Bionic nanotheranostic for multimodal imaging-guided NIR-II-photothermal cancer therapy.

In photothermal therapy (PTT), the photothermal conversion of the second near-infrared (NIR-II) window allows deeper penetration and higher laser irradiance and is considered a promising therapeutic strategy for deep tissues. Since cancer remains a leading cause of deaths worldwide, despite the numerous treatment options, we aimed to develop an improved bionic nanotheranostic for combined imaging and photothermal cancer therapy. We combined a gold nanobipyramid (Au NBP) as a photothermal agent and MnO2 as a magnetic resonance enhancer to produce core/shell structures (Au@MnO2; AM) and modified their surfaces with homologous cancer cell plasma membranes (PM) to enable tumour targeting. The performance of the resulting Au@MnO2@PM (AMP) nanotheranostic was evaluated in vitro and in vivo. AMP exhibits photothermal properties under NIR-II laser irradiation and has multimodal in vitro imaging functions. AMP enables the computed tomography (CT), photothermal imaging (PTI), and magnetic resonance imaging (MRI) of tumours. In particular, AMP exhibited a remarkable PTT effect on cancer cells in vitro and inhibited tumour cell growth under 1064 nm laser irradiation in vivo, with no significant systemic toxicity. This study achieved tumour therapy guided by multimodal imaging, thereby demonstrating a novel strategy for the use of bionic gold nanoparticles for tumour PTT under NIR-II laser irradiation.

PET/SPECT/Spectral-CT/CBCT imaging in a small-animal radiation therapy platform: A Monte Carlo study-Part II: Biologically guided radiotherapy.

BACKGROUND: This study addresses the technical gap between clinical radiation therapy (RT) and preclinical small-animal RT, hindering the comprehensive validation of innovative clinical RT approaches in small-animal models of cancer and the translation of preclinical RT studies into clinical practices. PURPOSE: The main aim was to explore the feasibility of biologically guided RT implemented within a small-animal radiation therapy (SART) platform, with integrated quad-modal on-board positron emission tomography (PET), single-photon emission computed tomography, photon-counting spectral CT, and cone-beam CT (CBCT) imaging, in a Monte Carlo model as a proof-of-concept. METHODS: We developed a SART workflow employing quad-modal imaging guidance, integrating multimodal image-guided RT and emission-guided RT (EGRT). The EGRT algorithm was outlined using positron signals from a PET radiotracer, enabling near real-time adjustments to radiation treatment beams for precise targeting in the presence of a 2-mm setup error. Molecular image-guided RT, incorporating a dose escalation/de-escalation scheme, was demonstrated using a simulated phantom with a dose painting plan. The plan involved delivering a low dose to the CBCT-delineated planning target volume (PTV) and a high dose boosted to the highly active biological target volume (hBTV) identified by the 18F-PET image. Additionally, the Bayesian eigentissue decomposition method illustrated the quantitative decomposition of radiotherapy-related parameters, specifically iodine uptake fraction and virtual noncontrast (VNC) electron density, using a simulated phantom with Kidney1 and Liver2 inserts mixed with an iodine contrast agent at electron fractions of 0.01-0.02. RESULTS: EGRT simulations generated over 4,000 beamlet responses in dose slice deliveries and illustrated superior dose coverage and distribution with significantly lower doses delivered to normal tissues, even with a 2-mm setup error introduced, demonstrating the robustness of the novel EGRT scheme compared to conventional image-guided RT. In the dose-painting plan, doubling the dose to the hBTV while maintaining a low dose for the PTV resulted in an organ-at-risk (OAR) dose comparable to the low-dose treatment for the PTV alone. Furthermore, the decomposition of radiotherapy-related parameters in Kidney1 and Liver2 inserts, including iodine uptake fractions and VNC electron densities, exhibited average relative errors of less than 1.0% and 2.5%, respectively. CONCLUSIONS: The results demonstrated the successful implementation of biologically guided RT within the proposed quad-model image-guided SART platform, with potential applications in preclinical RT and adaptive RT studies.

