Tissue Penetration Depth Research Articles

Advances in Lanthanide‐Based NIR‐IIb Probes for In Vivo Biomedical Imaging

AbstractThe past decades have witnessed the significant development and practical interest of in vivo biomedical imaging technologies and optical materials in the second‐near infrared (NIR‐II, 1000–1700 nm) window. Imaging with the extended emission wavelength toward the long‐wavelength end (NIR‐IIb, 1500–1700 nm) further offers micrometer imaging resolution and centimeter tissue penetration depth by taking advantage of the much‐reduced photon scattering and near‐zero tissue autofluorescence background, which have become a very hot research area. This review focuses on the recent advances in the development of lanthanide‐based NIR‐IIb probes for in vivo biomedical applications. The progress including ratiometric imaging, multiplexed imaging for wide‐field and microscopy, lifetime multiplexing and sensing, persistent luminescence, and multimodal imaging is summarized. Challenges and future directions concerning the investigation of the photophysical and photochemical properties of NIR‐IIb probes, the selection of near‐infrared cameras as well as the potential extension of the NIR‐IIb imaging sub‐window are pointed out. This review will inspire readers who have a strong interest in developing optical imaging technology and long‐wavelength fluorescence probes for high‐contrast in vivo biomedical applications.

A Flexible Antibacterial Gel Electrochemiluminescence Device for Monitoring and Therapy of Chronic Diabetic Wounds

ABSTRACTThe rapid development of internal light‐driven photodynamic therapy stems from its capability to eliminate bulky physical light sources, addressing the medical requirements for comfort and portability in long‐term diabetic wound management. To overcome limitations such as tissue penetration depth and controllability of internal light sources, this study introduces an antibacterial gel electrochemiluminescence device for the treatment of diabetic wounds and the monitoring of wound bacteria. We deploy a large‐area luminescent device combining flexible screen‐printed electrodes and a dual‐network hydrogel, in which photodynamic therapy is driven by Ru@COFs' nanoconfinement‐enhanced near‐infrared electrochemiluminescence to achieve a deeper and safer antibacterial effect. The custom‐sized screen‐printed electrodes inherit the inborn electrochemical sensing function and enable intimate contact between reactive oxygen species and the wound. The device avoids physical light sources and provides a new paradigm for developing miniaturized integrated diagnostic and therapeutic wearable devices.

Preliminary results of the non-invasive cardiac radioablation for ventricular tachycardia study; an in silico dosimetric comparison of photon vs proton radiotherapy for ventricular arrhythmias

Abstract Background Stereotactic arrhythmia radio-ablation (STAR) has been proposed as an alternative treatment for refractory ventricular arrhythmias (VA) in patients who are unsuitable or refractory to standard catheter ablation (CA). It consists in the application of external beam radiotherapy in a single dose of 25 Gy to the target areas. Most of the STAR treatments performed so far used photon radiotherapy. As compared to photons, particle therapy with protons, based on its finite penetration depth in tissue, might have the potential to reduce the dose to surrounding healthy tissues thus lowering the risk of side effects. Purpose The purpose of this in silico simulation study was to evaluate the feasibility of STAR with protons in patients with VA and to compare the doses of the organs at risk (OARs) in photon and proton treatment plans. Methods 14 patients (11 males) candidates to standard CA for VA were enrolled. ECG gated CT scans in expiratory breath-hold, and standard electroanatomical mapping were performed in each patients to reconstruct a 3D bipolar voltage map and identify the ablation target. Based on the information obtained by the contouring of the ablation target three treatment plans were simulated: one with photons, and two with protons - with and without cardiac gating- to assess the doses at the OARs. Results The median age was 68.5 (63.25-71.5), all patients had a history of recurrent VA and the indication for treatment with CA. 7 patients had an ischemic cardiomyopathy, 4 an idiopathic cardiomyopathy and 3 ventricular ectopic beats without structural heart disease. The mean left ventricular ejection fraction was 40±11% and 8 out of 14 patients were ICD carriers. Both photons and protons treatment plans reached the goals for target coverage (25 Gy on 98% of the target volume). A statistically significant reduction in the mean maximum dose (Dmax) to some OARs was observed in proton compared to photon plans (see table 1). Specifically, the Dmax delivered to the mitral valve, vena cava, descending aorta, esophagus and to the lungs have been largely reduced with the proton plans. However, in some specific cases, a higher maximum dose was observed for protons in structures close or overlapping with the target, mainly due to the need of an additional margin in the treatment plan to account for proton range uncertainty. The use of cardiac gating did not show a significant dose reduction to OARs compared to the non-gated proton plan. Conclusion The preliminary results of our in silico simulation study suggest that STAR therapy with the use of protons might be associated with a significant dose reduction to the surrounding organs. Nevertheless, the choice of the best treatment should be evaluated on a case by-case strategy since some specific cases may be better suitable for photon treatment.Table 1

