Second near-infrared photothermal therapy (NIR-II PTT, 1000-1500 nm) has recently emerged as a new phototherapeutic modality with the advantages of deeper penetration, less energy dissipation and ...minimal normal-tissue toxicity over traditional first NIR PTT (750-1000 nm). However, suboptimal photothermal conversion and limited therapeutic efficacy remain the major challenges for NIR-II PTT. With the convergence in materials science, nanomedicine and biology, multifunctional NIR-II photothermal inorganic or organic materials have been extensively developed to combine NIR-II PTT with other therapeutic modalities for improved efficacies in treating life-threatening diseases including cancer and infection. This review summarizes the recent advances of NIR-II photothermal combinational theranostics pertinent to chemotherapy, immunotherapy, radiotherapy, and photodynamic, sonodynamic, chemodynamic, gene, gas, ionic, vascular and magnetothermal therapy. Potential obstacles and perspectives for future research and clinical translation of this new theranostic modality are also discussed.
This review summarizes the recent development of second near-infrared photothermal combinational nanotheranostics for cancer, infectious diseases and regenerative medicine.
Biophotonics as a highly interdisciplinary frontier often requires the assistance of optical agents to control the light pathways in cells, tissues and living organisms for specific biomedical ...applications. Organic semiconducting materials (OSMs) composed of π-conjugated building blocks as the optically active components have recently emerged as a promising category of biophotonic agents. OSMs possess common features including excellent optical properties, good photostability and biologically benign composition. This review summarizes the recent progress in the development of OSMs based on small-molecule fluorophores, aggregation-induced emission (AIE) dyes and semiconducting oligomer/polymer nanoparticles (SONs/SPNs) for advanced biophotonic applications. OSMs have been exploited as imaging agents to transduce biomolecular interactions into second near-infrared fluorescence, chemiluminescence, afterglow or photoacoustic signals, enabling deep-tissue ultrasensitive imaging of biological tissues, disease biomarkers and physiological indexes. By fine-tuning the molecular structures, OSMs can also convert light energy into cytotoxic free radicals or heat, allowing for effective cancer phototherapy. Due to their instant light response and efficient light-harvesting properties, precise regulation of biological activities using OSMs as remote transducers has been demonstrated for protein ion channels, gene transcription and protein activation. In addition to highlighting OSMs as a multifunctional platform for a wide range of biomedical applications, current challenges and perspectives of OSMs in biophotonics are discussed.
Recent progress in developing organic semiconducting materials (OSMs) for deep-tissue optical imaging, cancer phototherapy and biological photoactivation is summarized.
Optical imaging plays a crucial role in biomedicine. However, due to strong light scattering and autofluorescence in biological tissue between 650–900 nm, conventional optical imaging often has a ...poor signal‐to‐background ratio and shallow penetration depth, which limits its ability in deep‐tissue in vivo imaging. Second near‐infrared fluorescence, chemiluminescence, and photoacoustic imaging modalities mitigate these issues by their respective advantages of minimized light scattering, eliminated external excitation, and ultrasound detection. To enable disease detection, activatable molecular probes (AMPs) with the ability to change their second near‐infrared fluorescence, chemiluminescence, or photoacoustic signals in response to a biomarker have been developed. This Minireview summarizes the molecular design strategies, sensing mechanisms, and imaging applications of AMPs. The potential challenges and perspectives of AMPs in deep‐tissue imaging are also discussed.
Activatable probes: Second near‐infrared fluorescence, chemiluminescence, and photoacoustic imaging, with their respective advantages of minimized light scattering, eliminated external excitation, and ultrasound detection, have attracted increasing attention for deep‐tissue in vivo imaging. This Minireview discusses the molecular design strategies and sensing mechanisms for activatable molecular probes, along with their deep‐tissue optical imaging applications.
