Near-infrared Photosensitizer Research Articles

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.

Mucus-Penetrating Nanoassembly as Potential Oral Phototherapeutic Formulation against Multi-Drug Resistant Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) infection presents increasing challenges to antibiotic therapies in limited penetration through gastric mucus, multi-drug resistance (MDR), biofilm formation, and intestinal microflora dysbiosis. To address these problems, herein, a mucus-penetrating phototherapeutic nanomedicine (RLs@T780TG) against MDR H. pylori infection is engineered. The RLs@T780TG is assembled with a near-infrared photosensitizer T780T-Gu and an anionic component rhamnolipids (RLs) for deep mucus penetration and light-induced anti-H. pylori performances. With optimized suitable size, hydrophilicity and weak negative surface, the RLs@T780TG can effectively penetrate through the gastric mucus layer and target the inflammatory site. Subsequently, under irradiation, the structure of RLs@T780TG is disrupted and facilitates the T780T-Gu releasing to target the H. pylori surface and ablate multi-drug resistant (MDR) H. pylori. In vivo, RLs@T780TG phototherapy exhibits impressive eradication against H. pylori. The gastric lesions are significantly alleviated and intestinal bacteria balance is less affected than antibiotic treatment. Summarily, this work provides a potential nanomedicine design to facilitate in vivo phototherapy in treatment of H. pylori infection.

π-extended porphyrin-based near-infrared photosensitizers for mitochondria-targeted photodynamic therapy

Near-infrared (NIR) photosensitizers have great potential to develop various fields of photochemistry, such as photodynamic therapy (PDT) and photocatalysts. Organelle-targeted PDT using NIR light attracts considerable attention to high-efficiency phototherapy. Although drug delivery system (DDS) carriers are often combined with NIR photosensitizers for effective PDT, the systematic correlations between the cargo and DDS carriers are still unclear. In this study, we develop NIR-photosensitizers from a π-extended porphyrin-type sensitizer (rTPA) that allows us to modify the structure and properties with a one-touch operation for the systematic study. Single-step amidations give five rTPA derivatives readily, facilitating comprehensive information about the properties according to their molecular structure and electric charge of the photosensitizer and DDS carriers prepared using a microfluidic device. One of the combinations, rTPA-NH2@MP, demonstrates the highest ability among the derivatives to kill pancreatic cancer cells, which are known to be highly lethal. The present study provides a guideline for inventing effective DDS-based NIR-PDT compounds for future photodrugs.

Endoplasmic reticulum and mitochondrial double-targeted NIR photosensitizer synergistically promote tumor cell death

The excessive production of reactive oxygen species (ROS) can damage the mitochondrial membrane and induce apoptosis, causing endoplasmic reticulum stress and triggering immunogenic cell death. Therefore, the combination of apoptosis and immunogenic death by the dual-targeted ROS generator has great potential to address inefficient cancer treatment. A near-infrared photosensitizer was developed for efficient ROS production and dual-targeted cancer treatment. Due to the modulation of electron structure, the reduced transition energy barrier affords TCy5-I-3F the highest efficiency to produce ROS. TCy5-I-3F has excellent mitochondrial and endoplasmic reticulum targeting ability, causing cell apoptosis and stress of the endoplasmic reticulum for destroying cancer cells. In the dual-targeted mode, high expression of GRP780, activation of heat shock protein (HSP70), the outflow of high mobility group protein B1, efflux of Calreticulin, and massive efflux of adenosine triphosphate are evaluated in the pharmacological experiments. In vivo experiments, the maturation of dendritic cells (DC, CD80+, CD86+), CD8+ T cells and CD3+ T cells also highlights the effectiveness. The tumors of mice treated with TCy5-I-3F and near-infrared (NIR) light are significantly inhibited. The multifunctional targeting design and corresponding mechanisms prove a new insight for exploring efficient photodynamic therapy drugs.

NQO-1 activatable NIR photosensitizer for visualization and selective killing of breast cancer cells

The diagnosis and treatment of breast cancer is of immense importance in improving patient outcomes. The biological marker NAD(P)H:quinone oxidoreductase 1 was utilized to design BrCyS-Q, a near-infrared activatable photosensitizer for breast cancer. BrCyS-Q was successfully employed to diagnose breast cancer cells using fluorescence and photodynamic inhibition. The findings of this research may offer novel insights for the diagnosis and treatment of clinical breast cancer via photodynamic therapy.