Stable Alkyne‐Bridged Conjugated Polymer Nanoparticles With a High NIR‐II Photothermal Conversion Efficiency of 71% for Effective Photothermal Tumor Therapy

AbstractOrganic photothermal materials (PTMs) in the near‐infrared (NIR) range (1000–1700 nm) are more favorable for photothermal therapy (PTT) therapeutic applications because of their greater depth of tissue penetration and better biosafety. However, the photothermal conversion efficiency (PCE) of the few NIR‐II‐responsive organic PTMs that have been investigated is still slightly low. Here, a stable alkyne‐bridged conjugated polymer, BBT‐BTE, are explored with a high PCE for tumor ablation within the NIR‐II window. The BBT‐BTE synthesized by the Stille coupling reaction has strong NIR‐II absorption, and their nanoparticles (NPs) achieved a 71% PCE under 1064 nm laser excitation, with good photothermal stability. BBT‐BTE NPs are shown to be effective in completely ablating tumors without any recurrence in both in vitro and in vivo experiments. Additionally, the biosafety of these NPs is further proven by biochemical analysis and tissue biopsy. This study developed a high‐performance NIR‐II PTM and offered practical and feasible insights into the design of efficient photothermal materials specifically for the NIR‐II window.

Monitoring focused ultrasound ablation surgery (FUAS) using echo amplitudes of the therapeutic focused transducer

ObjectiveB-mode sonography is commonly used to monitor focused ultrasound ablation surgery (FUAS), but has limitations in sensitivity. More accurate and reliable prediction of coagulation is required. MethodsThe focused ultrasound (FUS) transducer was adapted for echo reception. Numerical simulations compared the normalized echo amplitudes from the FUS transducer and imaging probe at varying tissue depths and frequencies with a 3 mm necrosis at focus. An ex vivo experiment then evaluated echo changes from the FUS transducer and ultrasound imaging probe under different settings. Finally, coagulation prediction using FUS echo data was compared to sonography in a clinical ex vivo context. ResultsThe echo amplitudes from the FUS transducer exhibit a less pronounced decline with increasing tissue penetration depth compared to the ultrasound imaging probe. In ex vivo bovine liver experiments at depths of 2 cm and 4 cm, the FUS transducer detected normalized echo amplitudes that were significantly larger (i.e., 2∼3 folds) than those received by the ultrasound imaging probe. Moreover, multi-layered ex vivo tissue experiments that replicate clinical conditions revealed that coagulation prediction utilizing the FUS transducer's echo amplitudes achieved superior accuracy (91.2% vs. 60.3 %), sensitivity (92.1% vs. 54.5 %), and negative prediction (78.9% vs. 30.6 %), but similar specificity (88.2% vs. 84.6 %) and positive prediction (95.9% vs. 93.8 %) in comparison to sonography. ConclusionThe echo amplitude of the FUS transducer serves as a sensitive and dependable metric for monitoring the FUAS outcomes. Its utilization may augment the procedure's safety and efficacy.

Ultrasound-Responsive Hydrogel Incorporated with TGF-β Mimetic Peptides for Endometrium Recovery to Restore Fertility.

Unavoidable damage to the basal layer of the endometrium has a huge negative impact on a woman's reproductive health and menstrual cycle. However, it is difficult for medicine to penetrate a series of biological barriers toward the basal layer in the deeper area of the endometrium. To meet this challenge, we developed an ultrasound-responsive hydrogel incorporated with a transforming growth factor-beta (TGF-β) mimetic peptide to enhance pregnancy outcomes by restoring the function of a wounded endometrium due to its deep-tissue-penetration capability. In vitro studies revealed that the TGF-β-mimetic-peptide-loaded hydrogel could achieve 64.35% of cell migration under ultrasound stimulation even in phosphate-buffered saline of pH 6.0. Upon in situ sonication at the uterus, carboxymethyl chitosan can be released from degraded hydrogel to open tight junctions with reduced interstitial pressure by ultrasound to promote deep penetration. Rat studies revealed that the penetration capability of TGF-β-mimetic-peptide-loaded hydrogel with sonication was 1.6 times higher than that of the control group. Besides the rat uterine model, ex vivo human uterine tissue was also collected and imaged, demonstrating up to ∼700 μm of tissue penetration depth. In addition, compared to control groups, effective uterus recovery without intrauterine stenosis and endometrial cavity fluid was observed from rats with severe uterine injury treated by TGF-β-mimetic-peptide-loaded hydrogel. In addition, fertility restoration in the endometrial injury model was observed after treatment with such an ultrasound-responsive hydrogel incorporated with TGF-β mimetic peptides. Overall, this work provides an effective approach to treating endometrial injury for enhanced pregnancy outcomes.

