Anticancer Photodynamic Therapy Research Articles

Enzyme-Activatable Near-Infrared Hemicyanines as Modular Scaffolds for in vivo Photodynamic Therapy.

Photodynamic therapy is an anti-cancer treatment that requires illumination of photosensitizers to induce local cell death. Current near-infrared organic photosensitizers are built from large and non-modular structures that cannot be tuned to improve safety and minimize off-target toxicity. This work describes a novel chemical platform to generate enzyme-activatable near-infrared photosensitizers. We optimized the Se-bridged hemicyanine scaffold to include caging groups and biocompatible moieties, and generated cathepsin-triggered photosensitizers for effective ablation of human glioblastoma cells. Furthermore, we demonstrated that enzyme-activatable Se-bridged hemicyanines are effective photosensitizers for the safe ablation of microtumors in vivo, creating new avenues in the chemical design of targeted anti-cancer photodynamic therapy agents.

Third-Generation Anticancer Photodynamic Therapy Systems Based on Star-like Anionic Polyacrylamide Polymer, Gold Nanoparticles, and Temoporfin Photosensitizer.

Photodynamic therapy (PDT) is a non-invasive anticancer treatment that uses special photosensitizer molecules (PS) to generate singlet oxygen and other reactive oxygen species (ROS) in a tissue under excitation with red or infrared light. Though the method has been known for decades, it has become more popular recently with the development of new efficient organic dyes and LED light sources. Here we introduce a ternary nanocomposite: water-soluble star-like polymer/gold nanoparticles (AuNP)/temoporfin PS, which can be considered as a third-generation PDT system. AuNPs were synthesized in situ inside the polymer molecules, and the latter were then loaded with PS molecules in an aqueous solution. The applied method of synthesis allows precise control of the size and architecture of polymer nanoparticles as well as the concentration of the components. Dynamic light scattering confirmed the formation of isolated particles (120 nm diameter) with AuNPs and PS molecules incorporated inside the polymer shell. Absorption and photoluminescence spectroscopies revealed optimal concentrations of the components that can simultaneously reduce the side effects of dark toxicity and enhance singlet oxygen generation to increase cancer cell mortality. Here, we report on the optical properties of the system and detailed mechanisms of the observed enhancement of the phototherapeutic effect. Combinations of organic dyes with gold nanoparticles allow significant enhancement of the effect of ROS generation due to surface plasmonic resonance in the latter, while the application of a biocompatible star-like polymer vehicle with a dextran core and anionic polyacrylamide arms allows better local integration of the components and targeted delivery of the PS molecules to cancer cells. In this study, we demonstrate, as proof of concept, a successful application of the developed PDT system for in vitro treatment of triple-negative breast cancer cells under irradiation with a low-power LED lamp (660 nm). We consider the developed nanocomposite to be a promising PDT system for application to other types of cancer.

Plants-occurring Anthraquinones as Photosensitive Compounds for Photodynamic Method: A Critical Overview.

The review focuses on the recent knowledge on natural anthraquinones (AQs) of plant origin and their potential for application in an exclusive medicinal curative and palliative method named photodynamic therapy (PDT). Green approach to PDT is associated with photosensitizers (PS) from plants or other natural sources and excitation light in visible spectrum. The investigations of plants are of high research interests due to their unique health supportive properties as herbs and the high percentage availability to obtain compounds with medical value. Up-to-date many naturally occurring compounds with therapeutic properties are known and are still under investigations. Some natural quinones have already been evaluated and clinically approved as anti-tumor agents. Recent scientific interests are beyond their common medical applications but also in directions to their photo-properties as natural PSs. The study presents a systematic searches on the latest knowledge on AQ derivatives that are isolated from the higher plants as photosensitizers for PDT applications. The natural quinones have been recognized with functions of natural dyes since the ancient times. Lately, AQs have been explored due to their biological activity including the photosensitive properties useful for PDT especially towards medical problems with no other alternatives. The existing literature' overview suggests that natural AQs possess characteristics of valuable PSs for PDT. This method is based on an application of a photoactive compound and light arrangement in oxygen media, such that the harmful general cytotoxicity could be avoided. Moreover, the common anticancer and antimicrobial drug resistance has been evaluated with very low occurrence after PDT. Natural AQs have been focused the scientific efforts to further developments because of the high range of natural sources, desirable biocompatibility, low toxicity, minimal side effects and low accident of drug resistance, together with their good photosensitivity and therapeutic capacity. Among the known AQs, only hypericin has been studied in anticancer clinical PDT. Currently, the natural PSs are under intensive research for the future PDT applications for diseases without alternative effective treatments.

Photodynamic Therapy with Targeted Release of Boron-Dipyrromethene Dye from Cobalt(III) Prodrugs in Red Light.

Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ ∼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 μM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.

Polydopamine-Coated Liposomes for Methylene Blue Delivery in Anticancer Photodynamic Therapy: Effects in 2D and 3D Cellular Models.

Photodynamic therapy (PDT) is a therapeutic option for cancer, in which photosensitizer (PS) drugs, light, and molecular oxygen generate reactive oxygen species (ROS) and induce cell death. First- and second-generation PSs presented with problems that hindered their efficacy, including low solubility. Thus, second-generation PSs loaded into nanocarriers were produced to enhance their cellular uptake and therapeutic efficacy. Among other compounds investigated, the dye methylene blue (MB) showed potential as a PS, and its photodynamic activity in tumor cells was reported even in its nanocarrier-delivered form, including liposomes. Here, we prepared polydopamine (PDA)-coated liposomes and efficiently adsorbed MB onto their surface. lipoPDA@MB vesicles were first physico-chemically characterized and studies on their light stability and on the in vitro release of MB were performed. Photodynamic effects were then assessed on a panel of 2D- and 3D-cultured cancer cell lines, comparing the results with those obtained using free MB. lipoPDA@MB uptake, type of cell death induced, and ability to generate ROS were also investigated. Our results show that lipoPDA@MB possesses higher photodynamic potency compared to MB in both 2D and 3D cell models, probably thanks to its higher uptake, ROS production, and apoptotic cell death induction. Therefore, lipoPDA@MB appears as an efficient drug delivery system for MB-based PDT.

Anion-π+ AIEgens for Fluorescence Imaging and Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (PDT) has attracted extensive attention due to its potential of real-time monitoring the lesion locations and visualizing the treatment process with high sensitivity and resolution. Aggregation-induced emission luminogens (AIEgens) show enhanced fluorescence and reactive oxygen species (ROS) generation after cellular uptake, giving them significant advantages in bioimaging and PDT applications. However, most AIEgens are unfavorable for the application in organisms due to their severe hydrophobicity. Anion-π+ type AIEgens carry intrinsic charges that can effectively alleviate their hydrophobicity and improve their binding capability to cells, which is expected to enhance the bioimaging quality and PDT performance. This concept summarizes the applications of anion-π+ type AIEgens in fluorescence imaging, fluorescence imaging-guided photodynamic anticancer and antimicrobial therapy in recent years, hoping to provide some new ideas for the construction of robust photosensitizers. Finally, the current problems and future challenges of anion-π+ AIEgens are discussed.

Se-substituted pentamethine cyanine for anticancer photodynamic therapy mediated using the hot band absorption process

Se-substituted pentamethine cyanine for anticancer photodynamic therapy mediated using the hot band absorption process

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(C∧N)Cl] and [Cp*Ir(C∧N)L]BF4 with different degrees of π-expansion in the C∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.

Lysosome-targeted Aza-BODIPY photosensitizers for anti-cancer photodynamic therapy

Developing effective near-infrared (NIR) photosensitizers (PSs) has been an attractive goal of photodynamic therapy (PDT) for cancer treatment. In this study, we synthesized N, N-diethylaminomethylphenyl-containing Aza-BODIPY photosensitizers and comprehensively investigated their photophysical/photochemical properties, as well as cell-based and animal-based anti-tumor studies. Among them, BDP 1 has strong NIR absorption at 680 nm and higher singlet oxygen yield in PBS which showed favorable pH-activatable and lysosome-targeting ability. BDP 1 could be easily taken up by tumor cells and showed negligible dark activity (IC50 > 50 μM), however strong phototoxicity upon exposure to light irradiation. The acceptable fluorescence emission from BDP 1 allowed convenient in vivo fluorescence imaging for organ distribution studies in mice. After PDT treatment with upon single time PDT treatment at the beginning using relatively low light dose (54 J/ cm2), BDP 1 (2 mg/kg, 0.1 mL) was found to have strong efficacy to inhibit tumor growth and even to ablate off tumor without causing body weight loss. Therefore, pH-activatable and lysosome-targeted PS may become an effective way to develop potent PDT agent.

Novel 2-(5-Arylthiophen-2-yl)-benzoazole Cyclometalated Iridium(III) dppz Complexes Exhibit Selective Phototoxicity in Cancer Cells by Lysosomal Damage and Oncosis.

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.