HIF‐1α‐inhibited Nanophotosensitizers for Near‐infrared Fluorescence Imaging‐guided Enhanced Photodynamic Therapy

AbstractPhotodynamic therapy (PDT) holds great potential in cancer therapy by virtue of its high precision, non‐invasiveness and low side effect. However, the hypoxic environment of solid tumor significantly restricts the efficacy of PDT. To improve the hypoxic microenvironment, inhibiting the hypoxia‐inducible factor 1α (HIF‐1α) is a rational approach. However, the related small molecule inhibitors suffer from the issue of poor tumor targeting. Herein, we design a nanophotosensitizer AmPPa NP which can inhibit HIF‐1α and conduct PDT with improved efficacy. AmPPa NP is prepared by first encapsulating a hydrophobic NIR photosensitizer mPPa into a carboxyl‐rich amphiphilic copolymer PSMA‐PEG, and then loading a positively charged HIF‐1α inhibitor acriflavine (ACF) on the surface of nanoparticle via electrostatic interaction. Under 635 nm laser irradiation, mPPa within nanoparticles can not only generate 1O2 for PDT but also emit NIR fluorescence signal for tumor imaging. In addition, such design makes ACF can be selectively released under acidic tumor microenvironment. Compared with mPPa NP without ACF loading, AmPPa NP can effectively inhibit HIF‐1α and shows improved PDT efficacy both in vitro and in vivo. This study thus provides a nanotheranostic platform for NIR fluorescence imaging‐guided enhanced PDT.

Near-Infrared Conjugated Polymers Containing Thermally Activated Delayed Fluorescence Units Enable Enhanced Photothermal Therapy.

Photothermal therapy (PTT) using near-infrared (NIR) conjugated polymers as photosensitizers has exhibited enormous potential for tumor treatment. However, most NIR conjugated polymers have poor therapeutic efficacy due to their faint absorbance in the NIR region and low photothermal conversion efficiency (PCE). Herein, a valuable strategy for designing NIR polymeric photosensitizer PEKBs with an enhanced PCE accompanied by strong NIR absorbance is proposed by means of inserting TPA-AQ as a thermally activated delayed fluorescence unit into a polymeric backbone. In these PEKBs, PEKB-244 with the appropriate molar content of the TPA-AQ unit displays the strongest NIR absorbance and the highest PCE of 64.5%. Theoretical calculation results demonstrate that the TPA-AQ unit in the polymeric backbone can modulate the intramolecular charge transfer effects and the excited energy decay routes for generating higher heat. The prepared nanoparticles (PEKB-244 NPs) exhibit remarkable photothermal conversion capacities and great biocompatibility in aqueous solutions. Moreover, PEKB-244 NPs also show outstanding photothermal stability, displaying negligible changes in the absorbance within 808 nm irradiation of 1 h (800 mW cm-2). Both in vitro and in vivo experimental results further indicate that PEKB-244 NPs can substantially kill cancer cells under NIR laser irradiation. We anticipate that this novel molecular design strategy can be employed to develop excellent NIR photosensitizers for cancer photothermal therapy.

Adoptive macrophage directed photodynamic therapy of multidrug-resistant bacterial infection

Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective, broad-spectrum, and accurate treatment for severe cases of infection is urgently needed. Here, we present an adoptive transfer of macrophages loaded with a near-infrared photosensitizer (Lyso700D) in lysosomes to boost innate immunity and capture and eliminate bacteria through a photodynamic effect. In this design, the macrophages can track and capture bacteria into the lysosomes through innate immunity, thereby delivering the photosensitizer to the bacteria within a single lysosome, maximizing the photodynamic effect and minimizing the side effects. Our results demonstrate that this therapeutic strategy eliminated MDR Staphylococcus aureus (MRSA) and Acinetobacter baumannii (AB) efficiently and cured infected mice in both two models with 100% survival compared to 10% in the control groups. Promisingly, in a rat model of central nervous system bacterial infection, we performed the therapy using bone marrow-divided macrophages and implanted glass fiber to conduct light irradiation through the lumbar cistern. 100% of infected rats survived while none of the control group survived. Our work proposes an efaficient and safe strategy to cure MDR bacterial infections, which may benefit the future clinical treatment of infection.

