Photodynamic Therapy Agents Research Articles

Enhanced Intracellular Delivery of Curcumin Using Polymeric Nanocarriers: A Natural Photosensitizing Agent for Anti-Cancer Photodynamic Therapy.

Curcumin ranks among the extensively investigated Phytocompounds with a wide array of therapeutic properties. It has bioactive and photoactive properties that enhance its potential as an anti-cancer agent. However, poor solubility and low bioavailability are associated with it which hinders its applications. To address the limitations related to free curcumin (CUR), the present study focuses on the synthesis of curcumin-loaded poly lactic-co-glycolic acid nanoparticles (CUR NPs). The single emulsion solvent evaporation technique was used to synthesize CUR NPs with an average size of 187nm and a zeta potential of -13.3 mV. Photophysical properties, drug loading efficiency, and drug release profile of synthesized CUR NPs were studied. Confocal fluorescence imaging was employed to study the cellular uptake of both formulations of CUR. The In-vitro investigation was conducted using BT-474 human breast cancer cells to evaluate the dark and phototoxic effect of both variants of curcumin (free CUR and CUR NPs). The cytotoxicity was quantified through half-maximal inhibitory concentration (IC50) obtained after conducting in-vitro dark and phototoxic experiments. The study revealed that CUR NPs showed better cytotoxic responses compared to the free CUR. During the phototoxic study, CUR NPs exhibit improved efficacy in the presence of light. The CUR NPs effectively deliver curcumin to enhance its potential in photodynamic therapy against cancer.

Photonic hydrogels combining the slow photon effect and NO gas therapy for synergetic enhanced photodynamic antibacterial therapy.

Photonic hydrogels combining the slow photon effect and NO gas therapy for synergetic enhanced photodynamic antibacterial therapy.

Inducing Cuproptosis with Copper Ion-Loaded Aloe Emodin Self-Assembled Nanoparticles for Enhanced Tumor Photodynamic Immunotherapy.

Immunotherapy has fundamentally transformed the clinical treatment landscape for non-small cell lung cancer (NSCLC). While its effectiveness is ultimately limited by patient heterogeneity and immunosuppressive tumor microenvironment. Photodynamic therapy (PDT), as an emerging antitumor immunotherapy, has shown its unique therapeutic advantages. However, previous studies often overlooked the potential toxicity of photosensitizers (PS), making the discovery of safe and effective PSa pressing clinical need. In this study, Aloe Emodin (AE), a medicinal plant natural compound, was loaded with copper ions(Cu), and self-assembled into nanoparticles (NPs) under the modification of PEG2k-DSPE-FA. NPs can target, accumulate, and reside within tumor sites, responsively releasing copper ions and AE, thus dual-functioning by inducing tumor cell death via cuproptosis and enhancing PDT effects. The LLC tumor-bearing mouse model demonstrated that NPs induce the maturation of dendritic cells (DCs) in vivo, promote lymphocyte infiltration, transform"cold tumors" into "hot tumors" and significantly enhance the efficacy of immune checkpoint blockade (ICB). This study provides experimental evidence of AE as a clinically promising PDT agent and offers a novel perspective for the synergistic treatment of clinical NSCLC.

Photostable Mn(II) Complex of Curcumin for Effective Photodynamic Therapy and Precise Three-Dimensional In Vivo Tumor Imaging.

