Metabolizable Semiconducting Polymer Nanoparticles for Second Near‐Infrared Photoacoustic Imaging

Photoacoustic (PA) imaging in the second near‐infrared (NIR‐II) window (1000–1700 nm) holds great promise for deep‐tissue diagnosis due to the reduced light scattering and minimized tissue absorption; however, exploration of such a noninvasive imaging technique is greatly constrained by the lack of biodegradable NIR‐II absorbing agents. Herein, the first series of metabolizable NIR‐II PA agents are reported based on semiconducting polymer nanoparticles (SPNs). Such completely organic nanoagents consist of π‐conjugated yet oxidizable optical polymer as PA generator and hydrolyzable amphiphilic polymer as particle matrix to provide water solubility. The obtained SPNs are readily degraded by myeloperoxidase and lipase abundant in phagocytes, transforming from nonfluorescent nanoparticles (30 nm) into NIR fluorescent ultrasmall metabolites (≈1 nm). As such, these nanoagents can be effectively cleared out via both hepatobiliary and renal excretions after systematic administration, leaving no toxicity to living mice. Particularly these nanoagents possess high photothermal conversion efficiencies and emit bright PA signals at 1064 nm, enabling sensitive NIR‐II PA imaging of both subcutaneous tumor and deep brain vasculature through intact skull in living animals at a low systematic dosage. This study thus provides a generalized molecular design toward organic metabolizable semiconducting materials for biophotonic applications in NIR‐II window.     

Dual‐Peak Absorbing Semiconducting Copolymer Nanoparticles for First and Second Near‐Infrared Window Photothermal Therapy: A Comparative Study

Near‐infrared (NIR) light is widely used for noninvasive optical diagnosis and phototherapy. However, current research focuses on the first NIR window (NIR‐I, 650–950 nm), while the second NIR window (NIR‐II, 1000–1700 nm) is far less exploited. The development of the first organic photothermal nanoagent (SPN_I‐II) with dual‐peak absorption in both NIR windows and its utilization in photothermal therapy (PTT) are reported herein. Such a nanoagent comprises a semiconducting copolymer with two distinct segments that respectively and identically absorb NIR light at 808 and 1064 nm. With the photothermal conversion efficiency of 43.4% at 1064 nm generally higher than other inorganic nanomaterials, SPN_I‐II enables superior deep‐tissue heating at 1064 nm over that at 808 nm at their respective safety limits. Model deep‐tissue cancer PTT at a tissue depth of 5 mm validates the enhanced antitumor effect of SPN_I‐II when shifting laser irradiation from the NIR‐I to the NIR‐II window. The good biodistribution and facile synthesis of SPN_I‐II also allow it to be doped with an NIR dye for fluorescence‐imaging‐guided NIR‐II PTT through systemic administration. Thus, this study paves the way for the development of new polymeric nanomaterials to advance phototherapy.     

Semiconducting Polymer Nanoparticles for Centimeters‐Deep Photoacoustic Imaging in the Second Near‐Infrared Window

Thienoisoindigo‐based semiconducting polymer with a strong near‐infrared absorbance is synthesized and its water‐dispersed nanoparticles (TSPNs) are investigated as a contrast agent for photoacoustic (PA) imaging in the second near‐infrared (NIR‐II) window (1000–1350 nm). The TSPNs generate a strong PA signal in the NIR‐II optical window, where background signals from endogenous contrast agents, including blood and lipid, are at the local minima. By embedding a TSPN‐containing tube in chicken‐breast tissue, an imaging depth of more than 5 cm at 1064 nm excitation is achieved with a contrast‐agent concentration as low as 40 µg mL^?1. The TSPNs under the skin or in the tumor are clearly visualized at 1100 and 1300 nm, with negligible interference from the tissue background. TSPN as a PA contrast in the NIR‐II window opens new opportunities for biomedical imaging of deep tissues with improved contrast.     

Ultrasmall Cu2‐xS Nanodots for Highly Efficient Photoacoustic Imaging‐Guided Photothermal Therapy

Monodisperse, ultrasmall (<5 nm) Cu_2?xS nanodots (u‐Cu_2?xS NDs) with significantly strong near‐infrared absorption and conversion are successfully demonstrated for effective deep‐tissue photoacoustic imaging‐guided photothermal therapy both in vitro and in vivo. Owing to ultrasmall nanoparticle size and high water dispersibility as well as long stability, such nanodots possess a prolonged circulation in blood and good passive accumulation within tumors through the enhanced permeability and retention effect. These u‐Cu_2?xS NDs have negligible side effects to both blood and normal tissues according to in vivo toxicity evaluations for up to 3 months, showing excellent hemo/histocompatibility. Furthermore, these u‐Cu_2?xS NDs can be thoroughly cleared through feces and urine within 5 days, showing high biosafety for further potential clinical translation. This novel photoacoustic imaging‐guided photothermal therapy based on u‐Cu_2?xS NDs composed of a single component shows great prospects as a multifunctional nanoplatform with integration and multifunction for cancer diagnosis and therapy.     

