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.     

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.     

Red‐Emitting Upconverting Nanoparticles for Photodynamic Therapy in Cancer Cells Under Near‐Infrared Excitation

Upconverting nanoparticles (UCNPs) have attracted considerable attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this work, a new and efficient NIR photosensitizing nanoplatform for PDT based on red‐emitting UCNPs is designed. The red emission band matches well with the efficient absorption bands of the widely used commercially available photosensitizers (Ps), benefiting the fluorescence resonance energy transfer (FRET) from UCNPs to the attached photosensitizers and thus efficiently activating them to generate cytotoxic singlet oxygen. Three commonly used photosensitizers, including chlorine e6 (Ce6), zinc phthalocyanine (ZnPc) and methylene blue (MB), are loaded onto the alpha‐cyclodextrin‐modified UCNPs to form Ps@UCNPs complexes that efficiently produce singlet oxygen to kill cancer cells under 980 nm near‐infrared excitation. Moreover, two different kinds of drugs are co‐loaded onto these nanoparticles: chemotherapy drug doxorubicin and PDT agent Ce6. The combinational therapy based on doxorubicin (DOX)‐induced chemotherapy and Ce6‐triggered PDT exhibits higher therapeutic efficacy relative to the individual means for cancer therapy in vitro.     

Self‐Assembled Semiconducting Polymer Nanoparticles for Ultrasensitive Near‐Infrared Afterglow Imaging of Metastatic Tumors

Detection of metastatic tumor tissues is crucial for cancer therapy; however, fluorescence agents that allow to do share the disadvantage of low signal‐to‐background ratio due to tissue autofluorescence. The development of amphiphilic poly(p‐phenylenevinylene) derivatives that can self‐assemble into the nanoagent (SPPVN) in biological solutions and emit near‐infrared afterglow luminescence after cessation of light irradiation for ultrasensitive imaging of metastatic tumors in living mice is herein reported. As compared with the counterpart nanoparticle (PPVP) prepared from the hydrophobic PPV derivate, SPPVN has smaller size, higher energy transfer efficiency, and brighter afterglow luminescence. Moreover, due to the higher PEG density of SPPVN relative to PPVP poly(ethylene glycol), SPPVN has a better accumulation in tumor. Such a high sensitivity and ideal biodistribution allow SPPVN to rapidly detect xenograft tumors with the size as small as 1 mm³ and tiny peritoneal metastatic tumors that are almost invisible to naked eye, which is not possible for PPVP. Moreover, the oxygen‐sensitive afterglow makes SPPVN potentially useful for in vivo imaging of oxygen levels. By virtue of enzymatic biodegradability and ideal in vivo clearance, these organic agents can serve as a platform for the construction of advanced afterglow imaging tools.     

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.     

Near‐Infrared Fluorescent Ag2Se–Cetuximab Nanoprobes for Targeted Imaging and Therapy of Cancer

Theranostic nanoprobes integrated with diagnostic imaging and therapy capabilities have shown great potential for highly effective tumor therapy by realizing imaging‐guided drug delivery and tumor treatment. Developing novel high‐performance nanoprobes is an important basis for tumor theranostic application. Here, near‐infrared (NIR) fluorescent and low‐biotoxicity Ag₂Se quantum dots (QDs) have been coupled with cetuximab, a clinical antiepidermal growth factor receptor antibody drug for tumor therapy, via a facile bioconjugation strategy to prepare multifunctional Ag₂Se–cetuximab nanoprobes. Compared with the Ag₂Se QDs alone, the Ag₂Se–cetuximab nanoprobes display faster and more enrichment at the site of orthotopic tongue cancer, and thus present better NIR fluorescence contrast between the tumor and the surrounding regions. At 24 h postinjection, the NIR fluorescence of Ag₂Se–cetuximab nanoprobes at the tumor site is still easily detectable, whereas no fluorescence is observed for the Ag₂Se QDs. Moreover, the Ag₂Se–cetuximab nanoprobes have also significantly inhibited the tumor growth and improved the survival rate of orthotopic tongue cancer‐bearing nude mice from 0% to 57.1%. Taken together, the constructed multifunctional Ag₂Se–cetuximab nanoprobes have achieved combined targeted imaging and therapy of orthotopic tongue cancer, which may greatly contribute to the development of nanotheranostics.     

