RESUMEN
Persistent luminescence without excitation light and tissue autofluorescence interference holds great promise for biological applications, but is limited by available materials with long-wavelength emission and excellent clinical potential. Here, we report that porphyrin derivatives can emit near-infrared persistent luminescence over 60â min after cessation of excitation light or on interaction with peroxynitrite. A plausible mechanism of the successive oxidation of vinylene bonds was demonstrated. A supramolecular probe with a ß-sheet structure was constructed to enhance the tumor targeting ability and the photoacoustic and persistent luminescence signals. Such probes featuring light-triggered function transformation from photoacoustic imaging to persistent luminescence imaging permit advanced image-guided cancer surgery. Furthermore, peroxynitrite-activated persistent luminescence of the supramolecular probe also enables rapid and precise screening of immunogenic cell death drugs.
Asunto(s)
Nanopartículas , Neoplasias , Porfirinas , Humanos , Luminiscencia , Nanopartículas/química , Ácido PeroxinitrosoRESUMEN
Photoacoustic (PA) imaging emerges as a promising technique for biomedical applications. The development of new strategies to boost PA conversion without depressing other properties (e.g., fluorescence) is highly desirable for multifunctional imaging but difficult to realize. Here, we report a new phenomenon that active intramolecular motions could promote PA signal by specifically increasing thermal-to-acoustic conversion efficiency. The compound with intense intramolecular motion exhibits amplified PA signal by elevating thermal-to-acoustic conversion, and the fluorescence also increases due to aggregation-induced emission signature. The simultaneously high PA and fluorescence brightness of TPA-TQ3 NPs enable precise image-guided surgery. The preoperative fluorescence and PA imaging are capable of locating orthotopic breast tumor in a high-contrast manner, and the intraoperative fluorescence imaging delineates tiny residual tumors. This study highlights a new design guideline of intramolecular motion amplifying PA effect.
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Colorantes Fluorescentes/química , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Técnicas Fotoacústicas , Fármacos Fotosensibilizantes/uso terapéutico , Acústica , Humanos , Neoplasias/cirugía , Cirugía Asistida por Computador , TemperaturaRESUMEN
Lysosome-relevant cell death induced by lysosomal membrane permeabilization (LMP) has recently attracted increasing attention. However, nearly no studies show that currently available LMP inducers can evoke immunogenic cell death (ICD) or convert immunologically cold tumors to hot. Herein, we report a LMP inducer named TPE-Py-pYK(TPP)pY, which can respond to alkaline phosphatase (ALP), leading to formation of nanoassembies along with fluorescence and singlet oxygen turn-on. TPE-Py-pYK(TPP)pY tends to accumulate in ALP-overexpressed cancer cell lysosomes as well as induce LMP and rupture of lysosomal membranes to massively evoke ICD. Such LMP-induced ICD effectively converts immunologically cold tumors to hot as evidenced by abundant CD8+ and CD4+ T cells infiltration into the cold tumors. Exposure of ALP-catalyzed nanoassemblies in cancer cell lysosomes to light further intensifies the processes of LMP, ICD and cold-to-hot tumor conversion. This work thus builds a new bridge between lysosome-relevant cell death and cancer immunotherapy.
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Antineoplásicos/uso terapéutico , Muerte Celular Inmunogénica/efectos de los fármacos , Lisosomas/metabolismo , Neoplasias/tratamiento farmacológico , Organofosfatos/uso terapéutico , Fosfatasa Alcalina/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Diseño de Fármacos , Células HEK293 , Humanos , Radical Hidroxilo/metabolismo , Membranas Intracelulares/metabolismo , Luz , Lisosomas/enzimología , Ratones , Organofosfatos/síntesis química , Organofosfatos/metabolismo , Organofosfatos/efectos de la radiación , Permeabilidad/efectos de los fármacosRESUMEN
Photodynamic therapy (PDT) is a promising noninvasive therapeutic technique and has attracted increasing interests in preclinical trials. However, the translation from laboratory to clinic often encounters the problem of undesired dark cytotoxicity of photosensitizers (PSs). Now, this challenge can be addressed by cascaded substitution activated phototheranostics using the host-guest strategy. Through electrostatical complexation of pyridinium-functionalized tetraphenylethylene, namely, TPE-PHO, and water-soluble calixarene, the dark cytotoxicity of TPE-PHO is dramatically inhibited. The nanoassemblies of the complex show enhanced biocompatibility and selectively locate at the cytoplasm in vitro. When TPE-PHO is competitively displaced from the cavity of calixarene by 4,4'-benzidine dihydrochloride at the tumor site, its dark cytotoxicity and photoactivity in tumor tissue are restored to give efficient PDT efficacy under light irradiation. The result from cell imaging reveals that TPE-PHO undergoes translocation from cytoplasm to mitochondria to kill the cancer cells during the cascaded supramolecular substitution process. In vivo tumor imaging and therapy are successfully implemented to evaluate the curative effect. Such a supramolecular strategy avoids tedious molecular synthesis and opens a new venue to readily tune the PS behaviors.
