Singlet Oxygen For Photodynamic Therapy Research Articles

Size-controlled synthesis and sensing properties of anthracene-based metal-organic frameworks for detection of singlet oxygen in photodynamic therapy

Developing fluorescent probes to detect singlet oxygen (1O2) is essential to understanding the critical role of 1O2 in immunological and pathological processes in various organs. In this study, size-controlled DPA-MOF (X) with good biocompatibility and excellent optical stability was used as a nanoprobe for real-time imaging and monitoring of 1O2 in photodynamic therapy (PDT). The experimentally synthesized DPA-MOF (X), which can be adjusted in particle size by dilution, exhibits blue fluorescence signals. The results show that smaller-sized DPA-MOF (60) has a faster response to 1O2 and higher cell uptake ability. The ratio of fluorescence intensity (F0/Fi) of DPA-MOF (60) showed a linear correlation with the concentration of 1O2 in the range of 0–7 mM, with a detection limit of 88 μM. DPA-MOF has a distinct advantage over most carrier loading sensors in that it effectively avoids the issue of fluorophore leakage from the nanomaterial matrix, thereby improving its stability. Additionally, the controlled synthesis of DPA-MOF can potentially improve probe accumulation in tumors and lower the uptake by the body system. This study presents a luminescent metal-organic framework (LMOF) sensor that utilizes a 1O2 capture unit as a measuring ligand. This sensor has been shown to have exceptional biocompatibility and can be utilized for highly specific and efficient detection of 1O2 in vivo or living cells.

Photo-Triggered Fluorescence Polyelectrolyte Nanoassemblies: Manipulate and Boost Singlet Oxygen in Photodynamic Therapy.

Photodynamic therapy (PDT) is a clinically approved therapeutic modality that has shown great potential for cancer treatment. However, there exist two major problems hindering PDT applications: the nonspecific phototoxicity requiring patients to stay in dark post-PDT, and the limited photodynamic efficiency. Herein, we report a photo-triggered porphyrin polyelectrolyte nanoassembling (photo-triggered PPN) strategy, in which porphyrin photosensitizer and photoswitchable energy accepter are assembled into polyelectrolyte micelles by a combined force of charge interaction and metal-ligand coordination. The polyelectrolyte-based PPN exhibits good biocompatibility, and bestows a unique "confining isolated" inner microenvironment for fully overcoming the π-π stacking of porphyrins with significant photodynamic efficiency (123-fold enhancement). Due to the high Förster resonance energy transfer (FRET) (91.5%) between porphyrin and photoswitch in closed-form, we could use light as a specific trigger to modulate photoswitch between closed- and open-form, and manipulate the 1O2 generation in three stages: pre-PDT (quenching 1O2 generation), during PDT (activating 1O2 generation), and post-PDT (silencing 1O2 generation). This de novo strategy has for the first time realized remotely manipulating and boosting 1O2 generation in PDT, well resolving the critical and general challenges of limited photodynamic efficiency and side effects from nonspecific phototoxicity.

Singlet Oxygen in Photodynamic Therapy.

Photodynamic therapy (PDT) is a therapeutic modality that depends on the interaction of light, photosensitizers, and oxygen. The photon absorption and energy transfer process can lead to the Type II photochemical reaction of the photosensitizer and the production of singlet oxygen (1O2), which strongly oxidizes and reacts with biomolecules, ultimately causing oxidative damage to the target cells. Therefore, 1O2 is regarded as the key photocytotoxic species accountable for the initial photodynamic reactions for Type II photosensitizers. This article will provide a comprehensive review of 1O2 properties, 1O2 production, and 1O2 detection in the PDT process. The available 1O2 data of regulatory-approved photosensitizing drugs will also be discussed.

Thiophene Stability in Photodynamic Therapy: A Mathematical Model Approach.

Thiophene-containing photosensitizers are gaining recognition for their role in photodynamic therapy (PDT). However, the inherent reactivity of the thiophene moiety toward singlet oxygen threatens the stability and efficiency of these photosensitizers. This study presents a novel mathematical model capable of predicting the reactivity of thiophene toward singlet oxygen in PDT, using Conceptual Density Functional Theory (CDFT) and genetic programming. The research combines advanced computational methods, including various DFT techniques and symbolic regression, and is validated with experimental data. The findings underscore the capacity of the model to classify photosensitizers based on their photodynamic efficiency and safety, particularly noting that photosensitizers with a constant rate 1000 times lower than that of unmodified thiophene retain their photodynamic performance without substantial singlet oxygen quenching. Additionally, the research offers insights into the impact of electronic effects on thiophene reactivity. Finally, this study significantly advances thiophene-based photosensitizer design, paving the way for therapeutic agents that achieve a desirable balance between efficiency and safety in PDT.