Photoactive complexes of first-row transition metals with emission properties offer a dual approach to cancer treatment, enabling precise optical tumor detection and subsequent eradication using light. We report a photostable and photoactive mixed-ligand Mn(II) complex, Mn4, featuring a naturally occurring curcumin ligand and dipyridophenazine base. Mn4 demonstrates significant visible and red light-triggered phototoxicity against cancer cells and precise tumor imaging capability in vivo. The complex exhibits an absorption band in the visible region, extending its tail into the red region, and shows excellent dark and photostability in solution. Mn4 induces significant phototoxicity against HeLa (cervical), A549 (lung), and MCF-7 (breast) cancer cells (IC50 ≈ 1.0 μM), as well as 3D multicellular tumor spheroids, under low-energy visible (400-700 nm) and red-light (660 nm). This effect is mediated by cytotoxic singlet oxygen and proceeds via an apoptotic mechanism. Importantly, Mn4 displays significantly lower toxicity toward normal HPL1D lung and HEK-293 kidney cells under similar conditions. Cellular uptake studies reveal selective accumulation of Mn4 in A549 cancer cells, with mitochondrial localization, and negligible accumulation in BEAS-2B normal lung cells. Furthermore, 3D optical tumor imaging demonstrated Mn4's selective tumor accumulation in a 4T1 breast tumor-bearing in vivo mouse model. In vivo efficacy studies using a 4T1 tumor-bearing orthotopic mouse model show that Mn4 significantly reduces tumor volume and weight in a dose-dependent manner under low-energy blue laser (450 nm) irradiation, highlighting its potential as an effective photodynamic therapy (PDT) agent. Toxicological studies confirm that Mn4 does not induce abnormal biochemical or hematological parameters in healthy mice. To our knowledge, this is the first report of a Mn(II) complex with curcumin and the first example of a metal complex with curcumin for combined in vivo PDT and noninvasive 3D optical tumor imaging, paving the way for nonmacrocyclic Mn-based cancer phototheranostics.

Oxygen Nanobubbles Enhance ICG/Fe(III)-Mediated Dual-Modal Therapy To Induce Ferroptosis in Tumor Treatment.

Noninvasive therapies such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), which rely on reactive oxygen species (ROS), are gaining attention for their low toxicity. However, single-modal treatments have individual limitations that restrict the therapeutic efficacy. Fe(III) can coordinate with the hydrophilic regions of indocyanine green (ICG) molecules to form the ICG/Fe(III) complex, making it a promising dual-modal agent for combined PDT and CDT. However, coordination with Fe(III) leads to the aggregation quenching of ICG, hindering its application in dual-modal therapy. We innovatively utilize oxygen nanobubbles, prepared solely from water and oxygen, to significantly reverse the aggregation-induced quenching of the ICG/Fe(III) complex, thereby enhancing its stability in aqueous environments. In this system, Fe(III) assembles at the nanobubble interface, coordinating with ICG's hydrophilic regions to form the ICG/Fe(III)-NBs. The oxygen nanobubbles boost PDT efficiency by improving the ICG/Fe(III) complex stability and oxygen content, while Fe(III) achieves CDT by generating hydroxyl radicals (•OH) through the Fenton reaction. This dual-modality treatment significantly disrupts the tumor's redox balance, induces ferroptosis, and demonstrates strong antitumor efficacy, reducing tumor volume to 34% of its initial size in mice. The strategy offers a promising and clinically viable approach to cancer treatment.

Computational Investigation of Meso-Substituted, Heavy Atom-Free BODIPY Derivatives as Photosensitizers: Insights From TDDFT and Dynamics Studies.

This study investigates the structural and electronic properties of BODIPY (BDP) derivatives featuring meso-substituted donors arranged orthogonally, leveraging Time-Dependent Density Functional Theory (TD-DFT). These deriva-tives, selected based on experimental evidence of their quantum yield towards singlet oxygen generation, exhibit intricate excited-state dynamics, transitioning from fluorescence to intersystem crossing (ISC), thereby presenting a promising avenue for applications in photodynamic therapy. Emphasizing heavy-atom-free organic triplet photosensitizers, with BDP dyes highlighted for their exceptional adaptability in photophysical characteristics, our analysis contributes to a deeper understanding of the fundamental design principles governing such photosensitizers. Through a combined approach of static and dynamic calculations, we elucidate the mechanisms underlying the population transfer from singlet to triplet states, thereby providing valuable insights for the development of efficient photodynamic therapy agents.

Encapsulation of synthesized purpurin-18-N-aminoimide methyl ester in lipid nanovesicles for use as agents in photodynamic cancer therapy.