RESUMEN
Afterglow imaging through the collection of persistent luminescence after the stopping of light excitation holds enormous promise for advanced biomedical uses. However, efficient near-infrared (NIR)-emitting afterglow luminescent materials and probes (particularly the organic and polymeric ones) are still very limited, and their in-depth biomedical applications such as precise image-guided cancer surgery are rarely reported. Here, we design and synthesize a NIR afterglow luminescent nanoparticle with aggregation-induced emission (AIE) characteristics (named AGL AIE dots). It is demonstrated that the AGL AIE dots emit rather-high NIR afterglow luminescence persisting over 10 days after the stopping of a single excitation through a series of processes occurring in the AIE dots, including singlet oxygen production by AIE luminogens (AIEgens), Schaap's dioxetane formation, chemiexcitation by dioxetane decomposition, and energy transfer to NIR-emitting AIEgens. The animal studies reveal that the AGL AIE dots have the innate property of fast afterglow signal quenching in normal tissues, including the liver, spleen, and kidney. After the intravenous injection of AGL AIE dots into peritoneal carcinomatosis bearing mice, the tumor-to-liver ratio of afterglow imaging is nearly 100-fold larger than that for fluorescence imaging. The ultrahigh tumor-to-liver signal ratio, together with low afterglow background noise, enables AGL AIE dots to give excellent performance in precise image-guided cancer surgery.
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Neoplasias Hepáticas/cirugía , Hígado/cirugía , Nanopartículas/química , Cirugía Asistida por Computador/métodos , Animales , Fluorescencia , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Humanos , Hígado/patología , Neoplasias Hepáticas/patología , Ratones , Nanopartículas/administración & dosificación , Imagen Óptica , Polímeros/químicaRESUMEN
Nanomedicines have been demonstrated as promising strategies for cancer therapy due to the advantages in pharmacokinetics and drug targeting delivery to tumor tissues. However, creation of delivery platforms able to intrinsically and spatially optimize drug cellular uptake during the entire delivering process remain challenging. To address this challenge, here we report on tumor microenvironment-adaptable self-assembly (TMAS) of pentapeptides regulated by the pH-sensitive cis/trans isomerization of 4-amino-proline (Amp) amide bonds for enhanced drug delivery and photodynamic therapeutic (PDT) efficacy. We found that decreasing solution pH led to the cis â trans isomerization of Amp amide bonds, thus promoting reversible self-assembly of pentapeptide FF-Amp-FF (AmpF) into superhelices and nanoparticles upon alternating exposure to neutral and mild acidic conditions. Co-assembly of peptide AmpF with its derivative containing a photosensitizer Chlorin e6 (AmpF-C) allows for creation of TMAS systems undergoing a morphological transition adaptable to the pH gradient present in cellular uptake pathway. Ex vivo studies revealed that TMAS nanomedicines prolonged circulation in the animal body and improved accumulation at tumor sites compared to morphology-persistent nanomedicines. In addition to the optimized cellular uptake, the morphological transition of TMAS into nanofibers in cytoplasm caused an enhanced intracellular ROS level compared to nanoparticle counterparts, thus leading to a lowered half lethal dose value for cancer cells. The combined advantages of TMAS eventually allowed in vivo PDT therapy for significant inhibition of tumor growth, thus demonstrating the improved drug delivery efficiency and therapeutic efficacy of TMAS systems toward new-generation nanomedicines.
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Neoplasias de la Mama/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Oligopéptidos/química , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Prolina/química , Animales , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Clorofilidas , Femenino , Isomerismo , Ratones , Nanoestructuras/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Microambiente Tumoral/efectos de los fármacosRESUMEN
Activatable phototheranostics is highly appealing to meet the demand of precision medicine. However, although it displays efficacy in the construction of activatable photosensitizers (PSs), direct covalent decoration still shows some inevitable issues, such as complex molecular design, tedious synthesis, possible photoactivity changes, and potential toxicity. Herein, we propose a novel concept of biomarker displacement activation (BDA) using host-guest strategy. To exemplify BDA, we engineered a PS-loaded nanocarrier by utilizing a macrocyclic amphiphile, where the fluorescence and photoactivity of PS were completely annihilated by the complexation of macrocyclic receptor (OFF state). When nanocarriers were accumulated into tumor tissues via the enhanced permeability and retention effect, the overexpressed biomarker adenosine triphosphates displaced PSs, accompanied by their fluorescence and photoactivity recovered (ON state). These reinstallations are unattainable in normal tissues, allowing us to concurrently achieve selective tumor imaging and targeted therapy in vivo. Compared with widely used covalent approach, the present BDA strategy provides the following advantages: (1) employment of approved PSs without custom covalent decoration; (2) traceless release of PSs with high fidelity by biomarker displacement; (3) adaptability to different PSs for establishing a universal platform and promised facile combination of diverse PSs to enhance photon utility in light window. Such a host-guest BDA strategy is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged.