Oxygen Vacancy Defect Enhanced NIR-II Photothermal Performance of BiOxCl Nanosheets for Combined Phototherapy of Cancer Guided by Multimodal Imaging.

Narrow photo-absorption range and low carrier utilization are significant barriers that restrict the antitumor efficiency of 2D bismuth oxyhalide (BiOX, X = Cl, Br, I) nanosheets (NSs). Introducing oxygen vacancy (OV) defects can expand the absorption range and improve carrier utilization, which are crucial but also challenging. In this study, a series of BiOxCl NSs with different OV defect concentrations (x = 1, 0.7, 0.5) is developed, which shows full spectrum absorption and strong absorption in the second near-infrared region (NIR-II). Density functional theory calculations are utilized to calculate the crystal structure and density states of BiOxCl, which confirm that part of the carriers is separated by OV enhanced internal electric field to improve carrier utilization. The carriers without redox reaction can be trapped in the OV, leading to great majority of photo-generated carriers promoting the photothermal performance. Triggered by single NIR-II (1064 nm), BiOxCl NSs' bidirectional efficient utilization of carriers achieves synchronously combined phototherapy, leading to enhanced tumor ablation and multimodal diagnostic in vitro and vivo. It is thus believed that this work provides an innovative strategy to design and construct nanoplatforms of indirect band gap semiconductors for clinical phototheranostics.

Multimodal Imaging-Guided Photoimmunotherapy of Pancreatic Cancer by Organosilica Nanomedicine.

Immune checkpoint blockade (ICB) treatments have contributed to substantial clinical progress. However, challenges persist, including inefficient drug delivery and penetration into deep tumor areas, inadequate response to ICB treatments, and potential risk of inflammation due to over-activation of immune cells and uncontrolled release of cytokines following immunotherapy. In response, this study, for the first time, presents a multimodal imaging-guided organosilica nanomedicine (DCCGP) for photoimmunotherapy of pancreatic cancer. The novel DCCGP nanoplatform integrates fluorescence, magnetic resonance, and real-time infrared photothermal imaging, thereby enhancing diagnostic precision and treatment efficacy for pancreatic cancer. In addition, the incorporated copper sulfide nanoparticles (CuS NPs) lead to improved tumor penetration and provide external regulation of immunotherapy via photothermal stimulation. The synergistic immunotherapy effect is realized through the photothermal behavior of CuS NPs, inducing immunogenic cell death and relieving the immunosuppressive tumor microenvironment. Coupling photothermal stimulation with αPD-L1-induced ICB, the platform amplifies the clearance efficiency of tumor cells, achieving an optimized synergistic photoimmunotherapy effect. This study offers a promising strategy for the clinical application of ICB-based combined immunotherapy and presents valuable insights for applications of organosilica in precise tumor immunotherapy and theranostics.

Polydopamine-Modified 2D Iron (II) Immobilized MnPS3 Nanosheets for Multimodal Imaging-Guided Cancer Synergistic Photothermal-Chemodynamic Therapy.

