Radiolabeled AIE Probes as Dual-modality Imaging Agents for PET/NIR-II Fluorescence-Guided Photothermal Therapy.

Breast cancer has become a huge burden with continued rise of incidence and death rate worldwide. Various methods for diagnosis and therapy of breast cancer have met the challenges of lack of complete information about the tumor location and limited therapy efficacy. Although aggregation-induced emission luminogens (AIEgens) have shown great promise for various cancer treatment applications, they may be incompetent for deep-seated tumor diagnosis due to the limited penetration depth. Herein, we designed and prepared a radiolabeled AIEgen-based organic photothermal agent for bimodal PET/fluorescence imaging-guided breast tumor photothermal therapy. The prepared multifunctional nanoparticles (68 Ga-TPA-TTINC NPs) with NIR-II fluorescence, gamma irradiation and photothermal conversion property could be efficiently taken up by tumor cells and induce reactive oxygen species burst in vitro, further boosting the photothermal treatment of tumor in vivo. More importantly, the nanoprobe could target and clearly visualize 4T1 tumor xenografts through PET and NIR-II fluorescence imaging with high tumor/muscle ratio up to 4.8, which provides a promising tool and solution for breast tumor theranostics.

177 Lu Radiolabelled AIE Dots for Multimodal Imaging Guided Photothermal/Radiopharmaceutical Tumor Therapy.

Aggregation-induced emission luminogens (AIEgens) in the second near-infrared region (NIR-II,1000-1700 nm) have shown tremendous potential as theragnostic probe for tumor multimodal diagnostic imaging and combined treatment owing to their programmable optical, structural and functional properties. Herein, we presented a radionuclide 177 Lu-labeled AIEgen, 177 Lu-2TT-oC6B dots, for NIR-II fluorescence and SPECT/CT imaging-guided tumor photothermal and radiopharmaceutical therapy. Intriguingly, 177 Lu-2TT-oC6B self-assembled into 10 nm dots, exhibited high NIR-II fluorescence quantum yield (QY, 1.34 %) and unprecedented photothermal conversion efficiency (PCE, 70.3 %) in vitro, furtherly performed extremely long blood circulation (T1/2 =52.4 h), persistent tumor accumulation and retention in tumor (NIR-II SNR=5.56; SPECT SNR=36.59) via intravenous administration in vivo. Furthermore, upon NIR light activation and 177 Lu irradiation, 177 Lu-2TT-oC6B demonstrated great application potential in synergistic photothermal/radiopharmaceutical tumor therapy.

A Mitochondria-Targeted NIR-II AIEgen Induced Pyroptosis for Enhanced Tumor Immunotherapy.

Cancer immunotherapy is a favorable strategy for facilitating anti-tumor immunity, but it shows limited benefits in clinical practice owing to the immunosuppressive tumor microenvironment. Pyroptosis shows great immunostimulatory effect on tumor, whereas the lack of pyroptotic inducer with imaging property has restricted its progress in tumor theranostics. Herein, a mitochondria-targeted aggregation-induced emission (AIE) luminogen (TPA-2TIN) with NIR-II emission is designed for highly efficient induction of tumor cell pyroptosis. The fabricated TPA-2TIN nanoparticles can be efficiently taken up by tumor cells and selectively accumulated in tumor for a long term observed by NIR-II fluorescence imaging. More importantly, the TPA-2TIN nanoparticles can effectively stimulate immune responses both in vitro and in vivo mediated by the mitochondrial dysfunctions and the subsequent activation of the pyroptotic pathway. Ultimately, the reversal of the immunosuppressive tumor microenvironment significantly enhances the immune checkpoint therapy. This study paves a new avenue for adjuvant immunotherapy of cancer.

Recent Advances in Microfluidic Devices for the Radiosynthesis of PET-imaging Probes.

In order to accommodate the growing demand for positron emission tomography (PET), it will be necessary to create innovative radiochemical and engineering technologies to optimize the manufacture and development of PET probes. Microfluidic devices allow radiosynthesis to be performed in microscale amounts, significantly impacting PET tracer production. Compared to traditional methods, microfluidic devices can produce PET tracers in a shorter time, higher yields, with lower reagent consumption, higher molar activity, and faster purification. This review examines microfluidic devices from an engineering perspective. Recently developed microfluidic radiosynthesis devices are classified into three categories according to their reaction volume: continuous-flow, batch-flow, and droplet-based microreactors. The principles of device architecture, radiosynthesis process, and the relative strengths and limitations of each category are emphasized by citing typical examples. Finally, the possible future applications of this technology are outlined. A flexible, miniature, fully automated radiochemical microfluidic platform will offer more straightforward and cheaper molecular imaging procedures and the potential for precision medicine that could allow operators to create customized tracers for individual patient doses.

