Inside Back Cover: A Near-Infrared Light-Activated Photocage Based on a Ruthenium Complex for Cancer Phototherapy (Angew. Chem. Int. Ed. 24/2023)

Conventional photocages only respond to short wavelength light, which is a significant obstacle to developing efficient phototherapy in vivo. The development of photocages activated by near-infrared (NIR) light at wavelengths from 700 to 950 nm is important for in vivo studies but remains challenging. Herein, we describe the synthesis of a photocage based on a ruthenium (Ru) complex with NIR light-triggered photocleavage reaction. The commercial anticancer drug, tetrahydrocurcumin (THC), was coordinated to the Ru^II center to create the Ru-based photocage that is readily responsive to NIR light at 760 nm. The photocage inherited the anticancer properties of THC. As a proof-of-concept, we further engineered a self-assembled photocage-based nanoparticle system with amphiphilic block copolymers. Upon exposure to NIR light at 760 nm, the Ru complex-based photocages were released from the polymeric nanoparticles and efficiently inhibited tumor proliferation in vivo.     

An enzyme-responsive metal-enhanced near-infrared fluorescence sensor based on functionalized gold nanoparticles

Near-infrared (NIR) fluorescence imaging is promising due to the high penetration depths and minimal levels of autofluorescence in living systems. However, it suffers from low fluorescent quantum yield, and metal-enhanced fluorescence (MEF) is considered to be a promising technique to overcome this. Stimuli-responsive NIR fluorescence enhancement shows remarkable potential for applications in medical imaging and diagnosis. Herein, we successfully fabricated an enzyme-responsive near-infrared sensor based on MEF by functionalizing gold nanoparticles with NIR fluorophores and enzyme-responsive self-aggregation moieties. The NIR fluorescence of fluorophores on the gold nanoparticles was significantly enhanced due to increases both in the light scattering intensity and in the radiative decay rate (k _r) of the NIR fluorophores, along with relatively small variation in the nonradiative decay rate. This novel strategy for NIR fluorescent sensors should be particularly promising for NIR fluorescence imaging of enzyme activities and early diagnosis based on rationally designed nanomaterials.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

Stable Near-infrared-emitting Radical Nanoparticles for Fluorescence Imaging

Stable neutral luminescent radicals with unpaired electrons exhibit unique spin-allowed doublet-doublet transitions, which has attracted significant attention. Although they are pure organic molecules without metal ions thus thought to have low biological toxicity, the application of luminescent radicals to bioimaging has rarely been reported. Here, a stable radical with efficient near-infrared(NIR) emission and good photostability was designed and synthesized. After being wrapped into nanoparticles, it was applied to cell fluorescence imaging. The cytotoxicity experiments suggested that the nanoparticles have remarkable biocompatibility and excellent stability. An NIR fluorescent signal was successfully observed in the cytoplasm of HCT116 cells. The experimental results gave the first example of NIR emitting radical nanoparticles for cell fluorescence imaging and proved the feasibility of the application of luminescent radicals to fluorescence imaging.     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

Fluorescent Phthalocyanine-Encapsulated Bovine Serum Albumin Nanoparticles: Their Deployment as Therapeutic Agents in the NIR Region

In recent times, researchers have aimed for new strategies to combat cancer by the implementation of nanotechnologies in biomedical applications. This work focuses on developing protein-based nanoparticles loaded with a newly synthesized NIR emitting and absorbing phthalocyanine dye, with photodynamic and photothermal properties. More precisely, we synthesized highly reproducible bovine serum albumin-based nanoparticles (75% particle yield) through a two-step protocol and successfully encapsulated the NIR active photosensitizer agent, achieving a good loading efficiency of 91%. Making use of molecular docking simulations, we confirm that the NIR photosensitizer is well protected within the nanoparticles, docked in site I of the albumin molecule. Encouraging results were obtained for our nanoparticles towards biomedical use, thanks to their negatively charged surface (−13.6 ± 0.5 mV) and hydrodynamic diameter (25.06 ± 0.62 nm), favorable for benefitting from the enhanced permeability and retention effect; moreover, the MTT viability assay upholds the good biocompatibility of our NIR active nanoparticles. Finally, upon irradiation with an NIR 785 nm laser, the dual phototherapeutic effect of our NIR fluorescent nanoparticles was highlighted by their excellent light-to-heat conversion performance (photothermal conversion efficiency 20%) and good photothermal and size stability, supporting their further implementation as fluorescent therapeutic agents in biomedical applications.     

Fabrication of Mesoporous‐Silica‐Coated Upconverting Nanoparticles with Ultrafast Photosensitizer Loading and 808 nm NIR‐Light‐Triggering Capability for Photodynamic Therapy

A novel photodynamic therapy nanoplatform based on mesoporous‐silica‐coated upconverting nanoparticles (UCNP) with electrostatic‐driven ultrafast photosensitizer (PS) loading and 808 nm near infrared (NIR)‐light‐triggering capabilities has been fabricated. By positively charging inner channels of the mesoporous silica shell with amino groups, a quantitative dosage of negatively charged PS, exemplified with Rose Bengal (RB) molecules, can be loaded in 2 min. In addition, the electrostatic‐driven technique simultaneously provides the platform with both excellent PS dispersity and leak‐proof properties due to the repulsion between the same‐charged molecules and the electrostatic attraction between different‐charged PS and silica channel walls, respectively. The as‐coated silica shell with an ultrathin thickness of 12±2 nm is delicately fabricated to facilitate ultrafast PS loading and efficient energy transfer from UCNP to PS. The outside surface of the silica shell is capped with hydrophilic β‐cyclodextrin, which not only enhances the dispersion of resulting nanoparticles in water but also plays a role of “gatekeeper”, blocking the pore opening and preventing PS leaking. The in vitro cellular lethality experiment demonstrates that RB molecules can be activated to effectively generate singlet oxygen and kill cancer cells upon 808 nm NIR light irradiation.     

