoxicity of PLP PDT was significantly higher than that of laserphyrin-based PDT, a conventional type of PDT. PLP PDT could also inhibit tumor growth in vivo.     

Advances in Multifunctional Chemotherapeutic Prodrugs for Near-infrared Fluorescence Imaging-guided Therapy

Conventional chemotherapy (CT) is associated with severe side effects and inducible resistance, making it difficult to meet clinical requirements, forcing the development of new multifunctional prodrugs for precision medicine. In recent decades, researchers and clinicians have focused on developing of multifunctional chemotherapeutic prodrugs with tumor-targeting capability, activatable and traceable chemotherapeutic activity, as a powerful tool to improve theranostic outcomes in cancer treatment. The conjugates of near-infrared (NIR) organic fluorophores and chemotherapy reagents create an exciting avenue for real-time monitoring of drug delivery and distribution, as well as the combination of chemotherapy and photodynamic therapy (PDT). Therefore, there are great opportunities for researchers to conceive and exploit multifunctional prodrugs that can visualize chemo-drugs release and tumor treatment in vivo. In this review, the design strategy and the recent progress of multifunctional organic chemotherapeutic prodrugs for activating NIR fluorescence imaging-guided therapy are described and discussed in detail. Finally, the prospects and challenges of multifunctional chemotherapeutic prodrugs for NIR fluorescence imaging-guided therapy are provided.     

Regulation of miRNA Expression by Low-Level Laser Therapy (LLLT) and Photodynamic Therapy (PDT)

Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression.     

Erlotinib-Modified BODIPY Photosensitizers for Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is an innovative, non-invasive and highly selective therapeutic modality for tumours and non-malignant diseases. BODIPY based molecules can function as new generation photosensitizers (PSs) in various PDT applications. Despite numerous conjugated PS systems are available, BODIPYs containing erlotinib lagged behind other photosensitizer units. In this study, smart photosensitizers containing BODIPY, erlotinib and hydrophilic units were prepared for the first time, their physicochemical properties and PDT effects were investigated. Compared with non-halogenated compound, halogenated derivatives possessed much lower fluorescence profile as well as the good ROS generation ability under red light. In vitro PDT studies were performed on both healthy (PNT1a) and prostate cancerous cells (PC3) to determine the selectivity of the compounds on cancerous cells and their effects under light. The halogenated conjugates, exposed to low dose of light illumination exhibited potent activity on cancer cell viability and the calculated IC₅₀ values proved the high phototoxicity of the photosensitizers. It was also determined that the PSs have very low dark toxicity and that the light illumination and ROS formation are required for the initiation of the cell death mechanism. As a result, erlotinib modified BODIPYs could serve as promising agents in anticancer photodynamic therapy.     

Photodynamic Therapy–Induced Angiogenic Signaling: Consequences and Solutions to Improve Therapeutic Response

Photodynamic therapy (PDT) can be a highly effective treatment for diseases ranging from actinic keratosis to cancer. While use of this therapy shows great promise in preclinical and clinical studies, understanding the molecular consequences of PDT is critical to designing better treatment protocols. A number of publications have documented alteration in angiogenic factors and growth factor receptors following PDT, which could abrogate treatment effect by inducing angiogenesis and reestablishment of the tumor vasculature. In response to these findings, work over the past decade has examined the efficacy of combining PDT with molecular targeting drugs, such as anti-angiogenic compounds, in an effort to combat these PDT-induced molecular changes. These combinatorial approaches increase rates of apoptosis, impair pro-tumorigenic signaling, and enhance tumor response. This report will examine the current understanding of PDT-induced angiogenic signaling and address molecular-based approaches to abrogate this signaling or its consequences thereby enhancing PDT efficacy.