Conspectus Cancer therapy is routinely performed in the clinic to cure cancer and control its progression, wherein therapeutic agents are generally used. To reduce side effects, protherapeutic agents ...that can be activated by overexpressed cancer biomarkers are under development. However, these agents still face certain extent of off-target activation in normal tissues, stimulating the interest to design external-stimuli activatable protherapeutics. In this regard, photoactivatable protherapeutic agents have been utilized for cancer treatments. However, because of the intrinsic features of photolabile moieties, most photoactivatable protherapeutic agents only respond to ultraviolet–visible light, limiting their in vivo applications. Thus, protherapeutic agents that can be activated by near-infrared (NIR) light with minimal phototoxicity and increased tissue penetration are highly desired. In this Account, we summarize our semiconducting polymer nanomaterials (SPNs) as NIR photoactivatable protherapeutic agents for cancer treatment. SPNs are transformed from π-conjugated polymers that efficiently convert NIR light into heat or singlet oxygen (1O2). With photothermal and photodynamic properties, SPNs can be directly used as photomedicine or serve as light transducers to activate heat or 1O2-responsive protherapeutic agents. The heat-activatable SPN-based protherapeutic agents are developed by loading or conjugating of SPNs with therapeutic agents (e.g., agonist, gene, and enzyme). For instance, photothermally triggered release of agonists specifically activates certain protein ion channels on the cellular membrane, leading to ion overinflux induced mitochondria dysfunction and consequently apoptosis of cancer cells. Moreover, photothermal activation of temperature-sensitive bromelain can promote the in situ degradation of collagens (the major components of extracellular matrix), resulting in an improved accumulation of agents in tumor tissues and thus amplified therapeutic outcome. The 1O2-activatable SPN-based protherapeutic agents are constructed through covalent conjugation of SPNs with caged therapeutic agents via hypoxia- or 1O2-cleavable linkers. Upon NIR photoirradiation, SPNs consume oxygen to generate 1O2, which leads to photodynamic therapy (PDT), and meanwhile breaks hypoxia- or 1O2-cleavable linkers for on-demand release and in situ activation of caged protherapeutic molecules (e.g., chemodrug, enzyme, and inhibitor). Such remote activation of SPN-based protherapeutic agents can be applied to induce DNA damage, ribonucleic acid degradation, inhibition of protein biosynthesis, or immune system activation in tumors of living animals. By synergizing PDT with NIR photoactivation of those biological actions, these protherapeutic agents effectively eliminate tumors and even fully inhibit tumor metastasis. This Account highlights the potential of SPNs for construction of versatile NIR photoactivatable protherapeutics to treat cancer at designated times and locations with high therapeutic outcome and precision.
Optical imaging has played a pivotal role in biology and medicine, but it faces challenges of relatively low tissue penetration and poor signal‐to‐background ratio due to light scattering and tissue ...autofluorescence. To overcome these issues, second near‐infrared fluorescence, self‐luminescence, and photoacoustic imaging have recently emerged, which utilize an optical region with reduced light–tissue interactions, eliminate real‐time light excitation, and detect acoustic signals with negligible attenuation, respectively. Because there are only a few endogenous molecules absorbing or emitting above the visible region, development of contrast agents is essential for those deep‐tissue optical imaging modalities. Organic semiconducting agents with π‐conjugated frameworks can be synthesized to meet different optical imaging requirements due to their easy chemical modification and legible structure–property relation. Herein, the deep‐tissue optical imaging applications of organic semiconducting agents including small‐molecule agents and nanoparticle derivatives are summarized. In particular, the molecular engineering and nanoformulation approaches to further improve the tissue penetration and detection sensitivity of these optical imaging modalities are highlighted. Finally, current challenges and potential opportunities in this emerging subfield of biomedical imaging are discussed.
Molecular optical imaging, including second near‐infrared fluorescence, self‐luminescence, and photoacoustic imaging, provides enhanced tissue penetration depth and detection sensitivity as compared with traditional optical imaging. The recent development of organic semiconducting agents for these deep‐tissue optical imaging modalities are summarized and the molecular design guidelines to amplify the signal intensity, improve the sensing specificity, and enhance the tissue penetration are highlighted.