Manganese phosphosulphide (MnPS3 ), a newly emerged and promising member of the 2D metal phosphorus trichalcogenides (MPX3 ) family, has aroused abundant interest due to its unique physicochemical properties and applications in energy storage and conversion. However, its potential in the field of biomedicine, particularly as a nanotherapeutic platform for cancer therapy, has remained largely unexplored. Herein, a 2D "all-in-one" theranostic nanoplatform based on MnPS3 is designed and applied for imaging-guided synergistic photothermal-chemodynamic therapy. (Iron) Fe (II) ions are immobilized on the surface of MnPS3 nanosheets to facilitate effective chemodynamic therapy (CDT). Upon surface modification with polydopamine (PDA) and polyethylene glycol (PEG), the obtained Fe-MnPS3 /PDA-PEG nanosheets exhibit exceptional photothermal conversion efficiency (η = 40.7%) and proficient pH/NIR-responsive Fenton catalytic activity, enabling efficient photothermal therapy (PTT) and CDT. Importantly, such nanoplatform can also serve as an efficient theranostic agent for multimodal imaging, facilitating real-time monitoring and guidance of the therapeutic process. After fulfilling the therapeutic functions, the Fe-MnPS3 /PDA-PEG nanosheets can be efficiently excreted from the body, alleviating the concerns of long-term retention and potential toxicity. This work presents an effective, precise, and safe 2D "all-in-one" theranostic nanoplatform based on MnPS3 for high-efficiency tumor-specific theranostics.

US/CT fusion imaging and virtual navigation to guide lumbar intradiscal oxygen-ozone therapy: a pilot study.

PURPOSE: To test the feasibility of US/CT fusion imaging to guide lumbar intradiscal O2/O3 therapy to treat discogenic degenerative low back pain due to lumbar disc herniation (LDH). METHODS: We retrospectively included consecutive patients affected by low back pain and/or sciatica due to LDH resistant to conservative therapies, who underwent to lumbar intradiscal O2/O3 injection under CT/US fusion imaging guidance (Fusion Group) and standard CT guidance (Control Group). For each procedure, we collected procedure operative time, room utilization time, number of CT passes, complications, and O2/O3 intradiscal diffusion adequacy. Technical success was defined as the ability to complete the procedure as initially planned to reach the disc. Technical efficacy was based on O2/O3 intradiscal diffusion adequacy, as demonstrated by the last CT scan. RESULTS: Six patients (4 males; mean age: 68 ± 15 years) were included in the Fusion group, six (4 males; mean age: 66 ± 12 years) in Control group. No complications were observed in both groups. In Fusion group we found significantly lower room utilization time (30 ± 6 min vs. 46 ± 10 min, p = 0.008), procedure operative time (14 ± 3 min vs. 24 ± 6 min, p = 0.008), and number of CT passes (2 [2,2] vs. 3 [3,3], p = 0.006) than in Control Group, respectively. Technical success and efficacy were 100% in both Groups. CONCLUSION: CT/US fusion imaging seems to be a feasible and safe guidance for intradiscal O2/O3 injections, allowing decrease of procedure time and number of CT passes.

Gold Nanocage-Based Multifunctional Nanosensitizers for Programmed Photothermal /Radiation/Chemical Coordinated Therapy Guided by FL/MR/PA Multimodal Imaging.

Background: Radiotherapy is one of the main clinical methods for the treatment of malignant tumors at present. However, its application is limited by the radiation resistance of some tumor cells and the irradiation damage to the surrounding normal tissues, and the limitation of radiotherapy dose also affects the therapeutic effect. Therefore, developing diagnostic and therapeutic agents with imaging and radiosensitizing functions is urgently needed to improve the accuracy and efficacy of radiotherapy. Materials and Strategy: Herein, we synthesized multifunctional nanotheranostic FRNPs nanoparticles based on gold nanocages (GNCs) and MnO2 for magnetic resonance (MR)/photoacoustic (PA) imaging and combined photothermal, radiosensitive and chemical therapy. A programmed therapy strategy based on FRNPs is proposed. First, photothermal therapy is applied to ablate large tumors and increase the sensitivity of the tumor tissue to radiotherapy, then X-ray radiation is performed to further reduce the tumor size, and finally chemotherapeutic agents are used to eliminate smaller residual tumors and distant metastases. Results: As revealed by fluorescence, MR and PA imaging, FRNPs achieved efficient aggregation and retention at tumor sites of mice after intravenous injection. In vivo studies have shown that the programmed treatment of FRNPs-injected nude mice which were exposed to X-ray after 808 laser irradiation achieved the greatest inhibition of tumor growth compared with other treatment groups. Moreover, no obvious systemic toxicity was observed in all groups of mice, indicating the good biocompatibility of FRNPs and the safety of the treatment scheme. Conclusion: To sum up, our work not only showed a new radiosensitizer, but also provided a promising theranostic strategy for cancer treatment.