RESUMEN
Much effort is devoted to develop agents with superior photoacoustic/photothermal properties for improved disease diagnosis and treatment. Herein, a new fused two isoindigo (DIID)-based semiconducting conjugated polymer (named PBDT-DIID) is rationally designed and synthesized with a strong near-infrared absorption band ranging from 700 to 1000 nm. Water-dispersing nanoparticles (NPs) of PBDT-DIID are prepared with good biocompatibility and a rather high photothermal conversion efficiency (70.6%), as the active excited-state intramolecular twist around the central double bonds in DIID permits most of the absorbed excitation energy flow to heat deactivation pathway through internal conversion. The photoacoustic signal can be further magnified by incorporation of polylactide (PLA) in the NP core to confine the generated heat of PBDT-DIID within NPs. The resultant doped NPs show excellent performance in photoacoustic imaging-guided photothermal therapy in an orthotopic 4T1 breast tumor-bearing mouse model. It is also found that the photothermal effect of the PBDT-DIID NPs is safe and quite efficacious to highly improve the root canal treatment outcome by heating the 1% NaClO solution inside the root canal upon 808 nm laser irradiation in a human extracted tooth root canal infection model.
Asunto(s)
Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Animales , Línea Celular Tumoral , Ratones , Nanopartículas/química , Fototerapia , Polímeros/química , Tratamiento del Conducto RadicularRESUMEN
J-aggregation is an efficient strategy for the development of fluorescent imaging agents in the second near-infrared window. However, the design of the second near-infrared fluorescent J-aggregates is challenging due to the lack of suitable J-aggregation dyes. Herein, we report meso-[2.2]paracyclophanyl-3,5-bis-N,N-dimethylaminostyrl BODIPY (PCP-BDP2) as an example of BODIPY dye with J-aggregation induced the second near-infrared fluorescence. PCP-BDP2 shows an emission maximum at 1010 nm in the J-aggregation state. Mechanism studies reveal that the steric and conjugation effect of the PCP group on the BODIPY play key roles in the J-aggregation behavior and photophysical properties tuning. Notably, PCP-BDP2 J-aggregates can be utilized for lymph node imaging and fluorescence-guided surgery in the nude mouse, which demonstrates their potential clinical application. This study demonstrates BODIPY dye as an alternate J-aggregation platform for developing the second near-infrared imaging agents.
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Compuestos de Boro/química , Colorantes Fluorescentes/química , Microscopía Intravital/métodos , Imagen Óptica/métodos , Neoplasias Peritoneales/diagnóstico por imagen , Animales , Compuestos de Boro/administración & dosificación , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Fluorescencia , Colorantes Fluorescentes/administración & dosificación , Humanos , Rayos Infrarrojos , Sistema Linfático/diagnóstico por imagen , Ratones , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , Cirugía Asistida por Video/métodosRESUMEN
Nitric oxide (NO) is an important signaling molecule overexpressed in many diseases, thus the development of NO-activatable probes is of vital significance for monitoring related diseases. However, sensitive photoacoustic (PA) probes for detecting NO-associated complicated diseases (e.g., encephalitis), have yet to be developed. Herein, we report a NO-activated PA probe for in vivo detection of encephalitis by tuning the molecular geometry and energy transformation processes. A strong donor-acceptor structure with increased conjugation can be obtained after NO treatment, along with the active intramolecular motion, significantly boosting "turn-on" near-infrared PA property. The molecular probe exhibits high specificity and sensitivity towards NO over interfering reactive species. The probe is capable of detecting and differentiating encephalitis in different severities with high spatiotemporal resolution. This work will inspire more insights into the development of high-performing activatable PA probes for advanced diagnosis by making full use of intramolecular motion and energy transformation processes.
