J-Aggregate Promoting NIR-II Emission for Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) are synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption >880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect, and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance.

Planar-structured thiadiazoloquinoxaline-based NIR-II dye for tumor phototheranostics.

Second near-infrared (NIR-II) fluorescence imaging shows huge application prospects in clinical disease diagnosis and surgical navigation, while it is still a big challenge to exploit high performance NIR-II dyes with long-wavelength absorption and high fluorescence quantum yield. Herein, based on planar π-conjugated donor-acceptor-donor systems, three NIR-II dyes (TP-DBBT, TP-TQ1, and TP-TQ2) were synthesized with bulk steric hindrance, and the influence of acceptor engineering on absorption/emission wavelengths, fluorescence efficiency and photothermal properties was systematically investigated. Compared with TP-DBBT and TP-TQ2, the TP-TQ1 based on 6,7-diphenyl-[1,2,5]thiadiazoloquinoxaline can well balance absorption/emission wavelengths, NIR-II fluorescence brightness and photothermal effects. And the TP-TQ1 nanoparticles (NPs) possess high absorption ability at a peak absorption of 877 nm, with a high relative quantum yield of 0.69% for large steric hindrance hampering the close π-π stacking interactions. Furthermore, the TP-TQ1 NPs show a desirable photothermal conversion efficiency of 48% and good compatibility. In vivo experiments demonstrate that the TP-TQ1 NPs can serve as a versatile theranostic agent for NIR-II fluorescence/photoacoustic imaging-guided tumor phototherapy. The molecular planarization strategy provides an approach for designing efficient NIR-II fluorophores with extending absorption/emission wavelength, high fluorescence brightness, and outstanding phototheranostic performance.

Benzobisthiadiazole-Based Small Molecular Near-Infrared-II Fluorophores: From Molecular Engineering to Nanophototheranostics.

Organic fluorescent molecules with emission in the second near-infrared (NIR-II) biological window have aroused increasing investigation in cancer phototheranostics. Among these studies, Benzobisthiadiazole (BBT), with high electron affinity, is widely utilized as the electron acceptor in constructing donor-acceptor-donor (D-A-D) structured fluorophores with intensive near-infrared (NIR) absorption and NIR-II fluorescence. Until now, numerous BBT-based NIR-II dyes have been employed in tumor phototheranostics due to their exceptional structure tunability, biocompatibility, and photophysical properties. This review systematically overviews the research progress of BBT-based small molecular NIR-II dyes and focuses on molecule design and bioapplications. First, the molecular engineering strategies to fine-tune the photophysical properties in constructing the high-performance BBT-based NIR-II fluorophores are discussed in detail. Then, their biological applications in optical imaging and phototherapy are highlighted. Finally, the current challenges and future prospects of BBT-based NIR-II fluorescent dyes are also summarized. This review is believed to significantly promote the further progress of BBT-derived NIR-II fluorophores for cancer phototheranostics.

Asymmetric aza-BODIPY photosensitizer for photoacoustic/photothermal imaging-guided synergistic photodynamic/photothermal therapy.

Cancer synergistic therapy usually shows improved therapeutic efficacy with low side effects. In this contribution, an aza-BODIPY-derived photosensitizer NBDP with asymmetric structure and the periphery phenyl ring modified with bromine atom was designed and synthesized for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Photosensitizer NBDP exhibited good singlet oxygen (1O2) generation capacity (1.43 times higher than that of ICG), and NBDP NPs showed an outstanding photothermal conversion efficiency (η) of 46.0% under 660 nm photoirradiation. Guided by in vivo photoacoustic (PA) imaging, NBDP NPs were found to targetedly accumulate in the tumor tissues in 6 h. All results showed that the aza-BODIPY-derived photosensitizer NBDP had great potential for PA/photothermal imaging-guided synergistic PTT/PDT.

Recent advances in Prussian blue-based photothermal therapy in cancer treatment.

