Conspectus Theranostic nanolights refer to luminescent nanoparticles possessing both imaging and therapeutic functions. Their shape, size, surface functions, and optical properties can be precisely ...manipulated through integrated efforts of chemistry, materials, and nanotechnology for customized applications. When localized photons are used to activate both imaging and therapeutic functions such as photodynamic or photothermal therapy, these theranostic nanolights increase treatment efficacy with minimized damage to surrounding healthy tissues, which represents a promising noninvasive nanomedicine as compared to conventional theranostic approaches. As one of the most promising theranostic nanolights, organic dots with aggregation-induced emission (AIE dots) are biocompatible nanoparticles with a dense core of AIE fluorogens (AIEgens) and protective shells, whose sizes are in the range of a few to tens of nanometers. Different from conventional fluorophores that suffer from aggregation-caused quenching (ACQ) due to π–π stacking interaction in the aggregate state, AIEgens emit strongly as nanoaggregates due to the restriction of intramolecular motions. Through precise molecular engineering, AIEgens could also be designed to show efficient photosensitizing or photothermal abilities in the aggregate state. Different from ACQ dyes, AIEgens allow high loading in nanoparticles without compromised performance, which makes them the ideal cores for theranostic nanolights to offer high brightness for imaging and strong photoactivities for theranostic applications. In this Account, we summarize the recent advance of AIE dots and highlight their great potential as theranostic nanolights in biomedical applications. Starting from the design of AIEgens, the fabrication of AIE dots and their bioimaging applications are discussed. The exceptional advantages of superbrightness, high resistance to photobleaching, lack of emission intermittency, and excellent biocompatibility have made them reliable cross platform contrast agents for different imaging techniques such as confocal microscopy, multiphoton fluorescence microscopy, super-resolution nanoscopy, and light-sheet ultramicroscopy, which have been successfully applied for cell tracking, vascular disease diagnosis, and image-guided surgery. The integration of therapeutic functions with customized AIEgens has further empowered AIE dots as an excellent theranostic platform for image-guided phototherapy. Of particular interest is AIE photosensitizer dots, which simultaneously show bright fluorescence and high photosensitization, yielding superior performance to commercial photosensitizer nanoparticles in image-guided therapy. Further development in multiphoton excited photodynamic therapy has offered precise treatment with up to 5 μm resolution at 200 μm depth, while chemiexcited photodynamic therapy has completely eliminated the limitation of penetration depth to realize power-free imaging and therapy. With this Account, we hope to stimulate more collaborative research interests from different fields of chemistry, materials, biology, and medicine to promote translational research of AIE dots as the theranostic nanolights.
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IJS, KILJ, NUK, PNG, UL, UM
The combination of diagnosis and therapeutics into one theranostics system has attracted great interest in life science and biomedical fields. The current theranostic platform largely relies on the ...integration of multiple materials with different functionalities. The all‐in‐one approach has the risk of high complicity with reduced reproducibility. Smart design of simple molecules born with multifunctions should represent one of the future directions in theranostics. Fluorogens with aggregation‐induced emission (AIEgens) are one type of such smart materials, which have attracted increasing attentions in recent years. In this concept, the key frontier developments of simple AIEgens with multifunctions for imaging and therapy are presented, which include fluorescence‐photoacoustic imaging, fluorescence‐magnetic resonance imaging, fluorescence image‐guided photodynamic therapy, fluorescence image‐guided chemotherapy and photoacoustic image‐guided photothermal therapy. The smart molecular design to endow each AIEgen with strong capability to simultaneously offer two or more theranostic functions should attract more scientists into this exciting research direction.
Fluorogens with aggregation‐induced emission (AIEgens) can inherently possess multiple imaging and therapeutic functions in a single molecule through elegant molecular design. This simple and powerful ‘one‐for‐all’ approach demonstrates one of the future directions for the development of functional materials for future theranostics, which represents an exciting field awaiting further exploration.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A multifunctional theranostic platform based on conjugated polymer nanoparticles (CPNs) with tumor targeting, fluorescence detection, photodynamic therapy (PDT), and photothermal therapy (PTT) is ...developed for effective cancer imaging and therapy. Two conjugated polymers, poly9,9‐bis(2‐(2‐(2‐methoxyethoxy)ethoxy)‐ethyl)fluorenyldivinylene‐alt‐4,7‐(2,1,3‐benzothiadiazole) with bright red emission and photosensitizing ability and poly(4,4,9,9‐tetrakis(4‐(octyloxy)phenyl)‐4,9‐dihydro‐s‐indacenol‐dithiophene‐2,7‐diyl)‐alt‐co‐4,9‐bis(thiophen‐2‐yl)‐6,7‐bis(4‐(hexyloxy)phenyl)‐thiadiazolo‐quinoxaline with strong near‐infrared absorption and excellent photothermal conversion ability are co‐loaded into one single CPN via encapsulation approach using lipid‐polyethylene glycol as the matrix. The obtained co‐loaded CPNs show sizes of around 30 nm with a high singlet oxygen quantum yield of 60.4% and an effective photothermal conversion efficiency of 47.6%. The CPN surface is further decorated with anti‐HER2 affibody, which bestows the resultant anti‐HER2‐CPNs superior selectivity toward tumor cells with HER2 overexpression both in vitro and in vivo. Under light irradiation, the PDT and PTT show synergistic therapeutic efficacy, which provides new opportunities for the development of multifunctional biocompatible organic materials in cancer therapy.