Single‐Photomolecular Nanotheranostics for Synergetic Near‐Infrared Fluorescence and Photoacoustic Imaging‐Guided Highly Effective Photothermal Ablation

Multi‐modality imaging‐guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single‐photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT‐S) into an amphiphilic lipid, water‐dispersible IT‐S nanoparticles (IT‐S NPs) are prepared. The obtained IT‐S NPs have a very simple construction and possess ultra‐stable near‐infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual‐modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT‐S NPs are successfully visualized by NIR FL/PA dual‐modal imaging. With the comprehensive in vivo imaging information provided by IT‐S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT‐S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.     

Second Near-Infrared Plasmonic Nanomaterials for Photoacoustic Imaging and Photothermal Therapy

Photoacoustic imaging (PAI) and imaging-guided photothermal therapy (PTT) in the second near-infrared window (NIR-II, 1000–1700 nm) have received increasing attention owing to their advantages of greater penetration depth and higher signal-to-noise ratio. Plasmonic nanomaterials with tunable optical properties and strong light absorption provide an alternative to dye molecules, showing great prospects for phototheranostic applications. In this review, the research progress in principally modulating the optical properties of plasmonic nanomaterials, especially affecting parameters such as size, morphology, and surface chemical modification, is introduced. The commonly used plasmonic nanomaterials in the NIR-II window, including noble metals, semiconductors, and heterostructures, are then summarized. In addition, the biomedical applications of these NIR-II plasmonic nanomaterials for PAI and PTT in phototheranostics are highlighted. Finally, the perspectives and challenges for advancing plasmonic nanomaterials for practical use and clinical translation are discussed.     

Flexible Photothermal Assemblies with Tunable Gold Patterns for Improved Imaging‐Guided Synergistic Therapy

Self‐assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic‐co‐glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion‐confined and polymer‐directed self‐assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid‐modified R‐PLGA‐Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real‐time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT‐enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging‐guided synergistic therapy.     

Tumor pH‐Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy

Tumor‐microenvironment‐responsive theranostics have great potential for precision diagnosis and effective treatment of cancer. Polyaniline (PANI) is the first reported pH‐responsive organic photothermal agent and is widely used as a theranostic agent. However, tumor pH‐responsive PANI‐based theranostic agents are not explored, mainly because the conversion from the emeraldine base (EB) to emeraldine salt (ES) state of PANI requires pH < 4, which is lower than tumor acidic microenvironment. Herein, a tumor pH‐responsive PANI‐based theranostic agent is designed and prepared for amplified photoacoustic imaging guided augmented photothermal therapy (PTT), through intermolecular acid–base reactions between carboxyl groups of bovine serum albumin (BSA) and imine moieties of PANI. The albumin/PANI assemblies (BSA–PANI) can convert from the EB to ES state at pH < 7, accompanied by the absorbance redshift from visible to near‐infrared region. Both in vitro and in vivo results demonstrate that tumor acidic microenvironment can trigger both the photoacoustic imaging (PAI) signal amplification and the PTT efficacy enhancement of BSA–PANI assemblies. This work not only highlights that BSA–PANI assemblies overcome the limitation of low‐pH protonation, but also provides a facile assembly strategy for a tumor pH‐responsive PANI‐based nanoplatform for cancer theranostics.     

Molecular Cancer Imaging in the Second Near‐Infrared Window Using a Renal‐Excreted NIR‐II Fluorophore‐Peptide Probe

In vivo molecular imaging of tumors targeting a specific cancer cell marker is a promising strategy for cancer diagnosis and imaging guided surgery and therapy. While targeted imaging often relies on antibody‐modified probes, peptides can afford targeting probes with small sizes, high penetrating ability, and rapid excretion. Recently, in vivo fluorescence imaging in the second near‐infrared window (NIR‐II, 1000–1700 nm) shows promise in reaching sub‐centimeter depth with microscale resolution. Here, a novel peptide (named CP) conjugated NIR‐II fluorescent probe is reported for molecular tumor imaging targeting a tumor stem cell biomarker CD133. The click chemistry derived peptide‐dye (CP‐IRT dye) probe afforded efficient in vivo tumor targeting in mice with a high tumor‐to‐normal tissue signal ratio (T/NT > 8). Importantly, the CP‐IRT probes are rapidly renal excreted (≈87% excretion within 6 h), in stark contrast to accumulation in the liver for typical antibody‐dye probes. Further, with NIR‐II emitting CP‐IRT probes, urethra of mice can be imaged fluorescently for the first time noninvasively through intact tissue. The NIR‐II fluorescent, CD133 targeting imaging probes are potentially useful for human use in the clinic for cancer diagnosis and therapy.     

