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.

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.

Space and Bond Synergistic Conjugation Controlling Multiple-Aniline NIR-II Absorption for Photoacoustic Imaging Guided Photothermal Therapy.

Currently, clinical photothermal therapy (PTT) is greatly limited by the poor tissue penetration of the excitation light sources in visible (390-780 nm) and first near-infrared (NIR-I, 780-900 nm) window. Herein, based on space and bond synergistic conjugation, a multiple-aniline organic small molecule (TPD), is synthesized for high-efficiency second near-infrared (NIR-II, 900-1700 nm) photoacoustic imaging guided PTT. With the heterogeneity of six nitrogen atoms in TPD, the lone electrons on the nitrogen atom and the π bond orbital on the benzene ring form multielectron conjugations with highly delocalized state, which endowed TPD with strong NIR-II absorption (maximum peak at 925 nm). Besides, according to the single molecular reorganization, the alkyl side chains on TPD make more free space for intramolecular motion to enhance the photothermal conversion ability. Forming TPD nanoparticles (NPs) in J-aggregation, they show a further bathochromic-shifted absorbance (maximum peak at 976 nm) as well as a high photothermal conversion efficiency (66.7%) under NIR-II laser irradiation. In vitro and in vivo experiments demonstrate that TPD NPs can effectively inhibit the growth of tumors without palpable side effects. The study provides a novel NIR-II multiple-aniline structure based on multielectron hyperconjugation, and opens a new design thought for photothermal agents.

Dual-Targeting Biomimetic Nanomaterials for Photo-/Chemo-/Antiangiogenic Synergistic Therapy.

Avoiding the low specificity of phototheranostic reagents at the tumor site is a major challenge in cancer phototherapy. Meanwhile, angiogenesis in the tumor is not only the premise of tumor occurrence but also the basis of tumor growth, invasion, and metastasis, making it an ideal strategy for tumor therapy. Herein, biomimetic cancer cell membrane-coated nanodrugs (mBPP NPs) have been prepared by integrating (i) homotypic cancer cell membranes for evading immune cell phagocytosis to increase drug accumulation, (ii) protocatechuic acid for tumor vascular targeting along with chemotherapy effect, and (iii) near-infrared phototherapeutic agent diketopyrrolopyrrole derivative for photodynamic/photothermal synergetic therapy. The mBPP NPs exhibit high biocompatibility, superb phototoxicity, excellent antiangiogenic ability, and double-trigging cancer cell apoptosis in vitro. More significantly, mBPP NPs could specifically bind to tumor cells and vasculature after intravenous injection, inducing fluorescence and photothermal imaging-guided tumor ablation without recurrence and side effects in vivo. The biomimetic mBPP NPs could cause drug accumulation at the tumor site, inhibit tumor neovascularization, and improve phototherapy efficiency, providing a novel avenue for cancer treatment.

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.

Thrombin Based Photothermal-Responsive Nanoplatform for Tumor-Specific Embolization Therapy.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

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.

Structural effect of NIR-II absorbing charge transfer complexes and its application on cysteine-depletion mediated ferroptosis and phototherapy.

Second near-infrared (NIR-II) absorbing organic photothermal agents (PTAs) usually suffer from laborious and time-consuming synthesis; therefore, it is of importance to develop a simple and easy-to-handle method for the preparation of NIR-II PTAs. Charge-transfer complexes (CTCs) can be easily used to construct NIR-II absorbing PTAs, although the relationship between their molecular structure and photophysical properties is yet to be uncovered. Herein, three kinds of electron donors with different substitutions (chloroethyl, ethyl, and methyl) were synthesized and assembled with electron-deficient F4TCNQ to afford corresponding CTC nanoparticles (Cl-F4, Et-F4, and Me-F4 NPs). The large energy gap (>0.61 eV) between HOMO of the donor and LUMO of the acceptor made the CTCs exhibit high charge transfer (>0.93) and dramatic differences in photophysical properties. Additionally, Et-F4 NPs possess the highest NIR-II absorption ability and best photothermal effect because of different packing modes (mass extinction coefficient of 11.0 L g-1 cm-1 and photothermal conversion efficiency of 40.2% at 1060 nm). The mixed stacking mode formed strong charge-transfer absorption bands, indicating that the photophysical properties of CTCs can be tailored by changing the molecular structure and aggregate behaviors. Furthermore, Et-F4 NPs with cyano groups could specifically react with cysteine to block the intracellular biosynthesis of GSH and result in ROS accumulation and ferroptosis. Et-F4 NPs possess outstanding antitumor efficacy for the combined actions of NIR-II triggered photothermal killing effect and ferroptosis in vivo.