Toward Upconversion (Yb-Er) and near-Infrared (Yb-Ho-Er, Nd-Yb) Thermometry with Sea Urchin Type GdPO4 Nanoarchitectures.

In recent years, optical temperature probes operating in the second near-infrared (BW-II) and third near-infrared (BW-III) biological windows have garnered significant attention in the scientific community. For biological applications these probes offer distinct advantages, including enhanced tissue penetration depth, minimal autofluorescence, and a remarkable improvement in imaging sensitivity and spatial resolution. Moving toward theranostic applications, there is a growing demand for the development of materials that integrate both BW-II and BW-III thermometry systems with drug delivery functionalities. In this study, we concentrate on the development of GdPO4 materials, utilizing both hard and sacrificial template routes to synthesize (hollow) GdPO4 porous sea urchin-like particles. We first investigated the development of a Boltzmann-type thermometer utilizing an Yb-Er upconversion system, designed to operate within the physiological temperature range. Our exploration extends to the potential of GdPO4 particles in near-infrared (NIR) thermometry, spanning the first, second, and third biological windows with systems like Yb-Ho-Er, Nd-Yb, and Ho-Yb, respectively. We further examined the temperature impact of the Yb-Ho-Er system on the NIR emission within a biologically relevant setting, using a phantom that replicates biological tissue. Furthermore, we illustrate the successful loading of these materials with doxorubicin (DOX·HCl), a model anticancer drug, showing these particles exhibit pH-dependent DOX release. This demonstrates the versatility of these materials as upconversion and NIR thermometers while simultaneously serving as an on-demand drug carrier. The investigation involves assessing their cytotoxicity on specific human cells (Normal Human Dermal Fibroblasts (NHDFs)), to determine their viability for potential use in biological applications. The study also investigates how effectively loading the particles with DOX enables targeted delivery to a cellular model of lymphoma (Jurkat E6-1), resulting in cell death. This comprehensive analysis highlights the promising potential of GdPO4 particles for medical applications.

MXene-based nanozymes remodel tumor microenvironment for heterojunction-enhanced sonodynamic and chemodynamic therapy to boost robust cancer immunotherapy

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth, but hardly controls remote metastasis. To trigger robust cancer immunotherapy against malignant metastatic cancers, we report the rational construction of Z-scheme heterojunctions through decorating biocompatible Co3O4 nanoparticles with multiple enzyme-like catalytic activities onto Ti3C2Tx nanosheets to realize the augmented SDT and chemodynamic therapy (CDT). The deposition of Co3O4 nanoparticles not only sensitizes the sonodynamic activity of Ti3C2Tx nanosheets owing to the regulation of separation dynamics of electron-hole pairs, but also achieves the cascade amplification of ROS generation through Co2+-mediated Fenton-like reaction, Co3+-facilitated GSH depletion, and catalytic decomposition of endogenous H2O2 to relieve hypoxia. More importantly, the immunosuppressive TME could be reversed by the greatly enhanced ROS levels, ultimately inducing immunogenic cell death that promotes robust systemic immune responses. The heterojunction-enhanced SDT and CDT via Co3O4@Ti3C2Tx could trigger robust cancer immunotherapy, which achieves the eradication of primary tumors and suppression of distant tumors. This work highlights the potential of heterojunction engineering-enhanced SDT and CDT to trigger robust cancer immunotherapy.

NIR-II Anti-Stokes Luminescence Nanocrystals with 1710 nm Excitation for in vivo Bioimaging.