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Técnicas Biosensibles/métodos , Encefalitis/diagnóstico , Encefalitis/metabolismo , Óxido Nítrico/aislamiento & purificación , Técnicas Fotoacústicas/métodos , Animales , Técnicas Biosensibles/instrumentación , Modelos Animales de Enfermedad , Encefalitis/patología , Masculino , Ratones , Imagen Molecular/métodos , Sondas Moleculares/química , Técnicas Fotoacústicas/instrumentaciónRESUMEN
Photothermal conversion nanoagents based on conjugated polymers (CPs) are attracting increasing attention for in vivo disease theranostics and high-performing ones are in urgent pursuit. Herein, we report a new and non-donor-acceptor approach to photothermal conversion CPs that combine several merits including low bandgaps, strong near-infrared absorption, low intersystem crossing rate and non-emissive nature. Three CPs based on 6,7; 6',7'-fused isoindigos (nIIDs), i.e., P2IIDV, P3IIDV and P4IIDV that have optical bandgaps of 1.30, 1.22 and 1.17 eV, respectively, are synthesized. The nanoparticles (NPs) of the CPs in water are prepared via nanocoprecipitation, which are non-fluorescent due to the rapid intramolecular twisting in the CP backbone within NPs, enabling most of the excitation energy flow to generate heat. The photothermal conversion efficiencies of the NPs as measured under irradiation at 808, 880 and 980 nm are 62.4%, 40.5% and 15.8% for P2IIDV, 65.1%, 41.0% and 38.9% for P3IIDV and 71.5%, 48.9% and 41.7% for P4IIDV, which are significantly higher than indocyanine green and many popularly reported photothermal conversion materials. In vivo studies using xenograft 4T1 tumor-bearing mouse model demonstrate that the P4IIDV NPs can serve as a rather effective photothermal conversion nanoagent for enhanced photoacoustic imaging and photothermal therapy of tumors.
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Nanopartículas , Técnicas Fotoacústicas , Animales , Ratones , Fototerapia , Polimerizacion , PolímerosRESUMEN
Organic near-infrared (NIR) emitters with simultaneously high absorption coefficient and photoluminescence quantum yield (PLQY) are highly desirable for biomedical imaging yet seldom reported because these two aspects are usually contradictory. The conjugated planar structures exhibit strong absorption but the emission is seriously quenched in aggregate state, whereas the twisted unplanar molecules display opposite phenomena. Herein, we report a kind of dragonfly-shaped NIR aggregation-induced emission luminogen (AIEgen) with both high absorption coefficient (6.24 × 104 M-1 cm-1) and superior PLQY (51.2%) for precise image-guided cancer surgery. The compound possessing a conjugated structure with vibrational substitutes has been synthesized, in which the good conjugation enables strong absorption, and the molecular vibration affords AIE signature. Moreover, the nonfluorescent processes are significantly suppressed, making every effort to boost fluorescence. The highly bright and stable AIE nanoparticles warrant efficient in vitro cellular imaging and in vivo tumor imaging. Moreover, the fluorescence imaging-guided cancer surgery helps to precisely delineate tiny tumor nodules, significantly improving the cancer surgery outcome. This work will inspire more insights into the development of organic NIR emitters with high brightness for biomedical applications.
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Nanopartículas , Neoplasias , Odonata , Animales , Fluorescencia , Colorantes FluorescentesRESUMEN
Organic near-infrared (NIR) emitters hold great promise for biomedical applications. Yet, most organic NIR fluorophores face the limitations of short emission wavelengths, low brightness, unsatisfactory processability, and the aggregation-caused quenching effect. Therefore, development of effective molecular design strategies to improve these important properties at the same time is a highly pursued topic, but very challenging. Herein, aggregation-induced emission luminogens (AIEgens) are employed as substituents to simultaneously extend the conjugation length, boost the fluorescence quantum yield, and increase the solubility of organic NIR fluorophores, being favourable for biological applications. A series of donor-acceptor type compounds with different substituent groups (i.e., hydrogen, phenyl, and tetraphenylethene (TPE)) are synthesized and investigated. Compared to the other two analogs, MTPE-TP3 with TPE substituents exhibits the reddest fluorescence, highest brightness, and best solubility. Both the conjugated structure and twisted conformation of TPE groups endow the resulting compounds with improved fluorescence properties and processability for biomedical applications. The in vitro and in vivo applications reveal that the NIR nanoparticles function as a potent probe for tumour imaging. This study would provide new insights into the development of efficient building blocks for improving the performance of organic NIR emitters.
RESUMEN
Stem cell-based therapies have emerged as promising platforms with the potential to treat serious diseases that are incurable by traditional medical approaches. To optimize the overall outcomes, it is important to understand the fate of transplanted stem cells (e.g., localization, migration, engraftment, survival, proliferation and differentiation). Fluorescent nanoparticles with good photostability and minimal perturbation of cell functions hold great promise for distinguishing transplanted stem cells from host tissues with high resolution, showing advantages over traditional histological methods. This review aims to summarize the recent advances in the use of fluorescent nanoparticles for the direct labelling of stem cells and the applications of such nanoparticles in stem cell tracking. The relevant fluorescent nanoparticles, including quantum dots, organic fluorogen-doped nanoparticles, fluorescent nanodiamonds, and upconversion nanoparticles are discussed. The advantages and limitations of the currently available fluorescent trackers are summarized, and perspectives on new research opportunities are discussed.