Near-infrared photosensitizers adaptive to tumor hypoxic microenvironment for synergistic photothermal-photodynamic and immunotherapy

For photodynamic therapy (PDT), traditional type II photosensitizers rely on local molecular oxygen to produce highly cytotoxic singlet oxygen (1O2) to kill tumor cells, which is severely restricted by the hypoxic tumor microenvironment (TME). We herein develop a heavy-metal-free and near-infrared (NIR) photosensitizer BTAC6 and its hydrophilic nanoparticles (BTAC6 NPs) with enhanced tumor-killing effects in both normoxic and hypoxic TME via synergistic photothermal therapy (PTT), PDT (both type I and II) and immunotherapy. BTAC6 possesses donor-acceptor alternating structure (A-DA'D-A) and large-conjugated skeleton, contributing to superb NIR light absorption, narrowed energy gap (ΔEST) and enhanced intersystem crossing (ISC) process for superior PTT and PDT performances. Under the stimulation of 808 nm NIR laser, BTAC6 NPs can adapt to both normoxic and hypoxic TME to effectively ablate tumors. It presents synergistic type II PDT/PTT to generate topical heat and 1O2 in normoxia, and exhibits type I PDT/PTT to produce hyperpyrexia, highly-reactive hydroxyl radical (•OH) and superoxide anion (O2•–) in hypoxia, achieving an over 98 % tumor inhibition rate in mice. Importantly, this synergistic PDT/PTT treatment can activate a durable anti-tumor immune response while destroying the tumors. This work provides a molecular structure design strategy of developing heavy-metal-free NIR photosensitizers to conquer hypoxia.

Near-Infrared BODIPY Photosensitizer for Modulating Mitochondrial Fusion Proteins and Inhibiting Choroidal Neovascularization.

Photosensitizers have emerged as cytotoxic reactive oxygen species (ROS) activators in photodynamic therapy (PDT), which induced cell apoptosis. As the major contributors to ROS and oxidative stress, mitochondria play an important role in cell apoptosis. Although there are many reports about near-infrared 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) as photosensitizers (PSs) for PDT, this kind of PS has rarely been used for treating mitochondrial function and choroidal neovascularization application at the same time. Herein, a novel near-infrared PS (BDP2) characterized by good water solubility, long wavelength excitation, and high ROS quantum yield has been made. Under near-infrared light irradiation, BDP2 would generate ROS with high yield, induce a mitochondrial morphology change, and trigger cell apoptosis by changing the fusion protein level. Deep investigation revealed that BDP2 can cause oxidative stress, break the balance between fusion and fission of mitochondrial dynamics protein through decreasing fusion protein MFN2 and OPA1 expression, and finally cause cell apoptosis. Due to these characteristics, the BDP2 PS was used to treat choroidal neovascularization in animal models and can inhibit neovascularization.

Powerful Synergy of Traditional Chinese Medicine and Aggregation-Induced Emission-Active Photosensitizer in Photodynamic Therapy.

Breast cancer (BC) remains a significant global health challenge for women despite advancements in early detection and treatment. Isoliquiritigenin (ISL), a compound derived from traditional Chinese medicine, has shown potential as an anti-BC therapy, but its low bioavailability and poor water solubility restrict its effectiveness. In this study, we created theranostic nanoparticles consisting of ISL and a near-infrared (NIR) photosensitizer, TBPI, which displays aggregation-induced emission (AIE), with the goal of providing combined chemo- and photodynamic therapies (PDT) for BC. Initially, we designed an asymmetric organic molecule, TBPI, featuring a rotorlike triphenylamine as the donor and 1-methylpyridinium iodide as the acceptor, which led to the production of reactive oxygen species in mitochondria. We then combined TBPI with ISL and encapsulated them in DSPE-PEG-RGD nanoparticles to produce IT-PEG-RGD nanoparticles, which showed high affinity for BC, better intersystem crossing (ISC) efficiency, and Förster resonance energy transfer (FRET) between TBPI and ISL. In both 4T1 BC cell line and a 4T1 tumor-bearing BC mouse model, the IT-PEG-RGD nanoparticles demonstrated excellent drug delivery, synergistic antitumor effects, enhanced tumor-killing efficacy, and reduced drug dosage and side effects. Furthermore, we exploited the optical properties of TBPI with ISL to reveal the release process and distribution of nanoparticles in cells. This study provides a valuable basis for further exploration of IT-PEG-RGD nanoparticles and their anticancer mechanisms, highlighting the potential of theranostic nanoparticles in BC treatment.