Acceptor engineering-facilitated versatile AIEgen for mitochondria-targeted multimodal imaging-guided cancer photoimmunotherapy.

Photoimmunotherapy has been acknowledged to be an unprecedented strategy to obtain significantly improved cancer treatment efficacy. In this regard, the exploitation of high-performance multimodal phototheranostic agents is highly desired. Apart from tailoring electron donors, acceptor engineering is gradually rising as a deliberate approach in this field. Herein, we rationally designed a family of aggregation-induced emission (AIE)-active compounds with the same donors but different acceptors based on the acceptor engineering. Through finely adjusting the functional groups on electron acceptors, the electron affinity of electron acceptors and the conformation of the compounds were simultaneously modulated. It was found that one of the molecules (named DCTIC), bearing a moderately electrophilic electron acceptor and the best planarity, exhibited optimal phototheranostic properties in terms of light-harvesting ability, fluorescence emission, reactive oxygen species (ROS) production, and photothermal performance. For the purpose of amplified therapeutic outcomes, DCTIC was fabricated into tumor and mitochondria dual-targeted DCTIC nanoparticles (NPs), which afforded good performance in the fluorescence/photoacoustic/photothermal trimodal imaging-guided photodynamic/photothermal-synergized cancer immunotherapy with the combination of programmed cell death protein-1 (PD-1) antibody. Not only the primary tumors were totally eradicated, but efficient growth inhibition of distant tumors was also realized.

Functionalized ZnMnFe2O4-PEG-FA nanoenzymes integrating diagnosis and therapy for targeting hepatic carcinoma guided by multi-modality imaging.

With its insidious onset and atypical early symptoms, hepatic carcinoma is one of the most common and malignant tumors in the world. Therefore, it is necessary to actively pursue efficient diagnostic and treatment modalities for this malignancy. Photothermal therapy (PTT) is a non-invasive treatment technique that can generate high temperatures locally to induce tumor cell death, but its effectiveness is limited by the tissue-penetration depth of infrared light. Enzyme-catalyzed therapy promotes the production of toxic hydroxyl groups (˙OH) from hydrogen peroxide in tumor cells in situ, but its efficacy is also affected by the catalytic efficiency of ˙OH. Thus, given the complexity of tumors, multimodal therapy is critical for cancer treatment. Herein, we report a novel biomimetic nanoparticle (NP) platform (ZnMnFe2O4-PEG-FA) that enables combined PTT and nanozyme-catalyzed therapy. Due to the excellent photothermal effect of ZnMnFe2O4-PEG-FA, these NPs can reach an ideal temperature and damage tumor cells under lower near-infrared laser power irradiation, while exhibiting enhanced catalytic ability, largely alleviating the limitations of conventional PTT and catalytic therapy. Hence, the combination of these two treatments can provide significantly greater cytotoxicity. Additionally, ZnMnFe2O4-PEG-FA NPs have excellent photoacoustic imaging and magnetic resonance imaging capabilities, which enable monitoring and can guide cancer treatment. Therefore, ZnMnFe2O4-PEG-FA NPs integrate the diagnosis and treatment of tumors. Hence, this study provides a potential model of combined cancer diagnosis and treatment, which could be applied as a multimodal antitumor strategy in clinical settings in the future.

Multimodal Imaging Study of Patients With Vitamin A Deficiency Retinopathy.