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.

Infection microenvironment-activated nanoparticles for NIR-II photoacoustic imaging-guided photothermal/chemodynamic synergistic anti-infective therapy.

Subcutaneous abscesses caused by drug-resistant bacteria pose huge challenges to human health. The design of infection microenvironment-activated biomaterials has an advantage for the diagnosis and treatment of infective diseases due to its high specificity and efficiency. Herein, a novel theranostic platform based on Cu2O nanoparticles (NPs) is successfully constructed via a simple, fast and low-cost approach. The Cu2O NPs exhibit high sensitivity to overexpressed H2S and H2O2 in the bacterial infection microenvironment. After in situ injection, the Cu2O NPs will rapidly react with the endogenous H2S to generate Cu9S8 NPs, which exhibits high absorbance in the second near-infrared (NIR-II) biowindow. The Cu9S8 NPs serving as NIR-II photoacoustic contrast agents can exactly distinguish between inflammatory and normal tissues. With the guidance of NIR-II photoacoustic imaging (PAI), H2S-activated photothermal antibacterial therapy (PTAT) can realize excellent antibacterial performance under 1060 nm laser irradiation. Meanwhile, the Cu2O NPs can effectively catalyze H2O2 at the site of inflammation to produce hydroxyl radicals with strong antibacterial property via Fenton-like reaction, resulting in the damage of bacterial cell membrane. Furthermore, the application of Cu2O NPs can enhance epidermic migration and facilitate the re-epithelialization of the infected skin. In vivo experiment shows that 97.9% methicillin-resistant Staphylococcus aureus are eliminated by the synergistic PTAT and chemodynamic antibacterial therapy.

Monotherapy and Combination Therapy Using Anti-Angiogenic Nanoagents to Fight Cancer.

Anti-angiogenic therapy, targeting vascular endothelial cells (ECs) to prevent tumor growth, has been attracting increasing attention in recent years, beginning with bevacizumab (Avastin) through its Phase II/III clinical trials on solid tumors. However, these trials showed only modest clinical efficiency; moreover, anti-angiogenic therapy may induce acquired resistance to the drugs employed. Combining advanced drug delivery techniques (e.g., nanotechnology) or other therapeutic strategies (e.g., chemotherapy, radiotherapy, phototherapy, and immunotherapy) with anti-angiogenic therapy results in significantly synergistic effects and has opened a new horizon in fighting cancer. Herein, clinical difficulties in using traditional anti-angiogenic therapy are discussed. Then, several promising applications of anti-angiogenic nanoagents in monotherapies and combination therapies are highlighted. Finally, the challenges and perspectives of anti-angiogenic cancer therapy are summarized. A useful introduction to anti-angiogenic strategies, which may significantly improve therapeutic outcomes, is thus provided.

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.

An acidity-responsive polyoxometalate with inflammatory retention for NIR-II photothermal-enhanced chemodynamic antibacterial therapy.

Subcutaneous abscesses caused by drug-resistant pathogens pose a serious challenge to human health. To overcome this problem, herein an acidity-responsive aggregated W/Mo-based polyoxometalate (POM) was developed for photothermal-enhanced chemodynamic antibacterial therapy in the second near-infrared (NIR) region. The POM can self-assemble into larger-sized aggregates with stronger absorption in the NIR region, making it remain in the acidic infected tissue. Furthermore, the hydrogen peroxide at the site of infection can be converted to a hydroxyl radical for chemodynamic therapy (CDT) and simultaneously the glutathione in organisms is consumed by the POM to further enhance the CDT effect. More importantly, under laser irradiation, the hyperthermia produced by the POM not only can kill drug-resistant Staphylococcus aureus, but also enhance the performance of CDT. Benefitting from the inflammatory retention and acidity-responsive photothermal-enhanced CDT properties, the POM exhibits an obvious therapeutic effect against drug-resistant bacterial infection without significant side effects under 1060 nm laser irradiation.