Cellular Mechanisms of Singlet Oxygen in Photodynamic Therapy

In this review, we delve into the realm of photodynamic therapy (PDT), an established method for combating cancer. The foundation of PDT lies in the activation of a photosensitizing agent using specific wavelengths of light, resulting in the generation of reactive oxygen species (ROS), notably singlet oxygen (1O2). We explore PDT’s intricacies, emphasizing its precise targeting of cancer cells while sparing healthy tissue. We examine the pivotal role of singlet oxygen in initiating apoptosis and other cell death pathways, highlighting its potential for minimally invasive cancer treatment. Additionally, we delve into the complex interplay of cellular components, including catalase and NOX1, in defending cancer cells against PDT-induced oxidative and nitrative stress. We unveil an intriguing auto-amplifying mechanism involving secondary singlet oxygen production and catalase inactivation, offering promising avenues for enhancing PDT’s effectiveness. In conclusion, our review unravels PDT’s inner workings and underscores the importance of selective illumination and photosensitizer properties for achieving precision in cancer therapy. The exploration of cellular responses and interactions reveals opportunities for refining and optimizing PDT, which holds significant potential in the ongoing fight against cancer.

A copper nanocluster-based multifunctional nanoplatform for augmented chemo/chemodynamic/photodynamic combination therapy of breast cancer

With the development of nano drug delivery system, the treatment mode that can overcome the shortcomings of chemotherapy drugs and integrate combined therapy remains to be explored. Herein, a nano drug system was designed to achieve the combined effect of chemo/chemodynamic/photodynamic therapy on cancer. Specifically, copper clusters (CuNCs) were used as the carrier, hyaluronic acid (HA) and doxorubicin (DOX) were coupled on CuNCs and then and chlorin e6 (Ce6) was introduced to form the self-assembled HA-CuNCs@DC nanoparticles. In this system, the HA-CuNCs@DC was involved in the reaction to the acidic tumor microenvironment (TME)-release of DOX, which could not only inhibit tumor growth through chemotherapy, but enhance the generation of hydrogen peroxide. CuNCs carriers had the properties of Fenton-like activity to realize chemodynamic therapy (CDT) and oxidase-like activity to deplete intracellular glutathione (GSH). Additionally, the chemotherapy drug susceptibility increased owing to the GSH depletion and the outbreak of reactive oxygen species, indicating the enhanced CDT efficacy and amplified chemotherapy efficacy. It was also noteworthy that Ce6 could be activated by 660 nm light to produce abundant singlet oxygen for photodynamic therapy. Overall, our platform demonstrated excellent biosafety and tumor suppression capabilities. This multimodal theranostic strategy provided new insights into cancer therapy.

Upconversion Nanoparticles for Cancer Therapy

Lanthanide‐doped upconversion nanoparticles (UCNPs) are anti‐Stokes emitters, which can produce higher‐energy ultraviolet/visible and near‐infrared (NIR) luminescence when excited with low‐energy NIR light. They are featured with nonphotobleaching, sharp emission peaks, superstability, low toxicity, low imaging background, and functional multimodality. These characteristics endow them to be useful as nanoprobes for diagnostic applications and imaging‐guided cancer therapy. Importantly, the ability to convert tissue‐penetrating NIR light into visible and ultraviolet range can expedite Fenton‐ or Fenton‐based processes in chemical dynamic therapy (CDT), activate photosensitizers (PSs) to produce singlet oxygen in photodynamic therapy (PDT), and regulate light‐controlled drug delivery processes for efficacious cancer therapy. The past decade witnessed fast progress of UCNPs as agents in single‐mode therapy or combined therapies in the forefront researches on fighting cancer. This review summarizes the fundamental roles of UCNPs in cancer therapy, highlights types of cell deaths induced by excessive reactive oxygen species (ROS), and showcases cutting‐edge applications in combined cancer therapies as well as imaging‐guided cancer therapy. Challenges and outlook on the use of UCNPs for future directions in cancer therapy are also discussed.

Spheroidal Model of SKBR3 and U87MG Cancer Cells for Live Imaging of Caspase-3 during Apoptosis Induced by Singlet Oxygen in Photodynamic Therapy.