Styrene Maleic Acid Polymer-Encapsulated Chlorophyll as a Stable Micellar Nanoprobe for Advanced Anticancer Photodynamic Therapy

Styrene Maleic Acid Polymer-Encapsulated Chlorophyll as a Stable Micellar Nanoprobe for Advanced Anticancer Photodynamic Therapy

Ruthenium(II)-Arene Curcuminoid Complexes as Photosensitizer Agents for Antineoplastic and Antimicrobial Photodynamic Therapy: In Vitro and In Vivo Insights.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Biotin receptor and mitochondria dual targeted AIE photosensitizer for fluorescence imaging guided photodynamic anticancer therapy

Rational design of organelle targeted therapeutic platform in where the drug can be targeted to destroy tumor cells as much as possible, is one of the effective ways to improve the therapeutic outcomes and minimize the cytotoxicity to normal cells. Here, photosensitizer TSPy-B with aggregation-induced emission (AIE) feature, biotin receptor and mitochondria dual-targeted capability, and high reactive oxygen species (ROS) generation efficiency was designed for fluorescence imaging guided photodynamic therapy (PDT) by linking biotin group to D-π-A type AIE dyes via ester bonds. Notably, cell imaging experiments showed that TSPy-B could selectively target tumor cells with biotin receptor overexpression and further exhibit mitochondria targeting ability. The in vitro anticancer mechanism confirmed that after cell internalization, TSPy-B localized in the mitochondrial site and produced ROS resulting in mitochondrial dysfunction and cell death. ROS generation experiments showed that TSPy-B could simultaneously produce 1O2 and highly toxic free radicals which not depended on the oxygen level of solid tumor. The cell killing effect of TSPy-B was also confirmed in hypoxic culture model. In vivo photodynamic therapy experiments demonstrated that TSPy-B could effectively inhibit tumor growth and had good biological safety. This work provides a choice for development of highly targeted photosensitizers for clinical fluorescence imaging guided PDT.

AIE photosensitizers in the first NIR window for high-fidelity imaging of cell membranes and photodynamic anticancer therapy

Irreversible damage to the cell membrane is extremely detrimental to the cell. The synthesis of near-infrared (NIR) aggregation-induced emission luminogens (AIEgens) for high-fidelity imaging of cell membranes and the induction of cancer cell necrosis through photo-driving is a desirable option for tumor treatment, but it remains challenging. In this study, a fluorescent probe molecule (ACTP-1) with an amphiphilic structure and AIE properties was designed and prepared. ACTP-1 can effectively bind with 1,2-dioleo-sn-glycerol-3-phosphatecholine or sensitively detect changes in viscosity in a solution and then emit strong red fluorescence in the first NIR window. Due to its specific embedding of the phospholipid bilayer, the rotational motion of the ACTP-1 molecule was suppressed and the luminescence property was activated, resulting in high resolution and excellent photostability for imaging the cell membrane. Furthermore, ACTP-1, which exhibits a high absorption coefficient in the visible region, can rapidly produce reactive oxygen species (ROS) when exposed to white light. Experiments in cell biology have shown that ACTP-1 can effectively disrupt the cytoskeleton through photodynamic therapy (PDT), leading to cell necrosis instead of apoptosis. This highlights its dual functionality as both a reliable imaging agent and a phototherapy agent.

Bacterial outer membrane vesicles as drug delivery carrier for photodynamic anticancer therapy.

Photodynamic Therapy (PDT) is an effective tumor treatment strategy that not only induces photocytotoxicity to kill tumor cells directly but also activates the immune system in the body to generate tumor-specific immunity, preventing cancer metastasis and recurrence. However, some limitations of PDT limit the therapeutic efficacy in deep tumors. Previous studies have used different types of nanoparticles (NPs) as drug carriers of photosensitizers (PSs) to overcome the shortcomings of PDT and improve therapeutic efficacy. Among them, bacterial outer membrane vesicles (OMVs) have natural advantages as carriers for PS delivery. In addition to the targeted delivery of PSs into tumor cells, their unique immunogenicity helps them to serve as immune adjuvants to enhance the PDT-induced immune effect, providing new ideas for photodynamic anticancer therapy. Therefore, in this review, we will introduce the biogenesis and anticancer functions of OMVs and the research on them as drug delivery carriers in PDT. Finally, we also discuss the challenges and prospects of OMVs as a versatile drug delivery carrier for photodynamic anticancer therapy.

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).

From cell membrane to mitochondria: Time-dependent AIE photosensitizer for fluorescence imaging and photodynamic anticancer therapy

Aggregation-induced emission photosensitizers (AIE-PSs) targeting different subcellular organelles with time-dependent manner are highly promising for clinical applications but rarely reported. Herein, we designed and synthesized the near-infrared (NIR) emission AIE-PS (CTQ-S) with broad absorption and excellent type I reactive oxygen species (ROS) generation efficiency that was superior to the widely used PS (Rose Bengal and Chlorine 6). With short-term incubation, CTQ-S anchored on the cell membrane (Rr: 0.843, Rr is for Pearson correlation coefficient) and gradually entered the mitochondria (Rr: 0.937) of cancer cells, showing excellent time-dependent fluorescence fluorescent imaging effect. Furthermore, CTQ-S realized the selective photodynamic therapy (PDT) effect in a time-dependent manner under white light irradiation. This work provided a new way for cancer cells fluorescence imaging and PDT.