Anti-Stokes luminescence (ASL) based on lanthanide nanocrystals holds immense promise for in vivo optical imaging and bio-detection, which benefits from filtered autofluorescence. However, the current longest emission and excitation wavelengths of lanthanide ASL system were shorter than 1200 nm and 1532 nm, respectively, which limited tissue penetration depth and caused low signal-to-noise ratio (SNR) of in vivo imaging due to tissue scattering and water absorption. In this work, we extended the excitation wavelength to 1710 nm with the second near-infrared (NIR-II, 1000-1700 nm) emission up to 1650 nm through a novel ASL nanocrystal LiYF4:10%Tm@LiYF4:70%Er@LiYF4. Compared with 1532 nm excited ASL nanoprobes, the 1710 nm excited nanocrystals could improve in vivo imaging SNR by 12.72 folds. Based on this excellent imaging performance of the proposed ASL nanoprobes, three-channel in vivo dynamic multiplexed imaging was achieved, which quantitatively revealed metabolic rates of intestinal dynamics and liver enrichment under anesthetized and awake states. This innovative ASL nanoprobes and dynamic multiplexed imaging technology would be conducive to optimizing dosing regimen and treatment plans across various physiological conditions.

NIR‐II Anti‐Stokes Luminescence Nanocrystals with 1710 nm Excitation for in vivo Bioimaging

Anti‐Stokes luminescence (ASL) based on lanthanide nanocrystals holds immense promise for in vivo optical imaging and bio‐detection, which benefits from filtered autofluorescence. However, the current longest emission and excitation wavelengths of lanthanide ASL system were shorter than 1200 nm and 1532 nm, respectively, which limited tissue penetration depth and caused low signal‐to‐noise ratio (SNR) of in vivo imaging due to tissue scattering and water absorption. In this work, we extended the excitation wavelength to 1710 nm with the second near‐infrared (NIR‐II, 1000‐1700 nm) emission up to 1650 nm through a novel ASL nanocrystal LiYF4:10%Tm@LiYF4:70%Er@LiYF4. Compared with 1532 nm excited ASL nanoprobes, the 1710 nm excited nanocrystals could improve in vivo imaging SNR by 12.72 folds. Based on this excellent imaging performance of the proposed ASL nanoprobes, three‐channel in vivo dynamic multiplexed imaging was achieved, which quantitatively revealed metabolic rates of intestinal dynamics and liver enrichment under anesthetized and awake states. This innovative ASL nanoprobes and dynamic multiplexed imaging technology would be conducive to optimizing dosing regimen and treatment plans across various physiological conditions.

Theoretical Investigation of Novel Nitrogen-Heterocyclic Iridium(III) Polypyridyl Complexes as Photosensitizers for Two-Photon Photodynamic Therapy.

Two-photon photodynamic therapy (TP-PDT) has become a major cancer treatment due to its larger tissue penetration depth, good spatial selectivity, and less damage to normal cells. In this contribution, a series of novel photosensitizer molecules (Ir-2, Ir-2-1∼Ir-2-4) have been designed based on the experimentally demonstrated photosensitizer [Ir(ppy)2(osip)] (PF6) by fine tuning the π-conjugated structure and introducing different nitrogen-heterocyclic substituents. The electronic structures, one- and two-photon absorption spectra, triplet excited state lifetime, solvation-free energy, and photosensitizing performance were evaluated by means of density functional theory (DFT) and time-dependent density functional theory (TDDFT). The results suggested that the molecule Ir-2, incorporating thiophene as the π-connecting group, exhibits a higher probability of triplet state formation, enhanced two-photon absorption cross-section, and prolonged triplet state lifetime. Furthermore, the four designed nitrogen-heterocyclic complexes Ir-2-1∼Ir-2-4 demonstrate favorable photosensitizing properties, with two-photon absorption cross-sections reaching up to 110 GM and triplet excited state lifetimes exceeding 1000 μs for Ir-2-4.

Activating Two-Photon Silica Nanoamplifier-Based CHA and FRET for Accurate Ratiometric Bioimaging of Intracellular MicroRNA.

