Tissue Penetration Depth Research Articles

DIAGNOSTIC COMPARABILITY OF RATIO OF TISSUE DIELECTRIC CONSTANT (TDC) BETWEEN PATIENTS WITH LIPEDEMA AND THOSE WITH LOWER LIMB LYMPHEDEMA (LLL): A PROSPECTIVE OBSERVATIONAL STUDY

Lipedema is usually thought of as a disease of women. Potentially diagnostic comparative data is needed between patients with lipedema and those with lower limb lymphedema (LLL). Since there is no gold standard to diagnose lipedema, some promising modalities such as Tissue Dielectric Constant (TDC) need to be investigated among patients with lipedema and lymphedema. This study was completed with a total of 26 patients (14 lipedema, 12 LLL). Local tissue water was assessed with Moisture MeterD compact (DelfinTech, Kuopio, Finland) according to the TDC method at 300 MHz within a 2.5 mm tissue penetration depth via the following reference points: Thigh, calf (20 cm upper and lower point of knee level, respectively), and malleoli (5 cm upper point of medial malleolus). Patients with LLL showed significantly higher TDC values and interlimb TDC ratios in all affected points and unaffected malleolus points compared to patients with lipedema. No significant difference was achieved between genders with LLL in all reference points. The area under the curve (AUC) for thigh, calf, and malleolus reference points were found as 0.851 (95%CI .678-1.00), 0.801 (95%CI 0.612-0.989) and 0.786 (95%CI 0.596- 0.976), respectively. Patients with LLL showed significantly higher TDC values compared to patients with lipedema, these differences should be carefully interpreted in patients with bilateral LLL and those with lipo-lymphedema.

Deep near infrared light-excited stable synergistic photodynamic and photothermal therapies based on P-IR890 nano-photosensitizer constructed via a non-cyanine dye

The cyanine dyes represented by IR780 can achieve synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) under the stimulation of near-infrared (NIR) light (commonly 808 nm). Unfortunately, the stability of NIR-excited cyanine dyes is not satisfactory. These cyanine dyes can be attacked by self-generated reactive oxygen species (ROS) during PDT processes, resulting in structural damage and rapid degradation, which is fatal for phototherapy. To address this issue, a novel non-cyanine dye (IR890) was elaborately designed and synthesized by our team. The maximum absorption wavelength of IR890 was located in the deep NIR region (ca. 890 nm), which was beneficial for further improving tissue penetration depth. Importantly, IR890 exhibited good stability when continuously illuminated by deep NIR light. To improve the hydrophilicity and biocompatibility, the hydrophobic IR890 dye was grafted onto the side chain of hydrophilic polymer (POEGMA-b-PGMA-g-CCH) via click chemistry. Then, the synthesized POEGMA-b-PGMA-g-IR890 amphiphilic polymer was utilized to prepare P-IR890 nano-photosensitizer via self-assembly method. Under irradiation with deep NIR light (850 nm, 0.5 W/cm2, 10 min), the dye degradation rate of P-IR890 was less than 5%. However, IR780 was almost completely degraded with the same light output power density and irradiation duration. In addition, P-IR890 could stably generate a large number of ROS and heat at the same time. It was rarely reported that the stable synergistic combination therapy of PDT and PTT could be efficiently performed by a single photosensitizer via irradiation with deep NIR light. P-IR890 exhibited favorable anti-tumor outcomes through apoptosis pathway. Therefore, the P-IR890 could provide a new insight into the design of photosensitizers and new opportunities for synergistic combination therapy of PDT and PTT.