Mesoporous silica nanoparticles boost aggressive cancer response to hydrophilic chlorin e6-mediated photodynamic therapy

BackgroundChlorin e6 trisodium salt (Ce6) is a newly developed hydrophilic photosensitizer designed to mediate anticancer photodynamic therapy (PDT). The response of different cancer types and strategies to boost anticancer efficiency of Ce6-PDT are poorly studied.ObjectivesThis study aimed to investigate the response of different cancer types to Ce6-PDT, identify the unresponsive ones, and develop a nanosystem for response enhancement.MethodsSk-Br-3, MCF-7, U87, and HF-5 cells were tested in 2D cell cultures. Ce6 uptake, PDT-mediated phototoxicity, ROS production, caspase 3/7 levels, and cell death mode were examined. Furthermore, U87 spheroids were treated with Ce6-PDT. Mesoporous silica nanoparticles (MSN) were synthesized and loaded with Ce6. Cellular uptake and phototoxicity of MSN-Ce6 were compared to free Ce6 in vitro and in vivo.ResultsCe6 was detectable in the cell cytoplasm within 15 min. U87 cells showed the highest Ce6 cellular uptake. Upon Ce6-PDT, U87 cells were the most responsive ones with an 11-fold increase in ROS production. Here, 5 µM Ce6 and 4 J/cm2 were enough to reach IC50. Ce6-PDT induced both necrotic and caspase-dependent apoptotic cell death and 75% reduction of spheroids volume. Also, MCF-7 and HF-5 cells responded well to Ce6-PDT treatment. Sk-Br-3 breast cancer cells, on the other hand, were the least responsive ones with 80% viability after treatment (5 µM Ce6, 8 J/cm2). However, MSN-Ce6 conjugates increased Sk-Br-3 cellular uptake of Ce6 sevenfold decreasing the IC50 irradiation dose by an order of magnitude. In a very aggressive breast cancer rat model, MSN-Ce6-PDT treatment led to suppression of tumor volume by 50% and elevation of both Bax and caspase 3 by 90% compared to the control while the corresponding values for Ce6-PDT were 30% and 70%, respectively.ConclusionThe newly developed hydrophilic chlorin and even more its MSN conjugate show high activities in anticancer PDT.

Photodynamic therapy of lung cancer with photosensitizers based on polycationic derivatives of synthetic bacteriochlorin (experimental study)

BackgroundOne of the tasks of anticancer photodynamic therapy is increasing the efficacy of treatment of cancer nodes with large (clinically relevant) sizes using near-infrared photosensitizers (PS). MethodsThe anticancer efficacy and mechanisms of the photodynamic action of PS based on polycationic derivatives of synthetic bacteriochlorin against Lewis lung carcinoma were studied in vitro and in vivo. ResultsIt was found that studied PS have high phototoxicity against Lewis lung carcinoma cells: the IC50 values were about 0.8 μM for tetracationic PS and 0.5 μM for octacationic PS. In vivo studies have shown that these PS provide effective inhibition of the tumor growth with an increase in the lifespan of mice in the group by more than 130%, and more than 50% survival of mice in the group. ConclusionsPhotosensitizers based on polycationic derivatives of synthetic bacteriochlorin have high photodynamic efficacy caused by the induction of necrosis and apoptosis of cancer cells, including cancer stem cells, and a sharp decrease of mitotic and proliferative activity. Studied polycationic photosensitizers are much more effective at destroying cancer stem cells and newly formed cancer vessels in comparison with anionic photosensitizers, and ensure the cessation of tumor blood flow without hemorrhages and thrombosis.

Cationic BODIPY Photosensitizers for Mitochondrion-Targeted Fluorescence Cell-Imaging and Photodynamic Therapy.

The straightforward synthesis of three cationic boron-dipyrromethene (BODIPY) derivatives and their mitochondria-targeting and photodynamic therapeutic (PDT) capabilities are reported. Two cancer cell lines (HeLa and MCF-7) were used to investigate the PDT activity of the dyes. Compared to their non-halogenated counterparts, halogenated BODIPY dyes exhibit lower fluorescence quantum yields and enable the efficient production of singlet oxygen species. Following LED light irradiation at 520 nm, the synthesized dyes displayed good PDT capabilities against the treated cancer cell lines, with low cytotoxicity in the dark. In addition, functionalization of the BODIPY backbone with a cationic ammonium moiety enhanced the hydrophilicity of the synthesized dyes and, consequently, their uptake by the cells. The results presented here collectively demonstrate the potential of cationic BODIPY-based dyes as therapeutic drugs for anticancer photodynamic therapy.