A New Co‐P Nanocomposite with Ultrahigh Relaxivity for In Vivo Magnetic Resonance Imaging‐Guided Tumor Eradication by Chemo/Photothermal Synergistic Therapy

Design of new nanoagents that intrinsically have both diagnostic imaging and therapeutic capabilities is highly desirable for personalized medicine. In this work, a novel nanotheranostic agent is fabricated based on polydopamine (PDA)‐functionalized Co‐P nanocomposites (Co‐P@PDA) for magnetic resonance imaging (MRI)‐guided combined photothermal therapy and chemotherapy. The ultrahigh relaxivity of 224.61 mm ^?1 s^?1 can enable Co‐P@PDA to be applied as an excellent contrast agent for MRI in vitro and in vivo, providing essential and comprehensive information for tumor clinical diagnosis. Moreover, Co‐P@PDA exhibit excellent photothermal performance owing to the strong near‐infrared (NIR) absorbance of both Co‐P nanocomposite and PDA. Highly effective ablation of tumors is achieved in a murine tumor model because the NIR laser not only induces photothermal effects but also triggers the chemotherapeutic drug on‐demand release, which endows the Co‐P@PDA with high curative effects but little toxicity and few side effects. These findings demonstrate that Co‐P@PDA are promising agents for highly effective and precise antitumor treatment and warrant exploration as novel theranostic nanoagents with good potential for future clinical translation.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

Water‐Dispersible Candle Soot–Derived Carbon Nano‐Onion Clusters for Imaging‐Guided Photothermal Cancer Therapy

Herein, water‐dispersible carbon nano‐onion clusters (CNOCs) with an average hydrodynamic size of ≈90 nm are prepared by simply sonicating candle soot in a mixture of oxidizing acid. The obtained CNOCs have high photothermal conversion efficiency (57.5%), excellent aqueous dispersibility (stable in water for more than a year without precipitation), and benign biocompatibility. After polyethylenimine (PEI) and poly(ethylene glycol) (PEG) modification, the resultant CNOCs‐PEI‐PEG have a high photothermal conversion efficiency (56.5%), and can realize after‐wash photothermal cancer cell ablation due to their ultrahigh cellular uptake (21.3 pg/cell), which is highly beneficial for the selective ablation of cancer cells via light‐triggered intracellular heat generation. More interestingly, the cellular uptake of CNOCs‐PEI‐PEG is so high that the internalized nanoagents can be directly observed under a microscope without fluorescent labeling. Besides, in vivo experiments reveal that CNOCs‐PEI‐PEG can be used for photothermal/photoacoustic dual‐modal imaging‐guided photothermal therapy after intravenous administration. Furthermore, CNOCs‐PEI‐PEG can be efficiently cleared from the mouse body within a week, ensuring their excellent long‐term biosafety. To the best of the authors' knowledge, the first example of using candle soot as raw material to prepare water‐dispersible onion‐like carbon nanomaterials for cancer theranostics is represented herein.     

Biodegradable Bi2O2Se Quantum Dots for Photoacoustic Imaging‐Guided Cancer Photothermal Therapy

As new 2D layered nanomaterials, Bi₂O₂Se nanoplates have unique semiconducting properties that can benefit biomedical applications. Herein, a facile top‐down approach for the synthesis of Bi₂O₂Se quantum dots (QDs) in a solution is described. The Bi₂O₂Se QDs with a size of 3.8 nm and thickness of 1.9 nm exhibit a high photothermal conversion coefficient of 35.7% and good photothermal stability. In vitro and in vivo assessments demonstrate that the Bi₂O₂Se QDs possess excellent photoacoustic (PA) performance and photothermal therapy (PTT) efficiency. After systemic administration, the Bi₂O₂Se QDs accumulate passively in tumors enabling efficient PA imaging of the entire tumors to facilitate imaging‐guided PTT without obvious toxicity. Furthermore, the Bi₂O₂Se QDs which exhibit degradability in aqueous media not only have sufficient stability during in vivo circulation to perform the designed therapeutic functions, but also can be discharged harmlessly from the body afterward. The results reveal the great potential of Bi₂O₂Se QDs as a biodegradable multifunctional agent in medical applications.     