Aspects related to the response of cells to photodynamic therapy (PDT) have been well studied in cell cultures, which often grow in monolayers. In this work, we propose a spheroidal model of U87MG and SKBR3 cells designed to mimic superficial tumor tissue, small spheroids (<500 µm) suitable for confocal fluorescence microscopy, and larger spheroids (>500 µm) that can be xenografted onto quail chorioallantoic membrane (CAM) to study the effects of PDT in real time. Hypericin was used as a model molecule for a hydrophobic photosensitizer that can produce singlet oxygen (1O2). 1O2 production by hypericin was detected in SKBR3 and U87MG spheroid models using a label-free technique. Vital fluorescence microscopy and flow cytometry revealed the heterogeneity of caspase-3 distribution in the cells of the spheroids. The levels of caspase-3 and apoptosis increased in the cells of spheroids 24 h after PDT. Lactate dehydrogenase activity was evaluated in the spheroids as the most reliable assay to detect differences in phototoxicity. Finally, we demonstrated the applicability of U87MG spheroids on CAM in photodiagnostics. Overall, the variability and applicability of the prepared spheroid models were demonstrated in the PDT study.

Aggregation-Induced Emission (AIE) Photosensitizer Combined Polydopamine Nanomaterials for Organelle-Targeting Photodynamic and Photothermal Therapy by the Recognition of Sialic Acid.

The construction of organelle-targeting nanomaterials is an effective way to improve tumor imaging and treatment. Here, a new type of composite nanomaterial named as PTTPB is developed. PTTPB is composed of organelle-targeting aggregation-induced emission photosensitizer TTPB and polydopamine nanomaterials. With the functional modification of TTPB, PTTPB can recognize sialic acid on the cell membrane and present mitochondrial targeted capabilities. The intake of PTTPB in cancerous cells can be increased by the recognition process of cell membrane. PTTPB can generate singlet oxygen for photodynamic therapy (PDT), and present good photothermal conversion ability with irradiation. The PTTPB with organelle-targeting imaging-guided can realize the tumor ablation with the synergistic effect of PDT and photothermal therapy.

Photonics of Viburnum opulus L. Extracts in Microemulsions with Oxygen and Gold Nanoparticles

In this paper, the optical properties of viburnum extract flavonoids in the visible region of the spectrum were investigated and their use as a potential photosensitizer of singlet oxygen for photodynamic therapy was evaluated. The presence of long-lived excited states in the extract molecules was established by spectral methods and time-resolved spectroscopy methods and the dependences of the absorption capacity and luminescence intensity of the extract molecules on the concentrations of oxygen and ablative nanoparticles of the gold in the reverse micelles of AOT (sodium dioctyl sulfosuccinate) were established. The plasmonic enhancement of the luminescence of the extract molecules and the processes of their complexation with oxygen were also established. Furthermore, the rate constants of the processes of conversion of exciting energy in complexes were determined.

Enabling In Vivo Photocatalytic Activation of Rapid Bioorthogonal Chemistry by Repurposing Silicon-Rhodamine Fluorophores as Cytocompatible Far-Red Photocatalysts.

Chromophores that absorb in the tissue-penetrant far-red/near-infrared window have long served as photocatalysts to generate singlet oxygen for photodynamic therapy. However, the cytotoxicity and side reactions associated with singlet oxygen sensitization have posed a problem for using long-wavelength photocatalysis to initiate other types of chemical reactions in biological environments. Herein, silicon-Rhodamine compounds (SiRs) are described as photocatalysts for inducing rapid bioorthogonal chemistry using 660 nm light through the oxidation of a dihydrotetrazine to a tetrazine in the presence of trans-cyclooctene dienophiles. SiRs have been commonly used as fluorophores for bioimaging but have not been applied to catalyze chemical reactions. A series of SiR derivatives were evaluated, and the Janelia Fluor-SiR dyes were found to be especially effective in catalyzing photooxidation (typically 3%). A dihydrotetrazine/tetrazine pair is described that displays high stability in both oxidation states. A protein that was site-selectively modified by trans-cyclooctene was quantitatively conjugated upon exposure to 660 nm light and a dihydrotetrazine. By contrast, a previously described methylene blue catalyst was found to rapidly degrade the protein. SiR-red light photocatalysis was used to cross-link hyaluronic acid derivatives functionalized by dihydrotetrazine and trans-cyclooctenes, enabling 3D culture of human prostate cancer cells. Photoinducible hydrogel formation could also be carried out in live mice through subcutaneous injection of a Cy7-labeled hydrogel precursor solution, followed by brief irradiation to produce a stable hydrogel. This cytocompatible method for using red light photocatalysis to activate bioorthogonal chemistry is anticipated to find broad applications where spatiotemporal control is needed in biological environments.