Encapsulation of synthesized purpurin-18-N-aminoimide methyl ester in lipid nanovesicles for use as agents in photodynamic cancer therapy.

The potential of photodynamic therapy combined with hyperthermia using porphyrin-nanomaterial hybrids against the triple-negative breast cancer cell line

The potential of photodynamic therapy combined with hyperthermia using porphyrin-nanomaterial hybrids against the triple-negative breast cancer cell line

Dyad System of BOAHY-BODIPY Conjugates as Novel Photoswitchable Photosensitizers for Photodynamic Therapy.

Photodynamic therapy (PDT) offers minimally invasive and repeatable cancer treatment options. Despite advancements in photosensitizer (PS) design, the optical control of PS activation remains unexplored. Here, we present the first photoswitchable PS based on a BOAHY-BODIPY dyad system. Inspired by BODIPY multimer structures and BOAHY's photoisomerization properties, we designed mono-(4 series) and bis-BOAHY-BODIPY (5 series) conjugates. These dyads primarily generate reactive oxygen species via a type-I process under white light. Notably, the 4 series compounds demonstrated effective photocytotoxicity and photoswitching properties in vitro. Building on these, we iodinated the monoconjugates to develop the highly efficient photoswitching PS, 6b, which exhibited enhanced intersystem crossing and type-II reactive oxygen species generation due to a reduced singlet-triplet energy gap. As the first demonstration of photoswitchable PDT agents, this strategy introduces a new approach with significant potential for selective cancer treatment and clinical applications.

Gold nanocages co-assembled with Spinacia oleracea extract combined photothermal/photodynamic therapy in 4T1 breast cancer cell line

Photothermal therapy (PTT) and photodynamic therapy (PDT) have been emerging as potential alternatives to conventional cancer treatment modalities. Gold nanoparticles, owing to their surface plasmon resonance properties, have been promising in cancer phototherapies, and extracts from potent medicinal plants are commonly employed for the green synthesis of various nanoparticles. Some researchers have used photosensitizers like chlorophyll to promote reactive oxygen species generation. In this research, the photothermal ability of gold and the photon-absorbing capability of chlorophyll derived fromSpinacia oleracea(S. oleracea) are combined to achieve the optimum results. Herein, we have synthesized the gold nanocages(AuNCs) co-assembled withS. oleraceaextract (SPAuNCs; 70 ± 10 nm) to be employed as a PTT and PDT agent to treat triple-negative breast cancer. This study found that SPAuNCs are promising PTT and PDT agents against breast cancer cell line.

Fullerene (C60 & C70)-Meso-Tris-4-Carboxyphenyl Porphyrin Dyads Inhibit Entry of Wild-Type and Drug-Resistant HIV-1 Clades B and C.

The biological applications of noncationic porphyrin-fullerene (P-F) dyads as anti-HIV agents have been limited despite the established use of several cationic P-F dyads as anti-cancer photodynamic therapy (PDT) agents. This article explores the potential of amphiphilic non-cationic porphyrin-fullerene dyads as HIV-1 inhibitors under both PDT (light-treated) and non-PDT (dark) conditions. The amphiphilic P-F dyads, PB3C60 and PB3C70, demonstrated enhanced efficacy in inhibiting the entry and production of HIV-1 (subtypes B and C). Under light-harvested conditions, the dyads exhibited potent inhibitory effects (EC50 for PB3C60 and PB3C70 < 10 nM) and also maintained significant inhibition under non-PDT conditions (EC50 for PB3C60 = 1.43 μM and PB3C70 = 1.50 μM), while displaying notably reduced toxicity compared to their water-soluble porphyrin precursor. The P-F dyads exhibited substantial efficacy in neutralizing the T20-resistant strain 9491, both at the entry and postentry phases, thereby addressing the challenge of drug resistance.

A Hypoxia-Activated BODIPY-Azo Anticancer Prodrug for Bimodal Chemo-Photodynamic Therapy.