ZnO quantum dots decorated BaTiO3 for cancer sonodynamic therapy

Sonodynamic therapy depending on ultrasound irradiation, which generates reactive species to kill cancer cells, has attracted considerable attention due to the deep tissue penetration depth. However, the insufficient separation of electron/hole pairs induces its limited therapeutic efficiency. Herein, we use oxygen vacancy and ZnO quantum dots decoration techniques to enhance electron/hole separation and reactive species production. In oxygen vacancy-engineered BaTiO3, the higher oxygen vacancy concentration leads to more efficient adsorption of activate O2 and thus results in production of more radicals. In BaTiO3/ZnO heterostructures, the built-in electric field further improves separation of electron/hole pairs. The separated electron/hole react with O2/H2O to produce reactive species of •OH/∙O2- and kill cancer cells upon ultrasound irradiation. The work provides a guidance for sonosensitizers to tumor therapy.

Mechanism and design of organic afterglow luminescent probes for cancer theranostics

Organic afterglow luminescent probes (OALPs), characterized by their long-lasting luminescence after irradiation (by light, ultrasound, or X-rays) cessation, are pivotal tools in autofluorescence-free optical imaging. They exhibit ultra-low background noise interference, enhancing imaging sensitivity and ensuring clearer, more reliable imaging results. Moreover, they offer deeper tissue penetration compared to traditional optical imaging modalities, providing various information from deep tissues. Recently developed sonoafterglow and radioafterglow further enhance tissue penetration depth. This review outlines 2 design approaches for OALPs: coencapsulation and conjugation, which are derived from their luminescent mechanism. Guided by these strategies, researchers have designed 3 types of OALPs: near-infrared OALPs, responsive OALPs, and ratiometric OALPs. Additionally, we also provided examples of how OALPs are integrated with therapy and applied in the field of cancer theranostics. Finally, we discuss certain challenges encountered in the advancement of the next generation of OALPs, aiming to broaden their scope of applications.

Multiplex Bioimaging with Near-Infrared Fluorescent Graphene Quantum Dots

Due to high tissue penetration depth and low autofluorescence backgrounds, near-infrared (NIR) fluorescence imaging has recently become an advantageous diagnostic technique used in a variety of fields. However, most of the NIR fluorophores do not have therapeutic delivery capabilities, exhibit low photostabilities, and raise toxicity concerns. To address these issues, we developed and tested five types of biocompatible graphene quantum dots (GQDs) exhibiting spectrally separated fluorescence in the NIR range of 928 – 1053 nm with NIR excitation. Their optical properties in the NIR are attributed to either rare-earth metal dopants (Ho-NGQDs, Yb-NGQDs, Nd-NGQDs) or defect-states (NGQDs, RGQDs) as verified by Hartree-Fock calculations. Moderate up to 1.34 % quantum yields of these GQDs are well-compensated by their remarkable >4-hour photostability. At the biocompatible concentrations of up to 0.5 – 2 mg/mL GQDs successfully internalize into HEK-293 cells and enable in vitro imaging in the visible and NIR. Tested all together in HEK-293 cells five GQD types enable simultaneous multiplex imaging in the NIR-I and NIR-II shown for the first time in this work for GQD platforms. Substantial photostability, spectrally-separated NIR emission, and high biocompatibility of five GQD types developed here suggest their promising potential in multianalyte testing and multiwavelength bioimaging of combination therapies.

Alkaline Phosphatase Activated Near-Infrared Frequency Upconversion Photosensitizers for Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising anticancer method due to its noninvasive features, high efficiency, and superior accuracy. The activated near-infrared upconversion photosensitizer has a high tissue penetration depth and could be explicitly released with minimal side effects. Therefore, we designed and synthesized a series of Br-substituted compounds (NFh-Br) based on the near-infrared upconversion hemicyanine dye. The heavy atomic effect improves the generation of 1O2 and upconversion luminous efficiency. Especially, NFh-Br11 exhibited an excellent 1O2 generation rate under 808 nm excitation and effectively killed tumor cells in vitro, and the alkaline phosphatase (ALP)-activatable photosensitizer (NFh-ALP) was obtained by modifying the NFh-Br11. NFh-ALP could be activated by ALP and release NFh-Br11, which induces apoptosis of tumor cells and has outstanding anticancer effects in vitro and in vivo. This work could provide a strategy for designing activatable upconversion photosensitizers.

Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

Near-Infrared Light-Mediated Antibacterial Photodynamic Therapy Based on Erythrosine-Functionalized Mesoporous Silica-Coated Upconversion Nanoplatform.

Infectious diseases caused by bacteria pose a serious threat to public health, and more worryingly, the unregulated application of antibiotics accelerates the emergence of bacterial resistance, presenting a major challenge to the effective treatment of infectious diseases caused by bacteria. Therefore, there is an urgent necessity to develop efficient and safe antimicrobial systems. Photodynamic therapy (PDT) is an attractive therapeutic approach that does not induce bacterial resistance. However, the clinical application of PDT has been limited by several factors, including the lower tissue penetration depth of photoactivation under visible light irradiation and the uncertain biosafety of photosensitizers (PS). This work presents an near infrared (NIR)-triggered core-shell upconversion nanoparticle-based PDT system composed of mesoporous silica-coated lanthanide-doped upconversion nanoparticles loaded with the photosensitizer erythrosine (UCSE). Upon NIR-triggering, erythrosine generates highly efficient reactive oxygen species that disrupt the cell membranes of Staphylococcus aureus and Escherichia coli, exhibiting a potent photodynamic antimicrobial effect. It is worth noting that the UCSE also exhibits excellent biosafety. In conclusion, we present an efficient NIR-triggered nanoantimicrobial system with excellent antimicrobial capacity and biosafety, which is a new therapeutic strategy for the control of bacterial infectious diseases.

730 nm Light‐Induced Cleavage of BODIPY Photocages via Entropy‐Driven Triplet Sensitization

AbstractLight‐activated drug delivery systems allow precise spatiotemporal control of a drug release process. However, safe and efficient drug release activation needs a low‐power nonpulsed red/near‐infrared light with high tissue penetration depth. Nevertheless, such systems remain a challenge. Herein, a self‐assembled nanovehicle made of 2,6‐diiodo‐B‐dimethyl‐boron dipyrromethene (BODIPY)‐based photocleavable trigonal molecules bearing Pt(II) meso‐tetraphenyltetranaphthoporhyrin photosensitizer and a fluorescent release marker Nile Red in hydrophobic core is introduced. The system employs endothermic triplet–triplet energy transfer between the photosensitizer and the trigonal molecule, leading to the cleavage of the trigonal molecule followed by cargo release. This allows to engage 730 nm light to cleave BODIPY photoremovable protecting groups (PPGs) instead of 530 nm light that would be needed for direct photocage excitation. Therefore, the approach unleashes the desired activation of drug release via photocleavage with longer wavelengths (within the phototherapeutic window) without any chemical modification of the PPGs. Cell studies demonstrate fast intracellular uptake of the nanovehices by PC3 human prostate cancer cells with accumulation in lysosomes in 2 h. Light irradiation at 730 nm on nanovehicles dispersed in cell media leads to payload release. Remarkably, the system exhibits higher release efficiency at low oxygen concentration than at ambient thus allowing to tackle aggressive hypoxic solid tumors.