Unusual Electron Donor-Acceptor Sequenced NIR AIEgen for Highly Efficient Mitochondria-Targeted Cancer Cell Photodynamic Therapy.

Photodynamic therapy (PDT) is recognized to be a promising strategy for anticancer treatment. Considering the progressive application of PDT in clinical trials, highly efficient and photostable photosensitizers (PSs) are in strong demand. Aggregation-induced emission (AIE) based PSs are promising phototheranostic materials for tumor imaging and PDT due to their high fluorescence efficiency and photostability. Herein, a mitochondria-targeted PS, TPA-2TCP with AIE characteristics is developed by adopting an acceptor-π-donor-π-acceptor (A-π-D-π-A) structure. The untypical sequence of the electron donors and electron acceptors endows the derived AIE PS with evident redshift of the absorption and emission, and efficient generation of reactive oxygen species. With the positively charged pyridinium groups, nanoparticulated AIE PS (TPA-2TCP NPs) exhibits high cell binding efficiency towards 4T1 breast cancer cells, leading to the massive cell death via the apoptotic pathway under white light irradiation, demonstrating its potential application in cancer imaging and PDT.

Highly Efficient Radiosynthesis and Biological Evaluation of [18 F]Safinamide, a Radiolabelled Anti-Parkinsonian Drug for Positron Emission Tomography Imaging.

As an add-on drug approved for Parkinson's disease treatment, safinamide has multiple functions, such as selective and reversible monoamine oxidase-B inhibition, voltage-sensitive sodium/potassium channel blockage, and glutamate release inhibition. Meanwhile, safinamide shows tremendous therapeutic potential in the context of other central nervous system diseases (e. g. ischaemic stroke, amyotrophic lateral sclerosis, depression, etc.). In this work, [18 F]safinamide, which is safinamide labelled by the positron-emitting radionuclide [18 F]fluorine, was synthesized automatically based on iodonium ylide precursors with high radiochemical yield and high molar activity. Density functional theory was applied to calculate the Gibbs free energy change during iodonium ylide-mediated fluorination and to interpret the effect of tetraethylammonium (TEA+ ) as the counter cation in these reactions to improve the nucleophilicity of [18 F/19 F]fluoride. In addition, positron emission tomography studies on Sprague Dawley rats were carried out to determine the imaging characteristics, pharmacokinetics, and metabolism of the [18 F]safinamide radiotracer. The results displayed the complete biodistribution of the radiotracer, especially in rat brains, and revealed that [18 F]safinamide has moderate brain uptake, rapid and reversible binding kinetics, and good stability.

A Mitochondria-targeted AIEgen Labelled with 18 F for Breast Cancer Cell Imaging and Therapy.

A lack of efficient diagnostic tools for early and noninvasive diagnosis of breast cancer has restricted the clinical treatment effect. This problem might be addressed by the combination of aggregation-induced emission (AIE) fluorescence imaging and positron emission tomography (PET) with the dual advantages of high resolution and easy operation, and unlimited penetration and high sensitivity. Here, a mitochondria-targeted AIE luminogen (AIEgen) radiolabeled with 18 F was developed through a two-step radiochemical reaction by virtue of a prosthetic group. The obtained 18/19 F-Bz-CP imaging probe was examined by in vitro cell uptake and cell proliferation inhibition in two breast cancer cell lines, showing that the probe can efficiently target and locate in the mitochondria through the analysis of fluorescence imaging and PET simultaneously. Additionally, the probe can induce cancer cell apoptosis with the half maximal inhibitory concentration (IC50) of 4.8 µM for MCF-7 cells and 7.2 µM for T47D cells, indicating its potential application for breast cancer therapy.

Aggregation-induced Emission Based Fluorogens for Mitochondria-targeted Tumor Imaging and Theranostics.

Occurrence and development of cancer are multifactorial and multistep processes which involve complicated cellular signaling pathways. Mitochondria, as the energy producer in cells, play key roles in tumor cell growth and division. Since mitochondria of tumor cells have a more negative membrane potential than those of normal cells, several fluorescent imaging probes have been developed for mitochondria-targeted imaging and photodynamic therapy. Conventional fluorescent dyes suffer from aggregation-caused quenching effect, while novel aggregation-induced emission (AIE) probes are ideal candidates for biomedical applications due to their large stokes shift, strong photo-bleaching resistance, and high quantum yield. This review aims to introduce the recent advances in the design and application of mitochondria-targeted AIE probes. The comprehensive review focuses on the structure-property relationship of these imaging probes, expecting to inspire the development of more practical and versatile AIE fluorogens (AIEgens) as tumor imaging and therapy agents for preclinical and clinical use.