In situ visualization of microRNA (miRNA) in cancer cells and diseased tissues is essential for advancing our comprehension of the onset and progression of associated diseases. Two-photon (TP) imaging, as an imaging technology with high spatiotemporal resolution, deep tissue penetration, and accurate target quantification, has distinctive advantages over single-photon imaging and has attracted increasing attention. Extensive research has been conducted on two-photon dye-doped silica nanoparticles, which exhibit a large two-photon absorption (TPA) cross-section, high fluorescence quantum yield, and excellent biocompatibility. However, the low abundance of RNA in tumor cells leads to insufficient signal output. Based on functional nucleic acid, a catalyzed hairpin self-assembly (CHA) signal amplification strategy, which has simplicity, robustness, and nonenzymatic characteristics, can achieve the amplification of DNA or RNA signals. Here, a two-photon silica nanoamplifier (TP-SNA) utilizing TP dye-doped silica nanoparticles (SiNPs) and functional nucleic acid was constructed, employing triggering catalyzed hairpin self-assembly and fluorescence resonance energy transfer (FRET) for highly sensitive detection and precise TP imaging of endogenous miRNAs in tumor cells and tissues at varying depths. The TP-SNA demonstrated the capability to detect miR-203 with a detection limit of 33 pM. The maximum two-photon tissue penetration depth of the two-photon nanoamplifier was 210 μm. The two-photon nanoamplifier developed in this study makes full use of the advantages of accurate TP ratiometric bioimaging and the CHA signal amplification strategy, which shows good application value for future transformation into clinical diagnosis.

Rapid full-color serial sectioning tomography with speckle illumination and ultraviolet excitation

Three-dimensional (3D) high-resolution large-volume imaging has remained a challenge. Translational rapid ultraviolet-excited sectioning tomography (TRUST) achieves rapid and cost-effective whole-organ subcellular imaging through iterative optical scanning and mechanical sectioning. However, the axial resolution is limited by the mechanical sectioning thickness or the UV light penetration depth in tissue. Here, assisted with high-and-low-frequency (HiLo) microscopy (HiLoTRUST), the optical sectioning thickness has been reduced from tens of micrometers to ~5.8 µm. In addition, HiLoTRUST has attained a finer mechanical sectioning thickness (10–15 µm) compared to TRUST (50 µm). For high-content imaging as in TRUST, we employed two additional UV light-emitting diodes (LEDs) specifically for uniform illumination. The full-color imaging ability and improved axial resolution of HiLoTRUST have been validated by two-dimensional (2D)/3D imaging of various mouse organs and human lung cancer specimens. HiLoTRUST offers a cost-effective, full-color, and high-resolution 3D imaging approach, showing its great potential in 3D histology applications.

Tumor Microenvironment Activated Cu Crosslinked Near-Infrared Sonosensitizers for Visualized Cuproptosis-Enhanced Sonodynamic Cancer Immunotherapy.

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth. However, the inevitable accumulation of sonosensitizers in normal tissues not only make it difficult to realize the in situ SDT, but also induces sonodynamic effects in normal tissues. Herein, this work reports the passivation and selective activation strategies for the sonodynamic and near-infrared (NIR) imaging performances of an intelligent antitumor theranostic platform termed Cu-IR783 nanoparticles (NPs). Owing to the ruptured coordination bond between IR783 with Cu ions by responding to tumor microenvironment (TME), the selective activation of IR783 only occurred in tumor tissues to achieve the visualized in-situ SDT. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu+-mediated Fenton-like reaction, but also triggered cuproptosis through Cu+-induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a distinct paradigm of the integration of SDT, CDT, and cuproptosis in a controlled manner to achieve visualized in-situ antitumor therapy.

Numerical simulation of heat transfer properties of skin tissue acted on repetitive laser irradiation

Pulsed laser has been widely used in the clinical treatment of various diseases and injuries due to its unique advantages in the process of interaction with skin tissue. In order to ensure the therapeutic effect and patient safety, it is necessary to accurately monitor the time-space response of the whole-field temperature of the target tissue irradiated by pulsed laser. A research strategy to explore the thermal response and incidental thermal damage of skin tissue induced by repeated pulses laser has been proposed in present work. A theoretical model involved variable physical properties was first proposed, in which the dual-phase lag (DPL) equation and Henrique burn equation were employed to evaluate the tissue temperature and thermal damage induced by repeated pulse laser irradiation. With the help of finite difference method, the governing equation with variable physical properties was then numerical solved to obtain the time-space distribution of tissue temperature, and the evolution process of the thermal damage was further calculated. The effects of laser input parameters and variable physical parameters on the laser penetration depth, temperature distribution and burn degree of the irradiated tissue were analyzed.