Hydrodynamics of a dual-orifice needle-free jet injector

In the recent literature, it has been shown that an enhanced, multi-faceted, balanced immune response can be generated using a combined intradermal (ID) and intramuscular (IM) delivery of vaccines, especially for novel DNA vaccines. However, needle-based injection for a combined ID/IM delivery may require separate injections, which may prove to be time consuming, and impractical for mass immunizations. In contrast, a novel multi-orifice jet injector could be used to deliver drugs at multiple penetration depths simultaneously, which may provide advantages such as ease of operation, elimination of sharps, and short injection timeframe (O (10 m)).Here, we consider a dual-orifice geometry with both a wide orifice (200 μm–400 μm) for IM drug delivery and a narrow orifice (100 μm) for ID drug delivery. Using numerical simulations, we found that, at a fixed upstream pressure, jet velocities through wide and narrow orifices do not vary significantly for low-viscosity fluids (≲4%). However, it was previously hypothesized that the jet power, Pj=π8ρdj2vj3, is a more appropriate parameter to characterize tissue penetration depth. Thus, the jet power could vary by a factor of ∼10, yielding different depths for the two orifices. Using non-dimensional analysis via Euler (Eu) and Reynolds (Re) numbers, we characterize the role of orifice geometry and driving pressure, to generate geometry-specific correlations in the Eu–Re parameter space to estimate the jet velocity and pressure losses. We also elucidate the orifice size ratios that are best suited for fractional doses of ∼100 μL to intradermal tissue from a total injection of 1 ml.Preliminary experiments to visualize the penetration of wide and narrow jet streams into gelatin and pork substrates showed that the wide jet stream leads to substantially greater penetration depth than the narrow jet stream. In summary, we provide the initial feasibility of simultaneous delivery of a drug to multiple penetration depths from the same injection cartridge using the needle-free jet injection technique.

Nanoparticles Encapsulated in Red Blood Cell Membranes for Near-Infrared Second Window Imaging-Guided Photothermal-Enhanced Immunotherapy on Tumors.

Photothermal therapy (PTT), which uses the high thermal conversion ability of photothermal agents to ablate tumor cells at high temperatures, has gained significant attention because it has the advantages of high selectivity and specificity, precise targeting of tumor sites, and low invasiveness and trauma. However, PTT guided by the NIR-I has limitations in tissue penetration depth, resulting in limited imaging monitoring and therapeutic effects on deep-seated tumor tissues. Moreover, nanoparticles are easily cleared by the immune system and difficult to passively target tumor sites during the process of treatment. To address these issues, we prepared nanoparticles using NIR-II dyes IR1048 and DSPE-PEG-OH and further encapsulated them in red blood cell membranes derived from mice. These biomimetic nanoparticles, called RDIR1048, showed reduced clearance by the immune system and had long circulation characteristics. They effectively accumulated at tumor sites, and strong fluorescence could still be observed at the tumor site 96 h after administration. Furthermore, through mouse thermal imaging experiments, we found that RDIR1048 exhibited good PTT ability. When used in combination with an immune checkpoint inhibitor, anti-PD-L1 antibodies, it enhanced the immunogenic cell death of tumor cells caused by PTT and improved the therapeutic effect of immunotherapy, which demonstrated good therapeutic efficacy in the treatment of tumor-bearing mice. This study provides a feasible basis for the future development of NIR-II nanoparticles with long circulation properties.

“Butterfly-effect” nano-platforms for cascade immune amplification and tumor clearance through multi-modal therapy and immune sensitization

Combined dynamic tumor therapy of photodynamic therapy (PDT), sonodynamic therapy (SDT) and microwave dynamic therapy (MDT) can overcome the limitations of single reactive oxygen species (ROS)-based therapy (including limited tissue penetration depth and low ROS production). However, changes in the tumor microenvironment caused by ROS amplification and oxygen depletion induce severe immunosuppression at the tumor site, indicating effective immunosensitization of the tumors are urgently needed. Here, melanin-hematoporphyrin-chloroquine R837-hyaluronic acid (MHRH) nanoplatform that can simultaneously respond to 980 nm laser /1064 nm laser/ultrasonic/microwave was prepared for PDT/SDT/MDT, achieving outbreak of ROS in deep tumor. More importantly, the photothermal ablation and the participation of chloroquine R837 of MHRH NPs reversed the immunosuppression caused by oxygen depletion after ROS outbreak by promoting DCs maturation and secretion of macrophage exosomes. In summary, the natural MHRH nano-platform supplies an obvious anti-tumor “butterfly effect” through ROS outbreak, thermal ablation and significant immunosuppressive reversal, which provides a new and promising combined strategy of ROS-dynamic therapy and immune agonists in deep tumor tissues.