NaYF4:Yb/Tm@SiO2-Dox/Cur-CS/OSA nanoparticles with pH and photon responses

Stimulus-triggered drug delivery systems (DDSs) based on lanthanide-doped upconversion nanoparticles (UCNPs) have attracted significant attention for treating cancers due to their merits of high drug availability, precisely controlled drug release, and low side-effects. However, such DDSs usually exhibit a single stimulus-response, which may limit the efficiency of cancer treatment. To extend response types in a single DDS, we construct NaYF4:Yb/Tm@SiO2-doxorubicin (Dox)/curcumin (Cur)-chitosan (CS)/2-Octen-1-ylsuccinic anhydride (OSA) nanoparticles with core-shell structures. Our method is based on the exploration of the synergistic effect of UCNPs and multiple drugs. In particular, the NaYF4:Yb/Tm is used to convert near-infrared light to visible light, activating Cur photosensitizers to produce singlet oxygen for photodynamic therapy, while CS/OSA responds to a low pH environment to release cancer drugs, including Dox and Cur for chemotherapy through breaking a free carboxyl group. The results show that the UCNPs with a 40 nm diameter, 23 nm thick mesoporous SiO2, and 19/1 mol% Yb3+/Tm3+concentrations could continuously release Dox and Cur at a pH value of 6.5 within 6 h after the excitation of a 980 nm-wavelength CW laser. Our study provides a promising approach for developing efficient DDSs for cancer treatment.

Triggered All-Active Metal Organic Framework: Ferroptosis Machinery Contributes to the Apoptotic Photodynamic Antitumor Therapy.

Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.

Vacancy-enhanced generation of singlet oxygen for photodynamic therapy.

Oxygen vacancy (OV) engineering in semiconductors can greatly enhance the separation of photo-induced electron-hole pairs, thereby enhancing the photocatalytic activity. Taking inspiration from this, we prepared a novel BiOBr-H/Rub2d composite by functionalizing OV-rich BiOBr (named BiOBr-H) with a carboxyl functionalized ruthenium photosensitizer (Ru(bpy)2C-pyCl2, abbreviated as Rub2d), which was then successfully applied for photodynamic therapy (PDT). Density functional theory (DFT) calculations confirmed efficient electron transfer from the Rub2d complex to the intermediate energy level of BiOBr-H under visible light irradiation. In vitro and in vivo studies demonstrated that BiOBr-H/Rub2d was a superior agent for photodynamic therapy compared with the free ruthenium complex. The theoretical and experimental data presented thus reveal for the first time that abundant OVs in BiOBr-H can significantly improve the photocatalytic activity of a photosensitizer, resulting in the generation of more reactive oxygen species to enhance PDT. The findings of this study thus offer a new strategy for the development of highly efficient cancer therapies.

PH-Dependent Assembly of Porphyrin-Silica Nanocomposites and Their Application in Targeted Photodynamic Therapy.

Structurally controlled nanoparticles, such as core-shell nanocomposite particles by combining two or more compositions, possess enhanced or new functionalities that benefited from the synergistic coupling of the two components. Here we report new nanocomposite particles with self-assembled porphyrin arrays as the core surrounded by amorphous silica as the shell. The synthesis of such nanocomposite nanoparticles was conducted through a combined surfactant micelle confined self-assembly and silicate sol-gel process using optically active porphyrin as a functional building block. Depending on kinetic conditions, these particles exhibit structure and function at multiple length scales and locations. At the molecular scale, the porphyrins as the building blocks provide well-defined macromolecular structures for noncovalent self-assembly and unique chemistry for high-yield generation of singlet oxygen for photodynamic therapy (PDT). On the nanoscale, controlled noncovalent interactions of the porphyrin building block result in an extensive self-assembled porphyrin network that enables efficient energy transfer and impressive fluorescence for cell labeling, evidenced by absorption and photoluminescence spectra. Finally, the thin silicate shell on the nanoparticle surface allows easy functionalization, and the resultant targeting porphyrin-silica nanocomposites can selectively destroy tumor cells upon receiving light irradiation.