X-ray triggered scintillator versatile nanocatalytic platform for synergistic photodynamic/chemodynamic therapy

Nanocatalysts with photodynamic therapy (PDT) and chemodynamic therapy (CDT) are excellent for tumor therapy. However, it is still challenging to achieve complete tumor eradication due to the drawbacks of limited penetration depth of intratumoural tissues, hypoxia and complexity of the tumor microenvironment (TME). Herein, we fabricated an integrated multifunctional nanoreactor (LuAG:Tb/Ce-RB@ZIF-8-Au2Pt-HA, LRZAPH) combining scintillating nanoparticles (SCNPs, LuAG:Tb/Ce), a metal-organic framework (ZIF-8), and bimetallic Au2Pt for X-ray-triggered PDT and dual noble-metal nanozyme catalyzed CDT. Such a nanoreactor not only significantly enhanced the PDT effect under X-ray irradiation through full resonance energy transfer from LuAG:Tb/Ce scintillator to Ross Bengal (RB), but also facilitated the reactive oxygen species (ROS) and oxygen (O2) production through the excellent peroxidase-like (POD-like) and catalase-like (CAT-like) catalytic properties of Au2Pt nanozymes. O2 also alleviates hypoxia in intratumoural tissues during coordinated PDT. In addition, the dissociation behavior of ZIF-8 with pH-responsive and targeted of hyaluronic acid (HA) in acidic TME significantly enhanced the therapeutic efficacy of LRZAPH nanocatalysts. Significantly, the high tumor growth inhibition rate of 93 % was revealed due to radiotherapy (RT)/PDT/CDT synergetic therapy in vivo, which minimized the toxic and side effects of conventional clinical radiotherapy/chemotherapy on human. The synergistic effect of LRZAPH nanocatalysts on PDT and catalytically induced CDT is expected to provide new pathways for effective treatment of deep tumors.

A DNA machine-based magnetic resonance imaging nanoprobe for in vivo microRNA detection

In situ monitoring microRNA (miRNA) expression in vivo holds immense potential for directly visualizing the occurrence and progression of tumors. However, the significant barrier to developing a probe that can overcome the low abundance of miRNAs while providing an output signal with unlimited tissue penetration depth remains formidable. In this study, we developed a DNA machine-based magnetic resonance imaging nanoprobe (MRINP) for amplified detection of miR-21 in vivo. The MRINP was constructed with superparamagnetic Fe3O4 nanoparticles (NPs), paramagnetic Gd-DOTA complexes, and miR-21-activated DNA machines; the DNA machine was composed of hairpin DNAzyme (HD) strands serving as the DNAzyme walker and hairpin substrate (HS) strands serving as the track. Once uptake into tumor cells, the intracellular miR-21 specifically recognized and hybridized with the HD strand, restoring the activity of DNAzyme. Subsequently, the DNAzyme walker autonomously traveled on the surface of MRINP, and each step movement of the DNAzyme walker resulted in the cleavage of its substrate strands and the ensued release of the Gd-DOTA complex-labeled oligonucleotides, turning on the T1 signal of Gd-DOTA complexes for in situ imaging of miR-21 in tumor-bearing mice. This strategy would offer a promising approach for mapping tumor-specific biomarkers in vivo with unlimited penetration depth.

Blood-brain barrier permeable carbon nano-assemblies for amyloid-β clearance and neurotoxic attenuation

Abnormal amyloid β-protein (Aβ42) fibrillation is a key event in Alzheimer's disease (AD), and photodynamic therapy (PDT) possesses great potential in modulating Aβ42 self-assembly. However, the poor blood-brain barrier (BBB) penetration, low biocompatibility, and limited tissue penetration depth of existing photosensitizers limit the progress of photo-oxidation strategies. In this paper, novel indocyanine green-modified graphene quantum dot nano-assemblies (NBGQDs-ICGs) were synthesized based on a molecular assembly strategy of electrostatic interactions for PDT inhibition of Aβ42 self-assembly process and decomposition of preformed fibrils under near-infrared light. Combining the small-size structure of graphene quantum dots and the near-infrared light-responsive properties of ICGs, the NBGQDs-ICGs could achieve BBB penetration under 808 nm irradiation. More importantly, the neuroprotective mechanism of NBGQDs-ICG was studied for the first time by AFM, which effectively weakened the adhesion of Aβ42 aggregates to the cell surface by blocking the interaction between Aβ42 and the cell membrane, and restored the mechanical stability and adhesion of the neuron membrane. Meanwhile, NBGQDs-ICG promoted phagocytosis of Aβ42 by microglia. In addition, the good biocompatibility and stability ensured the biosafety of NBGQDs-ICG in future clinical applications. We anticipate that such multifunctional nanocomponents may provide promising avenues for the development of novel AD inhibitors.

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.