Comparison of Vinyldimethylaniline and Indolizine Donor Groups on Si‐Substituted Xanthene Core Shortwave Infrared Fluorophores

AbstractSmall organic molecules absorbing and emitting in the shortwave infrared (SWIR, 1000–2000 nm) region are desirable for biological imaging applications due to low auto‐fluorescence, reduce photon scattering, and good tissue penetration depth of photons which allows for in vivo imaging with high resolution and sensitivity. Si‐substituted xanthene‐based fluorophores with indolizine donors have demonstrated some of the longest wavelengths of absorption and emission from organic dyes. This work seeks to compare an indolizine heterocyclic nitrogen with dimethyl aniline nitrogen donors on otherwise identical Si‐substituted xanthene fluorophores via optical spectroscopy, computational chemistry and electrochemistry. Three donors are compared including an indolizine donor, a ubiquitous dimethyl aniline donor, and a vinyl dimethyl aniline group that keeps the number of π‐bonds consistent with indolizine. Significantly higher quantum yields and molar absorptivity are observed in these studies for a dimethylamine‐based donor relative to a simple indolizine donor absorbing and emitting at similar wavelengths (~1312 nm emission). Substantially longer wavelengths are obtainable by appending aniline‐based groups to the indolizine donor (~1700 nm) indicating longer wavelengths can be accessed with indolizine donors while stronger emitters can be accessed with anilines in place of indolizine.

NIR-II Fluorescence Imaging for In Vivo Quantitative Analysis.

In vivo real-time qualitative and quantitative analysis is essential for the diagnosis and treatment of diseases such as tumors. Near-infrared-II (NIR-II, 1000-1700 nm) bioimaging is an emerging visualization modality based on fluorescent materials. The advantages of NIR-II region fluorescent materials in terms of reduced photon scattering and low tissue autofluorescence enable NIR-II bioimaging with high resolution and increasing depth of tissue penetration, and thus have great potential for in vivo qualitative and quantitative analysis. In this review, we first summarize recent advances in NIR-II imaging, including fluorescent probe selection, quantitative analysis strategies, and imaging. Then, we describe in detail representative applications to illustrate how NIR-II fluorescence imaging has become an important tool for in vivo quantitative analysis. Finally, we describe the future possibilities and challenges of NIR-II fluorescence imaging.

Erbium-based hydrothermal YOF with stark sublevels for in vivo NIR II luminescence nanothermometer

Rare earth luminescent materials have attracted extensive attention in the biomedical field as noncontact temperature monitoring devices with microscopic resolution due to their properties in the visible and near-infrared regions. At the application level, it is required to have a certain temperature monitoring capability in the near-infrared region II window to enhance the tissue penetration depth. Here, two kinds of YOFs: Er[Formula: see text], Yb[Formula: see text] were prepared by co-precipitation and hydrothermal method, and the luminescence was enhanced by ion doping. An Er[Formula: see text]-based ratiometric nanothermometer of 4F[Formula: see text]I[Formula: see text] (672[Formula: see text]nm, upconversion luminescence) to 4I[Formula: see text]I[Formula: see text] (1580[Formula: see text]nm/1566[Formula: see text]nm, NIR II downshifting luminescence) were designed with the Stark energy level. When doped with 2% Zn[Formula: see text], the relative temperature sensitivity of YOF prepared by co-precipitation method was improved from 0.30% [Formula: see text] (30∘C) to 0.59% [Formula: see text] (30∘C), expanding its use as a temperature monitoring device possibility. The temperature sensitivity of YOF prepared by hydrothermal method was 1.01% [Formula: see text] (30∘C). Finally, the NIR II luminescence of the prepared nanothermometer was used as a control for temperature monitoring of heating sites in mice. The results showed that it can distinguish heating site from control site and no significant cytotoxicity or damage to the tissues was revealed, indicating its broad prospects in the biomedical field and other temperature monitoring scenarios in the future.