The Nanoassembly of an Intrinsically Cytotoxic Near‐Infrared Dye for Multifunctionally Synergistic Theranostics

The combination of diagnostic and therapeutic functions in a single theranostic nanoagent generally requires the integration of multi‐ingredients. Herein, a cytotoxic near‐infrared (NIR) dye (IR‐797) and its nanoassembly are reported for multifunctional cancer theranostics. The hydrophobic IR‐797 molecules are self‐assembled into nanoparticles, which are further modified with an amphiphilic polymer (C18PMH‐PEG5000) on the surface. The prepared PEG‐IR‐797 nanoparticles (PEG‐IR‐797 NPs) possess inherent cytotoxicity from the IR‐797 dye and work as a chemotherapeutic drug which induces apoptosis of cancer cells. The IR‐797 NPs are found to have an ultrahigh mass extinction coefficient (444.3 L g^?1 cm^?1 at 797 nm and 385.9 L g^?1 cm^?1 at 808 nm) beyond all reported organic nanomaterials (<40 L g^?1 cm^?1) for superior photothermal therapy (PTT). In addition, IR‐797 shows some aggregation‐induced‐emission (AIE) properties. Combining the merits of good NIR absorption, high photothermal energy conversion efficiency, and AIE, makes the PEG‐IR‐797 NPs useful for multimodal NIR AIE fluorescence, photoacoustic, and thermal imaging‐guided therapy. The research exhibits the possibility of using a single ingredient and entity to perform multimodal NIR fluorescence, photoacoustic, and thermal imaging‐guided chemo‐/photothermal combination therapy, which may trigger wide interest from the fields of nanomedicine and medicinal chemistry to explore multifunctional theranostic organic molecules.     

Biosynthesis of Melanin Nanoparticles for Photoacoustic Imaging Guided Photothermal Therapy

Photothermal therapy (PTT) has attracted considerable attention in recent years due to their unique advantages in minimal invasiveness and spatiotemporal selectivity. However, the fabrication procedures of PTT agents frequently require complex chemical and/or physical methods that involves harsh and environmentally hazardous conditions. Here, a genetically engineered bacterium is developed to synthesize melanin nanoparticles under mild and environmentally friendly conditions. The biosynthetic melanin nanoparticles exhibit excellent biocompatibility, good stability, and negligible toxicity. In addition, the biosynthetic melanin nanoparticles have strong absorption at near-infrared (NIR) region and higher photothermal conversion efficiency (48.9%) than chemically synthesized melanin-like polydopamine nanoparticles under an 808 nm laser irradiation. Moreover, the results show that the biosynthetic melanin nanoparticles have excellent photoacoustic imaging (PAI) performance and can be used for PAI guided PTT in vivo. In conclusion, the study provides an alternative approach to synthesize PTT agents with broad application potential in the diagnosis and treatment of cancer.     

Integration of Indocyanine Green Analogs as Near‐Infrared Fluorescent Carrier for Precise Imaging‐Guided Gene Delivery

Codelivery of diagnostic probes and therapeutic molecules often suffers from intrinsic complexity and premature leakage from or degradation of the nanocarrier. Inspired by the “Y” shape of indocyanine green (ICG), the dye is integrated in an amphiphilic lipopeptide (RNF). The hydrophilic segment is composed of arginine‐rich dendritic peptides, while cyanine dyes are modified with two long carbon chains and employed as the hydrophobic moiety. They are linked through a disulfide linkage to improve the responsivity in the tumor microenvironment. After formulation with other lipopeptides at an optimized ratio, the theranostic system (RNS‐2) forms lipid‐based nanoparticles with slight positive zeta potential enabling efficient condensation of DNA. The RNS‐2 displays glutathione responded gene release, activatable fluorescence recovery, and up to sevenfold higher in vitro transfection than Lipofectamine 2000. Compared with a Cy3 and Cy5 labeled fluorescence resonance energy transfer indicator for gene release, the “turn‐on” indocyanine green analogs exhibit longer emission wavelength and better positive correlation with the dynamic processes of gene delivery. More importantly, the RNS‐2 system enables efficient near infrared imaging guided gene transfer in tumor‐bearing mice and thus provides more precise and accurate information on location of the cargo gene and synthesized carriers.