OBJECTIVES: To describe multimodal imaging findings of vitamin A deficiency retinopathy. METHODS: A retrospective study of patients with serum retinol < 0.3 mg/L. Fundus color photos, spectral domain-optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were reviewed and, when available, electrophysiological tests were analyzed. RESULTS: Forty-five eyes (63.9 ± 15.7 years) were included. Ultra-widefield fundus photography showed drusen-like deposits (53.3%) and macular retinal pigment epithelium (RPE) mottling (40%). The deposits were hypoautofluorescent, and a perifoveal hyperautofluorescent ring was present in 8.9%. By SD-OCT, the ellipsoid zone had an irregular appearance (100%) and conical deposits anterior to the RPE (33.3%). Electroretinogram (ERG) (66.7%) showed a decrease in b-wave in the scotopic registers, and microperimetry (4.4%) showed decreased foveal sensitivity. After vitamin A supplementation, SD-OCT and FAF showed resolution of all findings. Forty percent of eyes had restoration of the scotopic registers in ERG and improved macular sensitivity by microperimetry (4.4%). CONCLUSIONS: Vitamin A deficiency causes a mild cone dysfunction in addition to the more severe absent rod response. [Ophthalmic Surg Lasers Imaging Retina 2023;54:330-336.].

A novel multi-modality imaging phantom for validating interstitial needle guidance for high dose rate gynecological brachytherapy.

PURPOSE: To design, manufacture, and validate a female pelvic phantom for multi-modality imaging (CT, MRI, US) to benchmark a commercial needle tracking system with application in HDR gynecological (GYN) interstitial procedures. MATERIALS AND METHODS: A GYN needle-tracking phantom was designed using CAD software to model an average uterus from a previous patient study, a vaginal canal from speculum dimensions, and a rectum to accommodate a transrectal ultrasound (TRUS) probe. A target volume (CTVHR ) was designed as an extension from the cervix-uterus complex. Negative space molds were created from modeled anatomy and 3D printed. Silicone was used to cast the anatomy molds. A 3D printed box was constructed to house the manufactured anatomy for structural integrity and to accommodate the insertion of a speculum, tandem, needles, and TRUS probe. The phantom was CT-imaged to identify potential imperfections that might impact US visualization. Free-hand TRUS was used to guide interstitial needles into the phantom. The commercial tracking system was used to generate a 3D US volume. After insertion, the phantom was imaged with CT and MR and the uterus and CTVHR dimensions were verified against the CAD model. RESULTS/CONCLUSIONS: The manufactured phantom allows for accurate visualization with multiple imaging modalities and is conducive to applicator and needle insertion. The phantom dimensions from the CAD model were verified with those from each imaging modality. The phantom is low cost and can be reproducibly manufactured with the 3D printing and molding processes. Our initial experiments demonstrate the ability to integrate the phantom with a commercial tracking system for future needle tracking validation studies.

Self-delivery of metal-coordinated NIR-II nanoadjuvants for multimodal imaging-guided photothermal-chemodynamic amplified immunotherapy.

The effectiveness of phototheranostics induced immunotherapy is still hampered by limited light penetration depth, the complex immunosuppressive tumor microenvironment (TME) and the low efficiency of immunomodulator drug delivery. Herein, self-delivery and TME responsive NIR-II phototheranostic nanoadjuvants (NAs) were fabricated to suppress the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy (PTT-CDT) and immune remodeling. The NAs were constructed by the self-assembly of ultrasmall NIR-II semiconducting polymer dots and the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. Under acidic TME, the NAs responsively disintegrated and released therapeutic components, which enable NIR-II fluorescence/photoacoustic/magnetic resonance imaging-guided tumor PTT-CDT. Moreover, the synergistic treatment of PTT-CDT could induce significant tumor immunogenic cell death and evoke highly efficacious cancer immunosurveillance. The released R848 stimulated the maturation of dendritic cells, which both amplified the antitumor immune response by modulating and remodeling the TME. The NAs present a promising integration strategy of polymer dot-metal ion coordination and immune adjuvants for precise diagnosis and amplified anti-tumor immunotherapy against deep-seated tumors. STATEMENT OF SIGNIFICANCE: The efficiency of phototheranostics induced immunotherapy is still limited by insufficient light penetration depth, low immune response and the complex immunosuppressive tumor microenvironment (TME). In order to improve the efficacy of immunotherapy, self-delivery NIR-II phototheranostic nanoadjuvants (PMR NAs) were successfully fabricated via the facile coordination self-assembly of ultra-small NIR-II semiconducting polymer dots and toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. PMR NAs not only enable TME responsive cargo release and NIR-II fluorescence/photoacoustic/magnetic resonance imaging mediated precise localization of tumors, but also achieve synergistic photothermal-chemodynamic therapy, evoking an effective anti-tumor immune response by ICD effect. The responsively released R848 could further amplify the efficiency of immunotherapy by reversing and remodeling the immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor growth and lung metastasis.