Malignant tumours are a serious threat to human health. Traditional chemotherapy has achieved breakthrough improvements but also has significant detrimental effects, such as the development of drug resistance, immunosuppression, and even systemic toxicity. Photothermal therapy (PTT) is an emerging cancer therapy. Under light irradiation, the phototherapeutic agent converts optical energy into thermal energy and induces the hyperthermic death of target cells. To date, numerous photothermal agents have been developed. Prussian blue (PB) nanoparticles are among the most promising photothermal agents due to their excellent physicochemical properties, including photoacoustic and magnetic resonance imaging properties, photothermal conversion performance, and enzyme-like activity. By the construction of suitably designed PB-based nanotherapeutics, enhanced photothermal performance, targeting ability, multimodal therapy, and imaging-guided cancer therapy can be effectively and feasibly achieved. In this review, the recent advances in PB-based photothermal combinatorial therapy and imaging-guided cancer therapy are comprehensively summarized. Finally, the potential obstacles of future research and clinical translation are discussed.

Metal-free polymer nano-photosensitizer actuates ferroptosis in starved cancer.

The microenvironment in solid tumors drives the fate of cancer cells to ferroptosis, yet the underlying mechanism remains incompletely understood. Herein, we report a metal-free polymer photosensitizer (BDPB) as a new type ferroptosis inducer of starved cancer cells. The polymer consists of boron difluoride dipyrromethene dye as the photosensitizing unit and diisopropyl-ethyl amine as the electron-donating unit. Ultrafast spectroscopy and electron spin resonance mechanistically revealed the prolonged charge-separation process in BDPB, enabling complex-I like one-electron transfer effect to produce O2●-. Unexpectedly, the O2●--generating BDPB nanoparticles (NPs) served to deactivate the AMPK-mTOR signaling pathway in normal-state cancer cells to initiate cell repair activity and survive low-dose phototherapy. However, for cancer cells in a starved state, BDPB NPs triggered glutathione peroxidase 4 downregulation, lipid peroxides accumulation, and death to cancer cells, which was identified as ferroptosis but not apoptosis, necroptosis, or autosis. The application of BDPB NPs sheds new light on the design of individualized ferroptosis inducers for combating cancer progression.

Small Molecular NIR-II Fluorophores for Cancer Phototheranostics.

Phototheranostics integrates deep-tissue imaging with phototherapy (containing photothermal therapy and photodynamic therapy), holding great promise in early diagnosis and precision treatment of cancers. Recently, second near-infrared (NIR-II) fluorescence imaging exhibits the merits of high accuracy and specificity, as well as real-time detection. Among the NIR-II fluorophores, organic small molecular fluorophores have shown superior properties in the biocompatibility, variable structure, and tunable emission wavelength than the inorganic NIR-II materials. What's more, some small molecular fluorophores also display excellent cytotoxicity when illuminated with the NIR laser. This review summarizes the progress of small molecular NIR-II fluorophores with different central cores for cancer phototheranostics in the past few years, focusing on the molecular structures and phototheranostic performances. Furthermore, challenges and prospects of future development toward clinical translation are discussed.

NIR-II Organic Nanotheranostics for Precision Oncotherapy.

Precision oncotherapy can remove tumors without causing any apparent iatrogenic damage or irreversible side effects to normal tissues. Second near-infrared (NIR-II) nanotheranostics can simultaneously perform diagnostic and therapeutic modalities in a single nanoplatform, which exhibits prominent perspectives in tumor precision treatment. Among all NIR-II nanotheranostics, NIR-II organic nanotheranostics have shown an exceptional promise for translation in clinical tumor treatment than NIR-II inorganic nanotheranostics in virtue of their good biocompatibility, excellent reproducibility, desirable excretion, and high biosafety. In this review, recent progress of NIR-II organic nanotheranostics with the integration of tumor diagnosis and therapy is systematically summarized, focusing on the theranostic modes and performances. Furthermore, the current status quo, problems, and challenges are discussed, aiming to provide a certain guiding significance for the future development of NIR-II organic nanotheranostics for precision oncotherapy.

Nanoscale metal-organic frameworks for tumor phototherapy.