Π‐Radical Photosensitizer for Highly Efficient and Stable Near‐Infrared Photon Upconversion

AbstractNear‐infrared (NIR)‐to‐blue triplet–triplet annihilation upconversion (TTA‐UC) exhibits substantial potential for diverse applications, encompassing photovoltaics, photocatalysis, bioimaging, and photodynamic therapy. A major challenge in this field, however, is attaining high upconversion quantum yields (ΦUC) without using transition metals as NIR photosensitizers. This research presents an innovative organic π‐radical photosensitizer (TTM‐TPA) featuring extended absorption in the NIR region (≈760 nm) that is capable of generating pronounced anti‐Stokes emissions when coupled with suitable triplet acceptors. By eliminating energy loss associated with intersystem crossing and promoting rapid doublet–triplet energy transfer processes, the binary TTM‐TPA/perylene system achieves ΦUC values of up to 6.8% and an anti‐Stokes shift of 0.93 eV. Notably, the TTA‐UC system demonstrates exceptional stability when subjected to intense 733 nm laser irradiation (4 W cm−2), maintaining nearly constant upconversion intensity after 4 h. These findings underscore the considerable potential of doublet‐sensitized TTA‐UC for a broad array of practical applications.

Molecular Engineering of Aptamer to Solubilize Hydrophobic Near-Infrared Photosensitizer for Enhanced Cancer Photodynamic Therapy

Molecular Engineering of Aptamer to Solubilize Hydrophobic Near-Infrared Photosensitizer for Enhanced Cancer Photodynamic Therapy

Design, synthesis, and characterization of pH-responsive near infrared bithiophene Aza-BODIPY

Aza-boron-dipyrromethene (Aza-BODIPY) have been favored by researchers for their excellent performance in photothermal therapy, photodynamic therapy, and bioimaging. In the field of phototherapy, Aza-BODIPY have been pushed forward because of their extensive variety and structural flexibility. Here, two bithiophene Aza-boron-dipyrromethene (Aza-BODIPY) NIR photosensitizers have been successfully synthesized (B5 and B6). Both of the bithiophene Aza-BODIPY exhibit high molar extinction coefficients and are red-shifted in wavelength. The maximum characteristic absorption peak is at 880 nm, and the maximum emission peak is at 880 nm. Bithiophene Aza-boron-dipyrromethene could simultaneously generate heat and singlet oxygen (1O2) under the irradiation of a single laser (808 nm). B5 and B6 each had photothermal conversion efficiencies of 39.84% and 58.14%. At the same time, B5 and B6 have photoacoustic signal generation under laser in the range of 680–900 nm. In addition, the ability of both to produce 1O2 at pH = 5 was significantly enhanced compared to pH = 7. as well as excellent photoacoustic properties. Most significantly, phototoxicity experiments showed that bithiophene Aza-BODIPY (B5) achieved the effect of killing 4T1 tumor cells effect. Finally, to improve the application of Aza-BODIPY, Pluronic F127 was used in self-assembly with the bithiophene Aza-BODIPY.

A lysosomes and mitochondria dual-targeting AIE-active NIR photosensitizer: Constructing amphiphilic structure for enhanced antitumor activity and two-photon imaging.

Development of lysosomes and mitochondria dual-targeting photosensitizer with the virtues of near-infrared (NIR) emission, highly efficient reactive oxygen generation, good phototoxicity and biocompatibility is highly desirable in the field of imaging-guided photodynamic therapy (PDT) for cancer. Herein, a new positively charged amphiphilic organic compound (2-(2-(5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)vinyl)-3-methylbenzo[d]thiazol-3-ium iodide) (ADB) based on a D-A-π-A structure is designed and comprehensively investigated. ADB demonstrates special lysosomes and mitochondria dual-organelles targeting, bright NIR aggregation-induced emission (AIE) at 736​nm, high singlet oxygen (1O2) quantum yield (0.442), as well as good biocompatibility and photostability. In addition, ADB can act as a two-photon imaging agent for the elaborate observation of living cells and blood vessel networks of tissues. Upon light irradiation, obvious decrease of mitochondrial membrane potential (MMP), abnormal mitochondria morphology, as well as phagocytotic vesicles and lysosomal disruption in cells are observed, which further induce cell apoptosis and resulting in enhanced antitumor activity for cancer treatment. In vivo experiments reveal that ADB can inhibit tumor growth efficiently upon light exposure. These findings demonstrate that this dual-organelles targeted ADB has great potential for clinical imaging-guided photodynamic therapy, and this work provides a new avenue for the development of multi-organelles targeted photosensitizers for highly efficient cancer treatment.

Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy.

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging to precisely control PROTAC function in tumor regions in vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis in tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate of PROTAC linked with an NIR photosensitizer through a singlet oxygen (1O2)-cleavable linker. The activity of PROTAC is initially silenced but can be remotely switched on upon NIR photoirradiation to generate 1O2 by the photosensitizer. We demonstrated that NAP enabled tumor-specific degradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructed manner. This in combination with photodynamic therapy (PDT) elicited an effective suppression of tumor growth. This work thus presents a novel approach for spatiotemporal control over targeted protein degradation by PROTAC.

GSH-Responsive Prodrug Nanoassembly as a Carrier-Free Nanoplatform for Tumor-Targeting Delivery and Chemo-Photothermal Therapy.

Photothermal therapy, combined with chemotherapy, holds promising prospects for the therapeutic outcome of malignant tumors. However, the synergistic therapeutic effect suffers from low coloading capacity and inefficient synchronous tumor-targeting delivery of chemodrug and photothermal photosensitizers. Herein, we designed a versatile carrier-free nanoplatform to seek improvement for chemo-photothermal therapy. An NIR photosensitizer IR-808 was used for noninvasive cancer imaging, diagnosis, and imaging-guided photothermal therapy. A reduction-sensitive paclitaxel prodrug (PTX-SS-PEG2k) was rationally synthesized by covalently linking paclitaxel with polyethylene glycol 2000 via a disulfide bond. Then, the carrier-free nanoassemblies were constructed with an inner core of IR-808 and an amphiphilic paclitaxel prodrug shell. PTX-SS-PEG2k served as a stabilizer and chemodrug and could facilitate the self-assembly of IR-808 nanoparticles with high coloading efficiency and reduction-sensitive drug release. The versatile nanoplatform exhibited multiple advantages, including high drug payload, reduction-sensitive drug release, tumor-targeting drug delivery, and potent synergistic antitumor effect. We provide a versatile theranostic nanoplatform, which improves the effectiveness of synergetic chemo-photothermal therapy and reduces the off-target toxicity.

Synthesis of Glutathione-Responsive Cyclomatrix Polyphosphazene for Multimodal Theranostic Nanodrug Delivery

In this work, a multimodal (chemotherapeutic/photodynamic/photothermal) theranostic nanodrug delivery platform was developed based on the synergetic action of self-framed polyphosphazene prodrug and heptamethine cyanine dye IR-780. First, an electronegative glutathione (GSH)-responsive polyphosphazene prodrug abbreviated as HGEH was prepared via multicomponent condensation reaction of genistein (GEN), bis-(4-hydroxyphenyl)-disulfide, and hexachlorocyclotriphosphazene. The particle size of drug (GEN)-containing HGEH nanoparticles is adjustable. Subsequently, cationic near-infrared photosensitizer IR-780 was adsorbed onto the electron-rich HGEH to obtain the multimodal theranostic nanodrug delivery platform HGEH-IR780. The platform was demonstrated to retain high stability in avoiding drug leakage and enable controlled drug release in response to the tumor microenvironment, in which a higher GSH concentration exists. The in vitro experiments show that HGEH-IR780 undergoes photothermal and photodynamic processes to concurrently generate heat and reactive oxygen species for efficiently killing mouse breast cancer cells (4T1) upon exposure to a single-bandwidth near-infrared laser (808 nm). Specifically, HGEH-IR780 inhibits 4T1 cells by up to 80% at a concentration of 100 μg/mL. The as-developed HGEH-IR780 exhibits promising results in GSH-responsive anticancer activity and photodynamic/photothermal therapy, which provides a reference for the construction of the polyphenol flavonoid multimodal therapeutic nanoplatform.

Long-Wavelength Absorbing Benzimidazolo-Chlorin for Enhanced Photodynamic Therapy.

In this study, we condensed methyl pyropheophorbide-a (2) with 1,2-phenylenediamine to synthesize benzimidazolo-chlorin (3a) as an effective near-infrared photosensitizer (PS) with an absorption maximum of 730 nm. The ability of 3a to generate singlet oxygen, as well as its photodynamic effect on A549 and HeLa cells, was investigated. PS exhibited strong phototoxicity and negligible dark toxicity. Its structure was examined by UV-visible spectroscopy, nuclear magnetic resonance, and high-resolution fast atom bombardment mass spectrometry.

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.