Ultrasmall copper-based nanoplatforms for NIR-II light-triggered photothermal/ photodynamic and amplified nanozyme catalytic therapy of hypoxic tumor

The clinical applications of the photothermal therapy (PTT) and photodynamic therapy (PDT) are restricted by the limited tissue penetration depth of excitation light, while the enzyme catalysis therapy is hindered on account of the low treatment efficiency. Herein, we modify artificial nanozyme Pt nanoparticles on the surface of CuCo2S4 nanoparticles to prepare ultrasmall copper-based ternary bimetallic chalcogenides CuCo2S4-Pt-PEG nanocomposites for PTT/PDT/enzyme catalysis synergistic therapy. The as-fabricated CuCo2S4-Pt-PEG nanocomposites display peroxidase (POD)-like and catalase (CAT)-like activities, which can catalyze hydrogen peroxide to emerge highly toxic hydroxyl radicals and oxygen, respectively. The integration of Pt nanozyme significantly improves the POD-like and CAT-like activity of CuCo2S4 −PEG that can produce more hydroxyl radicals and oxygen to improve the effects of PDT. Furthermore, the nanocomposites exhibit outstanding photothermal properties derived from the enhanced photothermal conversion efficiency (η = 78.46 %) exposed to 1064 nm NIR-II light irradiation with a low power density (0.8 W cm−2). In particular, the photothermal performance of CuCo2S4-Pt-PEG significantly enhances the enzyme-like activity. Additionally, the T1-weighted magnetic resonance and photoacoustic imaging endow CuCo2S4-Pt-PEG with the advantages of guiding the treatment process. The synergistic treatment demonstrates significant anticancer treatment efficiency while also elicits immune response that suppressed metastasis. This study could further promote the application of ternary bimetallic chalcogenides in cancer diagnosis and treatment.

Intelligent Biogenic Missile for Two-Photon Fluorescence Imaging-Guided Combined Photodynamic Therapy and Chemotherapy in Tumors.

Photodynamic therapy (PDT) is a significant noninvasive therapeutic modality, but it is often limited in its application due to the restricted tissue penetration depth caused by the wavelength limitations of the light source. Two-photon (TP) fluorescence techniques are capable of having an excitation wavelength in the NIR region by absorbing two NIR photons simultaneously, which offers the potential to achieve higher spatial resolution for deep tissue imaging. Thus, the adoption of TP fluorescence techniques affords several discernible benefits for photodynamic therapy. Organic TP dyes possess a high fluorescence quantum yield. However, the biocompatibility of organic TP dyes is poor, and the method of coating organic TP dyes with silica can effectively overcome the limitations. Herein, based on the TP silica nanoparticles, a functionalized intelligent biogenic missile TP-SiNPs-G4(TMPyP4)-dsDNA(DOX)-Aptamer (TGTDDA) was developed for effective TP bioimaging and synergistic targeted photodynamic therapy and chemotherapy in tumors. First, the Sgc8 aptamer was used to target the PTK7 receptor on the surface of tumor cells. Under two-photon light irradiation, the intelligent biogenic missile can be activated for TP fluorescence imaging to identify tumor cells and the photosensitizer assembled on the nanoparticle surface can be activated for photodynamic therapy. Additionally, this intelligent biogenic missile enables the controlled release of doxorubicin (DOX). The innovative strategy substantially enhances the targeted therapeutic effectiveness of cancer cells. The intelligent biogenic missile provides an effective method for the early detection and treatment of tumors, which has a good application prospect in the real-time high-sensitivity diagnosis and treatment of tumors.

A Tandem-Locked Chemiluminescent Probe for Imaging of Tumor-Associated Macrophage Polarization.