Upconversion Nanocarriers Encapsulated with Photoactivatable Ru Complexes for Near‐Infrared Light‐Regulated Enzyme Activity

Enzyme activity is important for metabolism, cell functions, and treating diseases. However, remote control of enzyme activity in deep tissue remains a challenge. This study demonstrates near‐infrared (NIR) light‐regulated enzyme activity in living cells based on upconverting nanoparticles (UCNPs) and a photoactivatable Ru complex. The Ru complex is a caged enzyme inhibitor that can be activated by blue light. To prepare a nanocarrier for NIR photoinhibition of enzyme activity, a UCNP and the caged enzyme inhibitors are encapsulated in a hollow mesoporous silica nanoparticle. In such a nanocarrier, the UCNP can harvest NIR light and convert it into blue light, which can activate the caged enzyme inhibitors. This photoactivation process is feasible in deep tissue because of the tissue penetration ability of NIR light. The nanocarrier is compatible to LNCaP, PC3, and SAOS‐2 cells, which show high enzyme expression. NIR irradiation induces release of the inhibitors and inhibition of enzyme activity in living cells. NIR light provides high spatiotemporal resolution to regulate enzyme activity in deep tissue.     

Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.     

Photoactivatable Protherapeutic Nanomedicine for Cancer

Therapeutic systems with site-specific pharmaceutical activation hold great promise to enhance therapeutic efficacy while reducing systemic toxicity in cancer therapy. With operational flexibility, noninvasiveness, and high spatiotemporal resolution, photoactivatable nanomedicines have drawn growing attention. Distinct from traditional controlled release systems relying on the difference of biomarker concentrations between disease and healthy tissues, photoactivatable nanomedicines capitalize on the interaction between nanotransducers and light to either trigger photochemical reactions or generate reactive oxygen species (ROS) or heat effect to remotely induce pharmaceutical actions in living subjects. Herein, the recent advances in the development of photoactivatable protherapeutic nanoagents for oncology are summarized. The design strategies and therapeutic applications of these nanoagents are described. Representative examples of each type are discussed in terms of structure, photoactivation mechanism, and preclinical models. Last, potential challenges and perspectives to further develop photoactivatable protherapeutic nanoagents in cancer nanomedicine are discussed.     

Ultrastable Near‐Infrared Conjugated‐Polymer Nanoparticles for Dually Photoactive Tumor Inhibition

It is highly desired that satisfactory photoactive agents with ideal photophysical characteristics are explored for potent cancer phototherapeutics. Herein, bifunctional nanoparticles of low‐bandgap donor–acceptor (D–A)‐type conjugated‐polymer nanoparticles (CP‐NPs) are developed to afford a highly efficient singlet‐to‐triplet transition and photothermal conversion for near‐infrared (NIR) light‐induced photodynamic (PDT)/photothermal (PTT) treatment. CP‐NPs display remarkable NIR absorption with the peak at 782 nm, and perfect resistance to photobleaching. Photoexcited CP‐NPs undergo singlet‐to‐triplet intersystem crossing through charge transfer in the excited D–A system and simultaneous nonradiative decay from the electron‐deficient electron acceptor isoindigo derivative under single‐wavelength NIR light irradiation, leading to distinct singlet oxygen quantum yield and high photothermal conversion efficiency. Moreover, the CP‐NPs display effective cellular uptake and cytoplasmic translocation from lysosomes, as well as effective tumor accumulation, thus promoting severe light‐triggered damage caused by favorable reactive oxygen species (ROS) generation and potent hyperthermia. Thus, CP‐NPs achieve photoactive cell damage through their photoconversion ability for synergistic PDT/PTT treatment with tumor ablation. The proof‐of‐concept design of D–A‐type conjugated‐polymer nanoparticles with ideal photophysical characteristics provides a general approach to afford potent photoactive cancer therapy.     