Multifunctional conjugated polymer nanoparticles (CPNs) are developed for image‐guided phototherapy. With bright red fluorescence, efficient singlet oxygen generation, and excellent photothermal conversion abilities, the affibody decorated CPNs show excellent tumor targeting and synergistic therapeutic efficacy through the corporation of photodynamic and photothermal therapy both in vitro and in vivo.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The pursuing of photosensitizers (PSs) with efficient reactive oxygen species (ROS) especially type I ROS generation in aggregate is always in high demand for photodynamic therapy (PDT) and ...photoimmunotherapy but remains to be a big challenge. Herein, we report a cationization molecular engineering strategy to boost both singlet oxygen and radical generation for PDT. Cationization could convert the neutral donor-acceptor (D-A) typed molecules with the dicyanoisophorone-triphenylamine core (DTPAN, DTPAPy) to their A-D-A′ typed cationic counterparts (DTPANPF6 and DTPAPyPF6). Our experiment and simulation results reveal that such cationization could enhance the aggregation-induced emission (AIE) feature, promote the intersystem crossing (ISC) processes, and increase the charge transfer and separation ability, all of which work collaboratively to promote the efficient generation of ROS especially hydroxyl and superoxide radicals in aggregates. Moreover, these cationic AIE PSs also possess specific cancer cell mitochondrial targeting capability, which could further promote the PDT efficacy both in vitro and in vivo. Therefore, we expect this delicate molecular design represents an attractive paradigm to guide the design of type I AIE PSs for the further development of PDT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In modern medicine, precision diagnosis and treatment using optical materials, such as fluorescence/photoacoustic imaging-guided photodynamic therapy (PDT), are becoming increasingly popular. ...Photosensitizers (PSs) are the most important component of PDT. Different from conventional PSs with planar molecular structures, which are susceptible to quenching effects caused by aggregation, the distinct advantages of AIE fluorogens open up new avenues for the development of image-guided PDT with improved treatment accuracy and efficacy in practical applications. It is critical that as much of the energy absorbed by optical materials is dissipated into the pathways required to maximize biomedical applications as possible. Intersystem crossing (ISC) represents a key step during the energy conversion process that determines many fundamental optical properties, such as increasing the efficiency of reactive oxygen species (ROS) production from PSs, thus enhancing PDT efficacy. Although some review articles have summarized the accomplishments of various optical materials in imaging and therapeutics, few of them have focused on how to improve the phototherapeutic applications, especially PDT, by adjusting the ISC process of organic optics materials. In this review, we emphasize the latest advances in the reasonable design of AIE-active PSs with type I photochemical mechanism for anticancer or antibacterial applications based on ISC modulation, as well as discuss the future prospects and challenges of them. In order to maximize the anticancer or antibacterial effects of type I AIE PSs, it is the aim of this review to offer advice for their design with the best energy conversion.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A highly emissive far‐red/near‐infrared (FR/NIR) fluorescent conjugated polymer (CP), poly(9,9‐dihexylfluorene)‐co‐2,1,3‐benzothiadiazole‐co‐4,7‐di(thiophen‐2‐yl)‐2,1,3‐benzothiadiazole (PFBTDBT10) ...is designed and synthesized via Suzuki polymerization. Formulation of PFBTDBT10 using 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐methoxy(polyethylene glycol)‐2000 (DSPE‐PEG2000) and DSPE‐PEG5000‐folate as the encapsulation matrix yielded CP‐loaded DSPE‐PEG‐folic acid nanoparticles (CPDP‐FA NPs) with bright FR/NIR fluorescence (27% quantum yield) and a large Stoke's shift of 233 nm in aqueous solution. CPDP‐FA NPs show improved thermal/photostabilities and larger Stoke's shifts as compared to commercially available quantum dots (Qdot 655) and organic dyes such as Alexa Fluor 555 and Rhodamine 6G. In vivo studies of CPDP‐FA NPs on a hepatoma H22 tumor‐bearing mouse model reveal that they could serve as an efficient FR/NIR fluorescent probe for targeted in vivo fluorescence imaging and cancer detection in a high contrast and specific manner. Together with the negligible in vivo toxicity, CPDP‐FA NPs are promising FR/NIR fluorescent probes for future in vivo applications.