Metal-Organic Frameworks (MOFs) are constructed from metal ions/cluster nodes and functional organic ligands through coordination bonds. Owing to the advantages of diverse synthetic methods, easy modification after synthesis, large adsorption capacity for heavy metals, and short equilibrium time, considerable attention has recently been paid to MOFs for tumor phototherapy. Through rational tuning of metal ions and ligands, MOFs present abundant properties for various applications. Light-triggered phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an emerging cancer treatment approach. Nanosized MOFs can be applied as phototherapeutic agents to accomplish phototherapy with excellent phototherapeutic efficacy. This review outlines the latest advances in the field of phototherapy with various metal ion-based MOFs.

Recent advances in pH-responsive nanomaterials for anti-infective therapy.

Inspired by the slight acidic microenvironment, a variety of pH-responsive nanomaterials are designed for highly effective antibacterial therapy by improving the ability of drug penetration and retention to enhance the therapeutic efficacy of phototherapy or control surface adhesion. This review summarizes the common pH-responsive modes and highlights the recent and potential applications of pH-responsive nanomaterials in anti-infective therapy. Finally, the challenges and prospects of pH-responsive nanomaterials in clinical transformation are discussed.

Aza-BODIPY-Based Nanomedicines in Cancer Phototheranostics.

Cancer phototheranostics, composed of optical diagnosis and phototherapy (including photodynamic therapy and photothermal therapy), is a promising strategy for precise tumor treatment. Due to the unique properties of near-infrared absorption/emission, high reactive oxygen species generation, and photothermal conversion efficiency, aza-boron-dipyrromethene (aza-BODIPY), as an emerging organic photosensitizer, has shown great potential for tumor phototheranostics. By encapsulating aza-BODIPY photosensitizers within functional amphiphilic polymers, we can afford hydrophilic nanomedicines that selectively target tumor sites via an enhanced permeability and retention effect, thereby efficiently improving diagnosis and therapeutic efficacy. Herein, in this spotlight article, we attempt to highlight our recent contributions in the development of aza-BODIPY-based nanomedicines, which comprises three main sections: (1) to elucidate the design strategy of aza-BODIPY photosensitizers and corresponding nanomedicines; (2) to overview their photophysical properties and biomedical applications in phototheranostics, including fluorescence imaging, photoacoustic imaging, photodynamic therapy, photothermal therapy, and synergistic therapy; and (3) to depict the challenges and future perspectives of aza-BODIPY nanomedicines. It is believed that this Spotlight on Applications article would illuminate the way of developing new aza-BODIPY nanomedicines as well as other organic photosensitizer-based nanomedicines for future clinical translation.

Photothermal-pH-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy with negligible skin phototoxicity.

Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and hypoxia is demonstrated for multi-mode imaging guided synergistic cancer therapy with negligible skin phototoxicity. Upon 808-nm laser irradiation, TENAB NPs can generate hyperthermia to melt the phase change material (PCM-LASA) coat and thereafter release chemo-drug tirapazamine (TPZ). Meanwhile, under acidic pH, photosensitizer ENAB would turn "off" its charge-transfer state, generating prominent 1O2 for photodynamic therapy (PDT) and heat for photothermal therapy (PTT), respectively. Accompanied with PDT-induced hypoxia, the released TPZ can be activated into its cytotoxic form for tumor cells killing. Notably, owing to phase change material LASA coat and ENAB's pH sensitivity, TENAB NPs show negligible photosensitization to skin and normal tissues. As the multi-stimuli responsive mechanism, TENAB NPs demonstrate a promising future in cancer photo-chemo theranostics with excellent skin protection.

Penetration depth tunable BODIPY derivatives for pH triggered enhanced photothermal/photodynamic synergistic therapy.