Enhancing Photodynamic Therapy through Resonance Energy Transfer Constructed Near‐Infrared Photosensitized Nanoparticles

Photodynamic therapy (PDT) is an important cancer treatment modality due to its minimally invasive nature. However, the efficiency of existing PDT drug molecules in the deep‐tissue‐penetrable near‐infrared (NIR) region has been the major hurdle that has hindered further development and clinical usage of PDT. Thus, herein a strategy is presented to utilize a resonance energy transfer (RET) mechanism to construct a novel dyad photosensitizer which is able to dramatically boost NIR photon utility and enhance singlet oxygen generation. In this work, the energy donor moiety (distyryl‐BODIPY) is connected to a photosensitizer (i.e., diiodo‐distyryl‐BODIPY) to form a dyad molecule ( RET‐BDP ). The resulting RET‐BDP shows significantly enhanced absorption and singlet oxygen efficiency relative to that of the acceptor moiety of the photosensitizer alone in the NIR range. After being encapsulated with biodegradable copolymer pluronic F‐127‐folic acid (F‐127‐FA), RET‐BDP molecules can form uniform and small organic nanoparticles that are water soluble and tumor targetable. Used in conjunction with an exceptionally low‐power NIR LED light irradiation (10 mW cm^?2), these nanoparticles show superior tumor‐targeted therapeutic PDT effects against cancer cells both in vitro and in vivo relative to unmodified photosensitizers. This study offers a new method to expand the options for designing NIR‐absorbing photosensitizers for future clinical cancer treatments.     

Iodine‐Rich Semiconducting Polymer Nanoparticles for CT/Fluorescence Dual‐Modal Imaging‐Guided Enhanced Photodynamic Therapy

Photodynamic therapy (PDT) is a promising technique for cancer therapy, providing good therapeutic efficacy with minimized side effect. However, the lack of oxygen supply in the hypoxic tumor site obviously restricts the generation of singlet oxygen (¹O₂), thus limiting the efficacy of PDT. So far, the strategies to improve PDT efficacy usually rely on complicated nanosystems, which require sophisticated design or complex synthetic procedure. Herein, iodine‐rich semiconducting polymer nanoparticles (SPN‐I) for enhanced PDT, using iodine‐induced intermolecular heavy‐atom effect to elevate the ¹O₂ generation, are designed and prepared. The nanoparticles are composed of a near‐infrared (NIR) absorbing semiconducting polymer (PCPDTBT) serving as the photosensitizer and source of fluorescence signal, and an iodine‐grafted amphiphilic diblock copolymer (PEG‐PHEMA‐I) serving as the ¹O₂ generation enhancer and nanocarrier. Compared with SPN composed of PEG‐b‐PPG‐b‐PEG and PCPDTBT (SPN‐P), SPN‐I can enhance the ¹O₂ generation by 1.5‐fold. In addition, SPN‐I have high X‐ray attenuation coefficient because of the high density of iodine in PEG‐PHEMA‐I, providing SPN‐I the ability of use with computed tomography (CT) and fluorescence dual‐modal imaging. The study thus provides a simple nanotheranostic platform composed of two components for efficient CT/fluorescence dual‐modal imaging‐guided enhanced PDT.     

Semiconducting Polymer Nanoreporters for Near-Infrared Chemiluminescence Imaging of Immunoactivation

Real-time in vivo imaging of immunoactivation is critical for longitudinal evaluation of cancer immunotherapy, which, however, is rarely demonstrated. This study reports semiconducting polymer nanoreporters (SPNRs) with superoxide anion (O₂^•−)-activatable chemiluminescence signals for in vivo imaging of immunoactivation during cancer immunotherapy. SPNRs are designed to comprise an SP and a caged chemiluminescence phenoxy-dioxetane substrate, which respectively serve as the chemiluminescence acceptor and donor to enable intraparticle chemiluminescence resonance energy transfer. SPNRs are intrinsically fluorescent but only become chemiluminescent upon activation by O₂^•−. Representing the first O₂^•−-activatable near-infrared chemiluminescent reporter, SPNR3 sensitively differentiates higher O₂^•− levels in immune cells from other cells including cancer and normal cells. Following systemic administration, SPNR3 passively accumulates into tumors in living mice and activates the chemiluminescence signals responding to the concentration of O₂^•− in the tumor microenvironment. Moreover, the enhancement of in vivo chemiluminescence signal after cancer immunotherapy is correlated with increased population of T cells in the tumor, proving its feasibility in tracking of T cell activation. Thus, SPNRs represent the first kind of chemiluminescent reporters competent for in vivo imaging of immunoactivation.     