On-demand drug release nanoplatform based on fluorinated aza-BODIPY for imaging-guided chemo-phototherapy.

Intelligent drug delivery systems (DDS), integrating with multi-modal imaging guidance and controlled drug release, have practical significance in enhancing the therapeutic efficiency of tumors. Herein, fluorinated aza-boron-dipyrromethene (NBF) with high near-infrared absorption is synthesized by introducing nonadecafluorodecanoic acid into aza-BODIPY via the amide bond. Through the co-precipitation methods, nanoparticles (NPs) based on NBF are fabricated and the obtained NBF NPs can not only load with DOX with a high loading efficiency (25%, DNBF NPs), but also absorb PFC droplets (1H-perfluoropentane) with bp of 42 °C because of the fluorinated chains inside NBF NPs (PDNBF NPs). Under 808-nm laser irradiation, the hyperthermia effect of NBF could induce the liquid-gas phase transition of PFC droplets, triggering the burst release of DOX and enhancing echo signals for ultrasound imaging as well. With efficient enrichment of PDNBF NPs at tumor site as revealed by in vivo ultrasound imaging and photoacoustic imaging, significant improvement in inhibiting tumor growth is achieved with PDNBF NPs under laser irradiation without noticeable side effects. The work presents a multifunctional organic DDS with great biocompatibility, high drug loading efficiency and light-stimuli-responsive drug release, which provides a new strategy for the manufacture of intelligent composite theranostic nanoplatform.

Mitoxantrone as photothermal agents for ultrasound/fluorescence imaging-guided chemo-phototherapy enhanced by intratumoral H2O2-Induced CO.

Multimodal imaging integrated theranostic nanomaterials provides broad prospects for noninvasive and precise cancer treatment. However, the uncertain physiological metabolism of the existing phototherapy nanoagents greatly prevents its clinical application. Herein, a smart nanoplatform based on clinically chemotherapeutic drugs mitoxantrone (MTO) was prepared to realize ultrasound/fluorescence imaging-guided chemo-photothermal combined therapy. The nanoplatform encapsulating MTO and manganese carbonyl (MnCO), which denoted as MCMA NPs, could accumulate at tumor sites by enhanced permeability and retention (EPR) effect and effectively induce cell apoptosis. MTO with near-infrared absorption (~676 nm) not only acted as chemotherapy drug, but also served as photothermal reagent with high photothermal conversion efficiency (ƞ = 42.2%). Especially, H2O2 in tumor sites and the photothermal effect of MTO could trigger MnCO to generate CO, which made cancer cells more sensitive to MTO and significantly alleviated cell resistance. Simultaneously, CO released in tumor also could act as contrast agent for tumor ultrasound imaging to provide accurate guidance for anticancer treatment. Moreover, MCMA NPs could further promote oxidative stress damage in mitochondria and protect normal cells from side effects of chemotherapy. Both in vivo and in vitro studies indicated that MCMA NPs possessed excellent synergetic tumor inhibition ability with high efficiency and low chemotherapy resistance.

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.

Fe-Doped Polyoxometalate as Acid-Aggregated Nanoplatform for NIR-II Photothermal-Enhanced Chemodynamic Therapy.

The combination of reactive oxygen species-involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe-doped polyoxometalate (Fe-POM) cluster is fabricated via a simple method. The Fe-POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near-infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less-reactive H2 O2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self-assembling properties at lowered pH values, the Fe-POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe-POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT-enhanced CDT in a NIR-II biowindow.

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment.

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the 1 O2 generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release 1 O2 in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.