Tumor-associated macrophages (TAMs) play a role in both pro- and anti-tumor functions; and the targeted polarization from M2 to M1 TAMs has become an effective therapy option. Although detection of M1 TAMs is imperative to assess cancer immunotherapeutic efficacy, existing optical probes suffer from shallow tissue penetration depth and poor specificity toward M1 TAMs. Herein, we report a tandem-locked NIR chemiluminescent (CL) probe for specific detection of M1 TAMs. Through a combined molecular engineering approach via both atomic alternation and introduction of electron-withdrawing groups, near-infrared (NIR) chemiluminophores are screened out to possess record-long emission (over 800 nm), record-high CL quantum yield (2.7 % einstein/mol), and prolonged half-life (7.7 h). Based on an ideal chemiluminophore, the tandem-locked probe (DPDGN) is developed to only activate CL signal in the presence of both tumour (γ-glutamyl transpeptidase) and M1 macrophage biomarkers (nitric oxide). Such a tandem-lock design ensures its high specificity towards M1 macrophages in the tumor microenvironment over those in normal tissues or peripheral blood. Thus, DPDGN permits noninvasive imaging and tracking of M1 TAM in the tumor of living mice during R837 treatment, showing a good correlation with ex vivo methods. This study not only reports a new molecular approach towards highly efficient chemiluminophores but also reveals the first tandem-locked CL probes for enhanced imaging specificity.

A Tandem‐Locked Chemiluminescent Probe for Imaging of Tumor‐Associated Macrophage Polarization

AbstractTumor‐associated macrophages (TAMs) play a role in both pro‐ and anti‐tumor functions; and the targeted polarization from M2 to M1 TAMs has become an effective therapy option. Although detection of M1 TAMs is imperative to assess cancer immunotherapeutic efficacy, existing optical probes suffer from shallow tissue penetration depth and poor specificity toward M1 TAMs. Herein, we report a tandem‐locked NIR chemiluminescent (CL) probe for specific detection of M1 TAMs. Through a combined molecular engineering approach via both atomic alternation and introduction of electron‐withdrawing groups, near‐infrared (NIR) chemiluminophores are screened out to possess record‐long emission (over 800 nm), record‐high CL quantum yield (2.7 % einstein/mol), and prolonged half‐life (7.7 h). Based on an ideal chemiluminophore, the tandem‐locked probe (DPDGN) is developed to only activate CL signal in the presence of both tumour (γ‐glutamyl transpeptidase) and M1 macrophage biomarkers (nitric oxide). Such a tandem‐lock design ensures its high specificity towards M1 macrophages in the tumor microenvironment over those in normal tissues or peripheral blood. Thus, DPDGN permits noninvasive imaging and tracking of M1 TAM in the tumor of living mice during R837 treatment, showing a good correlation with ex vivo methods. This study not only reports a new molecular approach towards highly efficient chemiluminophores but also reveals the first tandem‐locked CL probes for enhanced imaging specificity.

X-ray-activated polymerization expanding the frontiers of deep-tissue hydrogel formation

Photo-crosslinking polymerization stands as a fundamental pillar in the domains of chemistry, biology, and medicine. Yet, prevailing strategies heavily rely on ultraviolet/visible (UV/Vis) light to elicit in situ crosslinking. The inherent perils associated with UV radiation, namely the potential for DNA damage, coupled with the limited depth of tissue penetration exhibited by UV/Vis light, severely restrict the scope of photo-crosslinking within living organisms. Although near-infrared light has been explored as an external excitation source, enabling partial mitigation of these constraints, its penetration depth remains insufficient, particularly within bone tissues. In this study, we introduce an approach employing X-ray activation for deep-tissue hydrogel formation, surpassing all previous boundaries. Our approach harnesses a low-dose X-ray-activated persistent luminescent phosphor, triggering on demand in situ photo-crosslinking reactions and enabling the formation of hydrogels in male rats. A breakthrough of our method lies in its capability to penetrate deep even within thick bovine bone, demonstrating unmatched potential for bone penetration. By extending the reach of hydrogel formation within such formidable depths, our study represents an advancement in the field. This application of X-ray-activated polymerization enables precise and safe deep-tissue photo-crosslinking hydrogel formation, with profound implications for a multitude of disciplines.