Sub‐10‐nm Pd Nanosheets with Renal Clearance for Efficient Near‐Infrared Photothermal Cancer Therapy

Efficient renal clearance is of fundamentally important property of nanoparticles for their in vivo biomedical applications. In this work, we report the successful synthesis of ultra‐small Pd nanosheets (SPNS) with an average diameter of 4.4 nm and their application in photothermal cancer therapy using a near infrared laser. The ultra‐small Pd nanosheets have strong optical absorption in the NIR region and high photothermal conversion efficiency (52.0%) at 808 nm. After being surface‐functionalized with reduced glutathione (GSH), the SPNS‐GSH was administered to mice to investigate the biodistribution, photothermal efficacy and tumor ablation in vivo. The in vivo photothermal therapy studies clearly demonstrate that surface modification with GSH allows the nanosheets to exhibit prolonged blood circulation and thus high accumulation in tumors. Upon 808 nm NIR irradiation, the tumors can be completely ablated. More importantly, with the size below the renal filtration limit (<10 nm), the GSHylated Pd nanosheets can be nicely cleared from body through the renal excretion route and into urine. Together with the high efficacy of NIR photothermal therapy, the unique renal clearance properties make the ultra‐small Pd nanosheets promising for practical use in photothermal cancer therapy.     

Biocompatible Conjugated Polymer Nanoparticles for Efficient Photothermal Tumor Therapy

Conjugated polymers (CPs) with strong near‐infrared (NIR) absorption and high heat conversion efficiency have emerged as a new generation of photothermal therapy (PTT) agents for cancer therapy. An efficient strategy to design NIR absorbing CPs with good water dispersibility is essential to achieve excellent therapeutic effect. In this work, poly[9,9‐bis(4‐(2‐ethylhexyl)phenyl)fluorene‐alt‐co‐6,7‐bis(4‐(hexyloxy)phenyl)‐4,9‐di(thiophen‐2‐yl)‐thiadiazoloquinoxaline] (PFTTQ) is synthesized through the combination of donor–acceptor moieties by Suzuki polymerization. PFTTQ nanoparticles (NPs) are fabricated through a precipitation approach using 1,2‐distearoyl‐ sn ‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000] (DSPE‐PEG₂₀₀₀) as the encapsulation matrix. Due to the large NIR absorption coefficient (3.6 L g^‐1 cm^‐1), the temperature of PFTTQ NP suspension (0.5 mg/mL) could be rapidly increased to more than 50 °C upon continuous 808 nm laser irradiation (0.75 W/cm²) for 5 min. The PFTTQ NPs show good biocompatibility to both MDA‐MB‐231 cells and Hela cells at 400 μg/mL of NPs, while upon laser irradiation, effective cancer cell killing is observed at a NP concentration of 50 μg/mL. Moreover, PFTTQ NPs could efficiently ablate tumor in in vivo study using a Hela tumor mouse model. Considering the large amount of NIR absorbing CPs available, the general encapsulation strategy will enable the development of more efficient PTT agents for cancer or tumor therapy.     

Near‐Infrared‐Resonant Gold/Gold Sulfide Nanoparticles as a Photothermal Cancer Therapeutic Agent

The development and optimization of near‐infrared (NIR)‐absorbing nanoparticles for use as photothermal cancer therapeutic agents has been ongoing. This work exploits the properties of gold/gold sulfide NIR‐absorbing nanoparticles (≈35–55 nm) that provide higher absorption (98% absorption and 2% scattering for gold/gold sulfide versus 70% absorption and 30% scattering for gold/silica nanoshells) as well as potentially better tumor penetration. The ability to ablate tumor cells in vitro and efficacy for photothermal cancer therapy is demonstrated, and an in vivo model shows significantly increased long‐term, tumor‐free survival. Furthermore, enhanced circulation and biodistribution is observed in vivo. This class of NIR‐absorbing nanoparticles has the potential to improve upon photothermal tumor ablation for cancer therapy.     

Advanced Photoacoustic Imaging Applications of Near‐Infrared Absorbing Organic Nanoparticles

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.