"Trojan Horse" Phototheranostics: Fine-Engineering NIR-II AIEgen Camouflaged by Cancer Cell Membrane for Homologous-Targeting Multimodal Imaging-Guided Phototherapy.

Multimodal phototheranostics on the basis of a single molecule with one-for-all characteristics represents a convenient approach for effective cancer treatment. In this report, a versatile molecule featured by aggregation-induced emission, namely DHTDP, synchronously enabling second near-infrared (NIR-II) fluorescence emission and efficient photothermal conversion is developed by elaborate structural modulation. By camouflaging DHTDP nanoparticles with cancer cell membrane, the resultant biomimetic nanoparticles exhibit significantly both facilitated delivery efficiency and homologous targeting capability, and afford precise imaging guidance and maximize therapeutic outcomes in form of NIR-II fluorescence imaging (FLI)-photoacoustic imaging (PAI)-photothermal imaging (PTI) trimodal imaging-guided photothermal therapy (PTT). This study presents the first example of biomimetic multimodal phototheranostics loaded by homogeneity-targeting cell membrane, thus brings a new insight into the exploration of superior phototheranostics for practical cancer theranostics.

Upconversion Nanoplatform Enables Multimodal Imaging and Combinatorial Immunotherapy for Synergistic Tumor Treatment and Monitoring.

Designing a novel nanoplatform that integrates multimodal imaging and synergistic therapy for precision tumor nanomedicines is challenging. Herein, we prepared rare-earth ion-doped upconversion hydroxyapatite (FYH) nanoparticles as nanocarriers coated and loaded respectively with polydopamine (PDA) and doxorubicin (DOX), i.e., FYH-PDA-DOX, for tumor theranostics. The developed FYH-PDA-DOX complexes exhibited desirable photothermal conversion, pH/near-infrared-irradiation-responsive DOX release, and multimodal upconversion luminescence/computed tomography/magnetic resonance imaging performance and helped monitor the metabolic distribution process of the complexes and provided feedback to the therapeutic effect. Upon 808 nm laser irradiation, the fast release of DOX facilitated the photothermal-chemotherapy effect, immunogenic cell death, and antitumor immune response. On combining with the anti-programmed cell death 1 ligand 1 antibody, an enhanced tri-mode photothermal-chemo-immunotherapy synergistic treatment against tumors can be realized. Thus, this treatment elicited potent antitumor immunity, producing appreciable T-cell cytotoxicity against tumors, amplifying tumor suppression, and extending the survival of mice. Therefore, the FYH-PDA-DOX complexes are promising as a smart nanoplatform for imaging-guided synergistic cancer treatment.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Dual receptor NIR-II organic nanoparticles for multimodal imaging guided tumor photothermal therapy.