For cancer treatment, collaborative strategies have been the mainstream for overcoming the restrictions resulting from monotherapy. Combining chemotherapy with photodynamic therapy (PDT) has been shown to increase the antitumor effect and reduce side impacts. This study reports a hypoxia-activated prodrug BOD-Azo-single with a PDT agent and aniline mustard connected by the azo bond. With light illumination, BOD-Azo-single exhibited some PDT. Under hypoxic conditions, the azo bond cleaved and released BOD-3-single of higher phototoxicity and aniline mustard of chemotoxicity. In vivo therapeutic experiments showed that BOD-Azo-single with light significantly reduced A375 tumor proliferation with 92% TGI value. Overall, in this study, PDT was employed to address the adverse systemic toxicity of chemotherapy and the released chemotoxicity made up for the inefficiency of PDT in the hypoxic tumor microenvironment, introducing a new strategy for developing combined therapeutic agents to be advantageous to each other. Under a hypoxic tumor environment, BOD-3-single and aniline mustard exerted a strong synergistic effect (CI = 0.25), indicating that BOD-Azo-single is a real bimodal chemo-photodynamic therapeutic agent.

Near-Infrared Photothermal Conversion by Isocorrole and Phlorin Derivatives.

Photothermal therapy is a promising strategy for treating tumors and bacterial infections by using light irradiation to locally heat tissues. Metalloisoporphyrinoid materials have been investigated for their use as singlet oxygen photosensitizers for photodynamic therapy but remain underexplored as photothermal agents. Recently, two metallophlorin and two metalloisocorrole materials were found to have strong near-infrared absorbance, with low photoluminescent quantum yields, suggesting high rates of nonradiative decay. Here we demonstrate that when encapsulated into aggregated organic nanoparticles (a-Odots), these materials show high photothermal conversion efficiencies between 67.3 ± 8.4 and 75.7 ± 4.1%. When considered alongside their ability to generate singlet oxygen, these materials may show promise as agents for dual photothermal and photodynamic therapy.

Applications of polymeric nanoparticles in drug delivery for glioblastoma.

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, necessitating innovative therapeutic approaches. Polymer-based nanotechnology has emerged as a promising solution, offering precise drug delivery, enhanced blood-brain barrier (BBB) penetration, and adaptability to the tumor microenvironment (TME). This review explores the diverse applications of polymeric nanoparticles (NPs) in GBM treatment, including delivery of chemotherapeutics, targeted therapeutics, immunotherapeutics, and other agents for radiosensitization and photodynamic therapy. Recent advances in targeted delivery and multifunctional polymer highlight their potential to overcome the challenges that GBM brought, such as heterogeneity of the tumor, BBB limitation, immunosuppressive TME, and consideration of biocompatibility and safety. Meanwhile, the future directions to address these challenges are also proposed. By addressing these obstacles, polymer-based nanotechnology represents a transformative strategy for improving GBM treatment outcomes, paving the way for more effective and patient-specific therapies.

Fluorescence tunable carbon dots for in vitro nuclear dynamics and gastrointestinal imaging in live zebrafish and their in vivo toxicity evaluation by cardio-craniofacial disfunction assessment.