Bright far‐red/near‐infrared conjugated polymer nanoparticles with surface folate ligand and 27% quantum yield in aqueous media are synthesized via a one‐step lipid‐PEG‐folate formulation. The obtained nanoparticles show good thermal/photostabilities and a large Stoke's shift, which compare favorably with commercially available quantum dots (Qdot 655) and organic dyes (Alexa Fluor 555 and Rhodamine 6G), making them a safe and efficient FR/NIR fluorescent probe for targeted in vivo fluorescence imaging and cancer detection in a high contrast and specific manner.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The isomerization and optical properties of the cis and trans isomers of tetraphenylethene (TPE) derivatives with aggregation‐induced emission (AIEgens) have been sparsely explored. We have now ...observed the tautomerization‐induced isomerization of a hydroxy‐substituted derivative, TPETH‐OH, under acidic but not under basic conditions. Replacing the proton of the hydroxy group in TPETH‐OH with an alkyl group leads to the formation of TPETH‐MAL, for which the pure cis and trans isomers were obtained and characterized by HPLC analysis and NMR spectroscopy. Importantly, cis‐TPETH‐MAL emits yellow fluorescence in DMSO at −20 °C whereas trans‐TPETH‐MAL shows red fluorescence under the same conditions. Moreover, the geometry of cis‐ and trans‐TPETH‐MAL remains unchanged when they undergo thiol–ene reactions to form cis‐ and trans‐TPETH‐cRGD, respectively. Collectively, our findings improve our fundamental understanding of the cis/trans isomerization and photophysical properties of TPE derivatives, which will guide further AIEgen design for various applications.
The cis and trans isomers of a tetraphenylethene derivative with aggregation‐induced emission, TPETH‐MAL, were characterized by HPLC analysis and NMR spectroscopy. cis‐TPETH‐MAL emits yellow fluorescence in DMSO at −20 °C whereas trans‐TPETH‐MAL shows red fluorescence under the same conditions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Fluorescent photoswitchable conjugated polymer nanoparticles (PCPNPs) bearing poly(9,9-dihexylfluorene-
alt
-2,1,3-benzoxadiazole) (PFBD) as the fluorescent host polymer and the photochromic ...diarylethene as toggle are synthesized
via
a modified nano-precipitation method using 1,2-distearoyl-
sn
-glycero-3-phosphoethanolamine-
N
-amino(polyethylene glycol)-2000 (DSPE-PEG-NH
2
) as the encapsulation matrix. The PCPNPs are spherical in shape with diameters around 34 nm. The fluorescence switching processes upon UV and white light illumination are successfully demonstrated with high contrast up to 90-fold, recovery efficiency of 95%, and excellent repeatability in solution. The cationic PCPNPs can be easily internalized into cancer cells, and accumulate in tumor tissues, where the fluorescence photoswitching processes can be used to self-validate the imaging results.
Fluorescent photoswitchable conjugated polymer nanoparticles for cell and
ex vivo
tumour imaging with fluorescence on/off contrast over 10-fold in tumour.
A series of BODIPY derivatives with tetraphenylethene (TPE) moieties were designed and synthesized. The effect of positions and numbers of substitution groups on the fluorescence of the BODIPYs was ...investigated. Theoretical calculation and single crystal structures proved that the TPE substitution groups on the 8-position of BODIPY contributed little to the conjugation, but benefited the aggregated state emission. On the other hand, the substitutions on the 3- or 5-position of BODIPY through vinyl bridges increased the conjugation length, and generated big coplanar π-conjugated structures with poor aggregated state emission. The compound with bright aggregated state emission has been further fabricated into biocompatible fluorescent nanoparticles and used as effective fluorescent contrast agents for intracellular imaging.
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IJS, KILJ, NUK, PNG, UL, UM
Transferrin receptor (TfR) represents a unique target for specific imaging of cancer cells and targeted delivery of therapeutic reagents. Detection and qualification of TfR is thus of great ...importance for cancer diagnosis and therapy. In this contribution, a light-up probe TPETH-2T7 was developed by conjugating a red-emissive photosensitizer with aggregation-induced emission (AIE) characteristics to a TfR-targeting peptide T7. The probe is almost nonemissive by itself, but it gives turn-on fluorescence in the presence of TfR with a detection limit of 0.45 μg/mL. Cellular experiments show that the probe specifically binds to TfR-overexpressed cancer cells. Real-time imaging results reveal that the probe stains the MDA-MB-231 cell membrane in 30 min, which is followed by probe internalization. Experiments on image-guided photodynamic cancer ablation show that the therapeutic performance is better when TPETH-2T7 is localized on the cell membrane as compared to that being internalized into cells. Confocal laser scanning microscopy (CLSM) study reveals that cytomembrane disintegration allows quick ablation of MDA-MB-231 cells.
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