The second near-infrared (NIR-II) fluorescence imaging has attracted continuous attention due to its excellent penetration depth and high spatial resolution. Compared with other fluorophores, NIR-II fluorophores, especially NIR-II organic small molecule fluorophores, are favored because of their controllable structure and good biocompatibility. In this study, we designed and synthesized an S-D-A-D-S type small molecule FEA. However, a new molecule was accidentally obtained in the process of synthesis, which was proved to be a double receptor (A-A) type small molecule, namely S-D-A-A-D-S type organic small molecule FEAA. Compared with FEA molecules, FEAA exhibits superior fluorescence performance and can effectively prevent fluorescence quenching. The fluorescence emission of its nanoparticles (NPs) reaches 1109 nm, extends to about 1400 nm, and has a Stokes shift of up to 472 nm. Subsequently, we realized fluorescence/photoacoustic dual-mode imaging (FI/PAI) of nude mouse liver, and finally effectively ablated 4T1 tumor by photothermal therapy (PTT). In general, FEAA NPs exhibit good fluorescence, photoacoustic, and photothermal effects, and are an excellent multifunctional NIR-II organic small molecule fluorophore. As far as we know, there are few reports on A-A type organic small molecules, most of which are cyanines or D-A-D type structures. Therefore, this study has good exploratory significance and reference value for the discovery of NIR-II fluorophores.

α-Fe2O3@Au-PEG-Ce6-Gd Nanoparticles as Acidic H2O2-Driven Oxygenators for Multimodal Imaging and Synergistic Tumor Therapy.

Nanoparticles with visual imaging capabilities and synergistic therapeutics have a bright future in antitumor applications. However, most of the current nanomaterials lack multiple imaging-guided therapeutic capabilities. In this study, a novel enhanced photothermal photodynamic antitumor nanoplatform with photothermal imaging, fluorescence (FL) imaging, and MRI-guided therapeutic capabilities was constructed by grafting gold, dihydroporphyrin Ce6, and Gd onto α-iron trioxide. This antitumor nanoplatform can convert NIR light into local hyperthermia at a temperature of up to 53 °C under NIR light irradiation, while Ce6 can generate singlet oxygen, which further synergizes the tumor-killing effect. At the same time, α-Fe2O3@Au-PEG-Ce6-Gd can also have significant photothermal imaging effect under light irradiation, which can guide to see the temperature change near the tumor tissue. It is worth noting that α-Fe2O3@Au-PEG-Ce6-Gd can have obvious MRI and FL imaging effects after tail vein injection in mice with blood circulation, realizing imaging-guided synergistic antitumor therapy. α-Fe2O3@Au-PEG-Ce6-Gd NPs provide a new solution for tumor imaging and treatment.

Molecular Engineering of NIR-II/IIb Emitting AIEgen for Multimodal Imaging-Guided Photo-Immunotherapy.

In view of the great challenges related to the complexity and heterogeneity of tumors, efficient combination therapy is an ideal strategy for eliminating primary tumors and inhibiting distant tumors. A novel aggregation-induced emission (AIE) phototherapeutic agent called T-TBBTD is developed, which features a donor-acceptor-donor (D-A-D) structure, enhanced twisted molecule conformation, and prolonged second near-infrared window (NIR-II) emission. The multimodal imaging function of the molecule has significance for its treatment time window and excellent photothermal/photodynamic performance for multimode therapy. The precise molecular structure and versatility provide prospects for molecular therapy for anti-tumor applications. Fluorescence imaging in the NIR-II window offers advantages with enhanced spatial resolution, temporal resolution, and penetration depth. The prepared AIE@R837 NPs also have controllable performance for antitumor photo-immunotherapy. Following local photo-irradiation, AIE@R837 NPs generate abundant heat, and 1 O2 directly kills tumor cells, induces immunogenic cell death (ICD) as a photo-therapeutic effect, and releases R837, which enhances the synergistic effect of antigen presentation and contributes to the long-lasting protective antitumor immunity. A bilateral 4T1 tumor model revealed that this photo-immunotherapy can eliminate primary tumors. More importantly, it has a significant inhibitory effect on distant tumor growth. Therefore, this method can provide a new strategy for tumor therapy.

Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.