Conspectus Biophotonics as an interdisciplinary frontier plays an increasingly important role in modern biomedical science. Optical agents are generally involved in biophotonics to interpret ...biomolecular events into readable optical signals for imaging and diagnosis or to convert photons into other forms of energy (such as heat, mechanical force, or chemical radicals) for therapeutic intervention and biological stimulation. Development of new optical agents including metallic nanoparticles, quantum dots, up-conversion nanoparticles, carbon dots, and silica nanoparticles has contributed to the advancement of this field. However, most of these agents have their own merits and demerits, making them less effective as multimodal biophotonic platforms. In this Account, we summarize our recent work on the development of near-infrared (NIR) semiconducting polymer nanoparticles (SPNs) as multimodal light converters for advanced biophotonics. SPNs are composed of π-electron delocalized semiconducting polymers (SPs) and often possess the advantages of good biocompatibility, high photostability, and large absorption coefficients. Because the photophysical properties of SPNs are mainly determined by the molecular structures of the precursor polymers, molecular engineering allows us to fine tune their photophysical processes to obtain different optical responses, even to light in the second NIR window (1000–1700 nm). Meanwhile, the facile nanoformulation methods of SPNs enable alteration of their outer and inner structures for diverse biological interactions. The unique photophysical properties of SPNs have brought about ultrasensitive deep-tissue molecular imaging. NIR-absorbing SPNs with strong charge-transfer backbones can convert photoenergy into mechanical acoustic waves, permitting photoacoustic imaging that bypasses the issue of light scattering and reaches the centimeter tissue penetration depth. Differently, phenylenevinylene-containing SPNs can store photon energy via chemical defects and emit long-NIR afterglow luminescence with a half-life of ∼6 min after cessation of light excitation. Such an afterglow process avoids tissue autofluorescence, giving rise to ultrahigh signal-to-background ratios. So far, SPN-based molecular photoacoustic or afterglow probes have been developed to image disease tissues (tumors), biomarkers (biothiols and reactive oxygen species), and physiological indexes (pH and temperature) in different preclinical animal models. The synthetic flexibility of SPNs further permits light-modulated biological and therapeutic interventions. Till now, SPNs with high photothermal conversion efficiencies have been shaped into photothermal transducers to remotely regulate biological events including protein ion channels, enzymatic activity, and gene expression. In conjunction with the desired biodistribution and tumor-homing ability, SPNs have been doped or coated with other inorganic agents for amplified photothermal or self-regulated photodynamic cancer therapy. This Account thus demonstrates that SPNs serve as a multimodal biophotonic nanoplatform to provide unprecedented opportunities for molecular imaging, noninvasive bioactivation, and advanced therapy.
Cancer immunotherapy is an emerging treatment strategy that modulates the immune system to fight against cancer. Although several immunotherapeutic agents have been utilized in the clinic for cancer ...treatment, low patient response rates and potential immune-related adverse events remain two major challenges. With the merits of delivery controllability and modular flexibility, nanomedicines provide opportunities to facilitate immunotherapies for clinical translation in a safe and effective manner. In this review, we discuss the convergence of nanomedicine with immunotherapy with a focus on molecular and nanoengineering approaches towards activatable cancer immunotherapy. These activatable nanoagents exert immunotherapeutic action only in response to internal or external stimuli. This allows them to locally reprogram the tumor microenvironment and activate antitumor immunity while reducing the incidence of immune-related adverse events. The category of activatable immunotherapeutic nanoagents are discussed along with an overview of their clinical translation prospects and challenges.
This review summarizes the development of activatable immunotherapeutic nanoagents that activate antitumor immunity only in response to internal or external stimuli, which potentially enhance patient response rates while reducing immune-related adverse events during cancer immunotherapy.
Nanomedicine in combination with immunotherapy offers opportunities to treat cancer in a safe and effective manner; however, remote control of immune response with spatiotemporal precision remains ...challenging. We herein report a photothermally activatable polymeric pro-nanoagonist (APNA) that is specifically regulated by deep-tissue-penetrating second near-infrared (NIR-II) light for combinational photothermal immunotherapy. APNA is constructed from covalent conjugation of an immunostimulant onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, which not only triggers tumor ablation and immunogenic cell death but also initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Such controlled immune regulation potentiates systemic antitumor immunity, leading to promoted cytotoxic T lymphocytes and helper T cell infiltration in distal tumor, lung and liver to inhibit cancer metastasis. Thereby, the present work illustrates a generic strategy to prepare pro-immunostimulants for spatiotemporal regulation of cancer nano-immunotherapy.
Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular ...renal probes (MRPs) with high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activate their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including the superoxide anion, N-acetyl-β-D-glucosaminidase and caspase-3, enabling an example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to non-invasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI.
Progress of nanotechnology in recent years has stimulated fast development of nanoparticles in biomedical research. Photoacoustic (PA) imaging as an emerging non‐invasive technique in molecular ...imaging has improved imaging depth relative to conventional optical imaging, demonstrating great potential in clinical applications. The convergence of nanotechnology and PA imaging has enabled a broad spectrum of new opportunities in fundamental biology and translation medicine. This review focuses on the recent advances of organic nanoparticles in PA imaging applications. Near‐infrared absorbing organic nanoparticles are classified and discussed according to their different imaging applications, which include tumor imaging, gastrointestinal imaging, sentinel lymph node imaging, disease microenvironment imaging and real‐time drug imaging. The chemistry and PA properties of organic nanoparticles are discussed in details to highlight their own merits, and their challenges and perspectives in PA imaging are also discussed.
Near‐infrared absorbing organic nanoparticles have advantages such as biocompatibility, size‐independent optical properties and structural versatility. This Review highlights the recent advances of organic nanoparticles as photoacoustic imaging probes for molecular imaging applications in living animals.
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