Improving the deep-tissue phototherapy (PDT) efficiency in the near-infrared (NIR) region has become one of the major challenges in clinics for cancer treatment. Developing intelligent photosensitizers (PSs) responding to tumor-specific signals sensitively to minimize side effects is another major challenge for tumor phototherapy. Herein, three phenyl-based boron dipyrromethene (BODIPY) compounds with different numbers of diethylaminophenyl groups introduced onto the BODIPY core have been designed and synthesized by the Knoevenagel condensation reaction. The absorbance of these compounds (BDPmPh, BDPbiPh, and BDPtriPh) can be controlled easily for realizing the tunable penetration depth. Moreover, the diethylamino groups in these designed PSs can serve as proton acceptors triggered by the low pH in lysosomes which can enhance the efficacy of photodynamic and photothermal therapy. The corresponding nanoparticles (NPs) of the compounds are prepared through a nanoprecipitation method and in vitro studies demonstrate that the ultra-low drug dosage of BDPtriPh NPs (half-maximal inhibitory concentration, IC50 = 4.16 µM) is much lower than that of BDPmPh NPs (50.09 µM) and BDPbiPh NPs (22.4 µM). In vivo fluorescence imaging shows that these NPs can be passively targeted to tumors by the enhanced permeability and retention (EPR) effect, and BDPtriPh NPs exhibit the fastest accumulation (about 4 hours). In vivo phototherapy indicates that BDPtriPh NPs with the longest NIR absorbance (813 nm) and highest photothermal conversion efficiency (60.5%) can effectively inhibit tumor growth and reduce side effects to normal tissues. This study provides a strategy to modulate the photoconversion characteristics of PSs for both penetration-depth-tunable and pH-dependent PDT/PTT synergistic cancer therapy in clinics.

Pyrrolopyrrole aza-BODIPY near-infrared photosensitizer for dual-mode imaging-guided photothermal cancer therapy.

A NIR photosensitizer pyrrolopyrrole aza-BODIPY (PPAB) was synthesized in a straightforward manner. Through the use of PPAB NPs as a photothermal agent, photoacoustic imaging (PAI) and NIR fluorescence imaging (NIR-FI) can be achieved in vivo. In addition, the photothermal ablation of tumor cells can be realized both in vitro and in vivo, even at a low concentration (0.5 mg kg-1).

Smart Aza-BODIPY Photosensitizer for Tumor Microenvironment-Enhanced Cancer Phototherapy.

Photoactivated cancer therapeutic methods emerging in recent decades, such as photothermal therapy (PTT) and photodynamic therapy (PDT), have drawn worldwide research interest. Herein, a smart near-infrared (NIR) photosensitizer 4-(4-(7-(4-Bromophenyl)-1,9-bis(3,4-dimethoxyphenyl)-5,5-difluoro-5H-5l4,6l4-dipyrrolo[1,2-c:2',1'-f][1,3,5,2]triazaborinin-3-yl)phenyl)morpholine (MAB) with morpholine decorating on the aza-BODIPY core is synthesized to achieve dual-modal imaging-guided synergistic PDT/PTT, exhibiting a tumor microenvironment (TME) enhanced cancer theranostic performance. The introduction of electron-donating morpholine offers MAB-enhanced intramolecular charge transfer (ICT) and a pronounced red-shift with maximum absorption peak (λmax) at 730 nm. After encapsulating with amphiphilic polymer DSPE-mPEG2000, as-obtained MAB nanoparticles (NPs) with good biocompatibility can enrich targeting in the lysosomes of tumor cells and afterward be activated under the acidic microenvironment inside the lysosome (pH 5.0) to generate intracellular reactive oxygen species (ROS) for enhanced PDT through interruption of photoinduced electron transfer (PET). Through in vitro cytotoxicity assay studies, the half-maximal inhibitory concentration (IC50) of MAB NPs under irradiation with the 730 nm laser is ∼10 µg/mL, indicating an excellent phototherapy effect. Furthermore, an in vivo study illustrates a prominent PDT/PTT synergistic therapeutic effect, and MAB NPs can be rapidly metabolized.

Tumor-Microenvironment-Responsive Nanoconjugate for Synergistic Antivascular Activity and Phototherapy.

Insufficient oxygen supply (hypoxia), short half-life (<40 ns) of singlet oxygen, and up-regulation of the heat shock protein expression in solid tumors impede the photodynamic and photothermal therapeutic efficacy. Herein, a near-infrared carrier-free nanoconjugate direct-acting antiviral (DAA) with synergistic antivascular activity and pH-responsive photodynamic/photothermal behavior was designed and synthesized to improve cancer treatment efficacy. Obtained by the self-assembly approach, the biocompatible DAA nanoparticles (NPs) displayed amplifying pH-responsive photodynamic/photothermal performance in an acidic tumor microenvironment due to the protonation of diethylaminophenyl units. Most important, the antivascular agent 5,6-dimethylxanthenone-4-acetic acid, targeting the vascular endothelial growth factor, can be smartly released from the pro-drug DAA via ester bond hydrolysis at the subacid endocytosis organelles in the endothelial cells, which can effectively destroy the vascular region to prevent tumor proliferation and metastasis. Hence, DAA NPs can specifically target vascular endothelial cells and tumorous lysosomes with desired cellular damage properties in vitro. Therefore, the tumors can be ablated completely with no recurrence and side effects in vivo, which implies that DAA NPs provide a promising approach for cancer treatment via synergistic antivascular activity and photodynamic/photothermal therapy.