Sub-cellular organelle anomalies are frequently observed in diseases such as cancer. Early and precise diagnosis of these alterations can be crucial for patient outcomes. However, current diagnostic tools using conventional organic dyes or metal quantum dots face limitations, including poor biocompatibility, stringent storage conditions, limited solubility in aqueous media, and slow staining speeds. These challenges underscore the need for safer, more effective diagnostic and therapeutic solutions. In these aspects, we have developed highly photostable, biocompatible, water-dispersible carbon dots (TNCDs) with an average size of 5.5 nm using tartaric acid and ethylenediamine via a hydrothermal route. The synthesized TNCDs have shown bright blue fluorescence under the irradiation of UV-light at an excitation wavelength of 365 nm. They exhibit a quantum yield (QY) of 25.1% with maximum emission at 390 nm. A nice tri-exponential fitting of the decay curve with characteristic lifetimes of 1.52 ns, 3.05 ns and 6.11 ns for TNCDs was obtained. In vitro studies demonstrated that TNCDs have high biocompatibility (20 μg ml-1) with almost 100% cell viability and excellent nucleus targeting and staining capabilities with low background interference (with 10-12 times enhancement in fluorescence intensity). Additionally, if tagged with photosensitizers or radionuclides, TNCDs can serve as therapeutic agents in photodynamic therapy against cancer cells. Importantly, TNCDs exhibited negligible toxicity in developing zebrafish even at high concentrations (up to 400 mg L-1) as investigated by cardio and craniofacial disfunction assessment. Live organism imaging revealed that TNCDs produced aggregation-induced strong and specific green fluorescence in the gut of zebrafish larvae even at low concentrations, indicating their potential for nucleus staining and gut-specific optical imaging (at 50 mg L-1). Thus, our TNCDs represent a robust nanoplatform for cellular and whole-organism fluorescence imaging, offering both diagnostic and therapeutic potential.

Zinc Phthalocyanine Core-First Star Polymers Through Nitroxide Mediated Polymerization and Nitroxide Exchange Reaction.

Nitroxide-mediated polymerization (NMP) and nitroxide exchange reaction (NER) are very efficient methodologies that require only suitable alkoxyamine derivatives and create different polymeric architectures in a controlled manner. Herein, the synthesis of star polymers containing TEMPO-substituted symmetric zinc phthalocyanine (ZnPc) is presented via NMP and NER. Moreover, linear polymer formation is conducted in a single arm on TEMPO-substituted asymmetric ZnPc to elucidate the properties of star polymers. All linear and star polymers are characterized by FT-IR, UV-vis, fluorescence, GPC, NMR, and EPR techniques. The results show that the proposed reactions are capable of forming controlled star-shaped polymers. The increasing arm number (from a single to four arms) results in variable dispersity values (Đ) (1.2-3) due to different arm lengths, especially in NMP. However, this difficulty has been overcome via NER, and star polymers have been successfully synthesized with relatively low molecular weight (30 K > 10 K) and low dispersity (1.2-1.9). The results clearly indicate that while styrene and 4-vinyl benzyl chloride monomers are introduced to the structure equally, star polymers with phthalocyanine can be synthesized in a controlled manner, and their quarternized derivatives have the potential to be effective as photoactive agents in photodynamic therapy.

Photodynamic therapy photosensitizers and photoactivated chemotherapeutics exhibit distinct bioenergetic profiles to impact ATP metabolism.

Energy is essential for all life, and mammalian cells generate and store energy in the form of ATP by mitochondrial (oxidative phosphorylation) and non-mitochondrial (glycolysis) metabolism. These processes can now be evaluated by extracellular flux analysis (EFA), which has proven to be an indispensable tool in cell biology, providing previously inaccessible information regarding the bioenergetic landscape of cell lines, complex tissues, and in vivo models. Recently, EFA demonstrated its utility as a screening tool in drug development, both by providing insights into small molecule-organelle interactions, and by revealing the peripheral and potentially undesired off-target effects small molecules have within cells. Surprisingly, technologies to quantify cellular bioenergetics have not been systematically applied in phototherapy development, leaving open several questions about how the mechanism of action of a compound can impact essential cellular functions. Here, we utilized the Seahorse analyzer to address this question for photosensitizers (PSs) for photodynamic therapy (PDT) and contrast these systems to molecules that photo-release a ligand and thus act as photocages or photoactivated chemotherapeutics (PACT), intending to understand the influence these two classes of compounds have on cellular bioenergetics. EFA results show that acute treatment of A549 lung adenocarcinoma cells with PDT agents induces a quiescent bioenergetic response as a result of mitochondrial respiration shutdown. The loss of oxidative phosphorylation is followed by disruption of glycolysis, which occurs after an initial increase in glycolytic respiration is unable to compensate for the interruption of the electron transport chain (ETC). In contrast, the PACT agents tested had little impact on cellular respiration, and the minor inhibition of these metabolic processes was not related to the mechanism of action, as reflected by a lack of correlation with photoejection efficiency. Notably, a system capable of both generating 1O2 and photo-releasing a ligand exhibited the dominant profile of a PDT agent and induced the quiescent bioenergetic state, indicating potential implications on cellular bioenergetics for so-called dual-action agents. These findings are presented with the aim to provide the necessary groundwork for expanding the application and utility of EFA to phototherapeutics and to highlight the role of metabolic alterations in PDT.