Ultrafast Carrier Dynamics and Efficient Triplet Generation in Black Phosphorus Quantum Dots

The two-dimensional few-layer black phosphorus (BP) has been proposed as a new type of semiconductor for optoelectronic applications. Beyond optoelectronics, the BP nanostructures have recently shown great potential in producing singlet oxygen for photodynamic therapy, but its underlying mechanism remains elusive. Here, we report the observation of efficient triplet formation in BP quantum dots, which might be responsible for the singlet oxygen generation. In addition to the common dynamic behaviors of semiconductors, a long-lived photoinduced bleaching signal with a lifetime of 26 μs has been explicitly identified in BP quantum dots, which can be ascribed to the intersystem crossing from singlet to triplet states as confirmed by oxygen quenching test. The observation of highly efficient intersystem crossing in BPQDs well explains its superior performance in photodynamic therapy and indicates its exotic spintronic and magneto-optical properties.

ICG-conjugated Magnetic Graphene Oxide for Dual Photothermal and Photodynamic Therapy.

Aptamer-functionalized magnetic graphene oxide conjugates loaded with indocyanine green (ICG) dye, or Apt@ICG@mGO, have been successfully developed for dual-targeted photothermal and photodynamic therapy. In general, a drug or its carrier or their dosage can be imprtant important issues in terms of toxicity. However, in this system, each component used is quite safe, biocompatibe and clean. For instance, ICG, a Food and Drug Administration (FDA) approved near-infrared (NIR) dye, serves as both a photothermal and photodynamic agent. It is immobilized on the surface of mGO via a physical interaction called "π-π stacking". The mGO, as a most biocomptible member of the carbo family, is selected for use as a platform for aptamer and ICG dye conjugation, as well as as a photothermal agent. The light in the near-infrared region (NIR) was chosen as a harmless light source for activating the agents for photothermal therapy (PTT) and photodynamic therapy (PDT). The magnetic properties of mGO are also used for separation of Apt@ICG@mGO conjugates from the reaction medium. Aptamer sgc8 acts as a targeting ligand to selectively and specifically bind to a protein on the membrane of cancer cell line CCRF-CEM. After the aptamer- functionalized ICG@mGO conjugates are incubated with target CEM cells at 37 °C for 2 hours, they are bound to cells or they may be internalized into the cell via endocytosis. More significantly, we demonstrated that the Apt@ICG@mGO conjugates produce heat for photothermal therapy (PTT) and singlet oxygen for photodynamic therapy (PDT) upon NIR laser irradiation at 808 nm. Thus, remarkably efficient cancer cell destructions with ~41% and ~60% and ~82% cell killing using 10, 50 and 100 ppm Apt@ICG@mGO, respectively are achieved in 5 min light exposure.

Iridium complexes for the application of photodynamic therapy

Photodynamic therapy can destruct tumor cells by singlet oxygen which is generated via a photodynamic reaction of the photosensitizer under a specfic excitation wavelength. Due to the heavy atom effect of metal iridium,iridiumcomplexes are excited by suitable light and then reach their excited triple state through intersystem crossing. The excited iridium complexes transfer energy to oxygen molecules to produce singlet oxygen for photodynamic therapy.

Mesoporous silica nanorods intrinsically doped with photosensitizers as a multifunctional drug carrier for combination therapy of cancer

Mesoporous silica nanoparticles (MSNs) have attracted tremendous attention in recent years as drug delivery carriers due to their large surface areas, tunable sizes, facile modification and considerable biocompatibility. In this work, we fabricate an interesting type of MSNs which are intrinsically doped with photosensitizing molecules, chlorin e6 (Ce6). By increasing the amount of Ce6 doped inside the silica matrix, it is found that the morphology of MSNs changes from spheres to rod-like shapes. The obtained Ce6-doped mesoporous silica nanorods (CMSNRs) are not only able to produce singlet oxygen for photodynamic therapy, but can also serve as a drug delivery platform with high drug loading capacity by utilizing their mesoporous structure. Compared to spherical nanoparticles, it is found that CMSNRs with a larger aspect ratio show much faster uptake by cancer cells. With doxorubicin (DOX) employed as a model drug, the combined photodynamic and chemotherapy is carried out, achieving synergistic anti-tumor effects both in vitro and in vivo. Our study presents a new design of an MSN-based drug delivery platform, which intrinsically is fluorescent and able to serve as a photodynamic agent, promising for future imaging-guided combination therapy of cancer.

A smart and versatile theranostic nanomedicine platform based on nanoporphyrin.

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nano-construct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart “all-in-one” nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumor detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumors. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumors for photothermal-therapy (PTT), and light to singlet oxygen for photodynamic-therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs into tumors.