2-Pyridone-functionalized Aza-BODIPY photosensitizer for imaging-guided sustainable phototherapy.

To overcome irradiation-dependence of cancer phototherapy, a near infrared aza-BODIPY-based photothermogenic photosensitizer BDY with 2-Pyridone group has been synthesized for imaging-guided photothermal synergistic sustainable photodynamic therapy. Multifunctional water-soluble BDY nanoparticles (NPs), with high photothermal conversion efficiency of 35.7% and excellent singlet oxygen (1O2) generation ability, are prepared by self-assembling. The reversible transformation between 2-pyridone moiety and its endoperoxide form endows BDY with continuous 1O2 generation ability under illumination and non-illumination conditions. Simultaneously, BDY NPs exhibit excellent tumor targeting properties by enhanced permeability and retention (EPR) effect and photoacoustic imaging (PAI) ability. Furthermore, the photothermal assisted sustainable photodynamic therapy can significantly inhibit tumor growth (93.4% inhibition) with almost no side effects by intermittent laser illumination. The finding highlights that this photothermal synergistic sustainable phototherapy presents great potential for clinical applications.

Organic Dye Based Nanoparticles for Cancer Phototheranostics.

Phototheranostics, which simultaneously combines photodynamic and/or photothermal therapy with deep-tissue diagnostic imaging, is a promising strategy for the diagnosis and treatment of cancers. Organic dyes with the merits of strong near-infrared absorbance, high photo-to-radical and/or photothermal conversion efficiency, great biocompatibility, ready chemical structure fine-tuning capability, and easy metabolism, have been demonstrated as attractive candidates for clinical phototheranostics. These organic dyes can be further designed and fabricated into nanoparticles (NPs) using various strategies. Compared to free molecules, these NPs can be equipped with multiple synergistic functions and show longer lifetime in blood circulation and passive tumor-targeting property via the enhanced permeability and retention effect. In this article, the recent progress of organic dye-based NPs for cancer phototheranostic applications is summarized, which extends the anticancer arsenal and holds promise for clinical uses in the near future.

Black Phosphorus Nanosheets Immobilizing Ce6 for Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

In preclinical and clinical research, to destroy cancers, particularly those located in deep tissues, is still a great challenge. Photodynamic therapy and photothermal therapy are promising alternative approaches for tissue cancer curing. Black phosphorus (BP)-based nanomaterials, with broad UV-vis near-infrared absorbance and excellent photothermal effect, have shown great potential in biomedical applications. Herein, a biocompatible therapeutic platform, chlorin e6 (Ce6)-decorated BP nanosheets (NSs), has been developed for fluorescence and thermal imaging-guided photothermal and photodynamic synergistic cancer treatment. Taking advantage of the relatively high surface area of exfoliated BP NSs, the PEG-NH2-modified BP NSs (BP@PEG) are loaded with a Ce6 photosensitizer. The resulted BP@PEG/Ce6 NSs not only have good biocompatibility, physiological stability, and tumor-targeting property but also exhibit enhanced photothermal conversion efficiency (43.6%) compared with BP@PEG NSs (28.7%). In addition, BP@PEG/Ce6 NSs could efficiently generate reactive oxygen species because of the release of the Ce6 photosensitizer, which is also verified by in vitro studies. In vivo fluorescence imaging suggests that BP@PEG/Ce6 NSs can accumulate in the tumor targetedly through the enhanced permeability and retention effect. Both in vitro and in vivo studies suggest that BP@PEG/Ce6 can be a promising nanotheranostic agent for synergetic photothermal/photodynamic cancer therapy.