Transdermal therapeutic polymer: in situ synthesis of biocompatible polymer using 5-aminolevulinic acid as a photosensitizer precursor and a polymer initiator.

Melanoma is the most malignant skin tumor caused by the malignancy of melanocytes that produce the melanin pigment. Various methods have been developed to combat melanoma, with photodynamic therapy (PDT) gaining the spotlight for its ability to eliminate cancer cells by generating reactive oxygen species through light-sensitive photosensitizers. 5-aminolevulinic acid (5-ALA) is the most commonly used PDT agent, which could be converted to the PpIX photosensitizer molecule within cancer cells. However, its high hydrophilicity limits effective transdermal and oral delivery. In this work, we present a novel polymer formulation, named 5-AP, designed for the transdermal delivery of 5-ALA to deep melanoma tumor sites. 5-AP was prepared by the in situ polymerization of dimethylsiloxane, using 5-ALA as a photosensitizer precursor and a ring-opening polymerization initiator. 5-AP exhibited enhanced hydrophobicity compared to 5-ALA, facilitating improved transdermal penetration. In a melanoma mouse model, 5-ALA was released from the polymer and then converted to PpIX, emitting fluorescence and demonstrating high tumor treatment efficacy under laser irradiation. We believe these findings can usher in a new era of transdermal photodynamic therapy.

A red light-activable hetero-bimetallic [Fe(iii)-Ru(ii)] complex as a dual-modality PDT tool for anticancer therapy.

We developed a novel red light activable hetero-bimetallic [Fe(III)-Ru(II)] complex by combining hydroxyl radical-generating Fe(III)-catecholate as a type I PDT agent and the singlet oxygen generating Ru(II)-paracymene complex as a type II PDT agent and it potentially functions as a dual-modality PDT tool for enhanced phototherapeutic applications. 2-Amino-3-(3,4-dihydroxyphenyl)-N-(1,10-phenanthrolin-5-yl)propenamide (L2) acted as a bridging linker. The single-pot synthesis of the hetero-bimetallic [Fe(III)-Ru(II)] complex was carried out through acid-amine coupling. Various photophysical assays confirmed the photo-activated production of (˙OH) radicals and (1O2) oxygen generation upon activation of the [Fe(III)-Ru(II)] complex with red light (600-720 nm, 30 J cm-2), which resulted in enhanced cytotoxicity with a photo-index of ∼45. The complex, [Fe(III)-Ru(II)], potentially bonded to the DNA through the ruthenium moiety was responsible for minimal dark toxicity. The cytotoxic potential of the complex under red light was a result of the photo-induced accumulation of reactive oxygen species through both type I and type II photodynamic therapy (PDT) mechanisms in A549 and HeLa cells, while non-cancerous HPL1D cells remained unaffected. We probed the caspase 3/7-dependent apoptosis of the complex, [Fe(III)-Ru(II)], in vitro. Overall, the hetero-bimetallic [Fe(III)-Ru(II)] complex is an ideal example of a red light activable dual-modality next-generation PDT tool for phototherapeutic anticancer therapy.

Organelle-targeting activity-based hemicyanine derivatives for enhanced and selective type-I photodynamic therapy under hypoxia conditions

Two organelle-targeted and hydrogen sulfide responsive type-I photodynamic therapy agents are developed for selective and effective treatment of hypoxic cancer cells.