Preparation and Characterization of Uniform Near IR Polystyrene Nanoparticles

Biomaterials for in vivo fluorescence imaging are required to be biocompatible, nontoxic, photostable and highly fluorescent. Fluorescence must be in the near infrared (NIR) region of the electromagnetic spectrum to avoid absorption and autofluorescence of endogenous tissues. NIR fluorescent polystyrene nanoparticles may be considered ideal biomaterials for in vivo imaging applications. These NIR nanoparticles were prepared by a swelling process of polystyrene template nanoparticles with a hydrophobic NIR dye dissolved in a water‐miscible swelling solvent, a method developed for preparation of nonbiodegradable nanoparticles, for NIR fluorescent bioimaging applications. This method overcomes common problems that occur with dye entrapment during nanoparticle formation such as loss of fluorescence and size polydispersity. Fluorescence intensity of the nanoparticles was found to be size dependent, and was optimized for differently sized nanoparticles. The resulting NIR nanoparticles were also found to be more fluorescent and highly photostable compared to the free dye in solution, showing their potential as biomaterials for in vivo fluorescence imaging.     

具有聚集诱导发光性质的近红外荧光染料

聚集诱导发光(AIE)现象的发现为解决传统有机荧光分子在高浓度和聚集形态下存在的荧光猝灭问题提供了最佳方案,并实现了在光电器件、化学传感、生物成像和靶向治疗等众多领域的广泛应用.随着对AIE 发光机理研究的不断深入,AIE 分子体系得到了极大的扩展.其中,一类具有给体-受体结构的AIE分子能够显著降低分子能隙,使发光分...     

Disassembly‐Driven Fluorescence Turn‐on of Polymerized Micelles by Reductive Stimuli in Living Cells

Stimuli‐response nanoparticles have emerged as powerful tools for imaging and therapeutic applications. Ideally, they should be assembled from biodegradable materials featuring small size and cooperative response to biological stimuli that trigger particle disassembly and release of an active molecule that could be readily monitored in situ. A concept is developed that consists of organic nanoparticles, assembled from fluorescent amphiphiles and polymerized with a redox‐cleavable cross‐linker. We obtained 20 nm nanoparticles bearing self‐quenched Nile Red dye residues, which can disassemble in living cells into highly fluorescent molecular units owing to an external or internal reductive stimulus. The obtained results pave the way to new stimuli‐responsive nanomaterials for applications in background‐free imaging as well as in drug delivery, as the concept can be further extended to other active molecules including drugs and to cross‐linkers cleavable by other biological stimuli.     

Near‐Infrared Light and pH‐Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo‐Photothermal Cancer Therapy

We have rationally designed a new theranostic agent by coating near‐infrared (NIR) light‐absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO₂ NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO₂) core–shell NPs. Meanwhile, DOX‐loaded PPY@PAA/fmSiO₂ NPs as pH and NIR dual‐sensitive drug delivery vehicles were employed for fluorescence imaging and chemo‐photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO₂ NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo‐photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH‐stimuli responsive PPY‐based multifunctional platform for cancer theranostics.     

Biocompatible organic dots with aggregation-induced emission for in vitro and in vivo fluorescence imaging

Fluorescent probes play a key role in modern biomedical research. As compared to inorganic quantum dots (QDs) composed with heavy metal elements, organic dye-based fluorescent nanoparticles have higher biocompatibility and are richer in variety. However, traditional organic fluorophores tend to quench fluorescence upon aggregation, which is known as aggregation-caused quenching (ACQ) effect that hinders the fabrication of highly emissive fluorescent nanoparticles. In this work, we demonstrate the synthesis of organic fluorescent dots with aggregation-induced emission (AIE) in far-red/near-infrared (FA/NIR) region. A conventional ACQ-characteristic fluorescent dye, 3,4:9,10-tetracarboxylic perylene bisimide (PBI), is converted into an AIE fluorogen through attaching two tetraphenylethylene (TPE) moieties. The fluorescent dots with surface folic acid groups are fabricated from PBI derivative (DTPEPBI), showing specific targeting effect to folate receptor-overexpressed cancer cells. In vivo studies also suggest that the folic acid-functionalized AIE dots preferentially accumulate in the tumor site through enhanced permeability and retention (EPR) effect and folate receptor-mediated active targeting effect. The low cyto-toxicity, good FR/NIR contrast and excellent targeting ability in in vitro/in vivo imaging indicate that the AIE dots have great potentials in advanced bioimaging applications.     

C=C Bond Oxidative Cleavage of BODIPY Photocages by Visible Light

Photocages for protection and the controlled release of bioactive compounds have been widely investigated. However, the vast majority of these photocages employ the cleavage of single bonds and high-energy ultraviolet light. The construction of a photoactivation system that uses visible light to cleave unsaturated bonds still remains a challenge. Herein, we report a regioselective oxidative cleavage of C=C bonds from a boron-dipyrrolemethene (BODIPY)-based photocage by illumination at 630 nm, resulting in a free aldehyde and a thiol fluorescent probe. This strategy was demonstrated in live HeLa cells, and the generated α-formyl-BODIPY allowed real-time monitoring of aldehyde release in the cells. In particular, it is shown that a mannose-functionalized photocage can target HepG2 cells.     

光笼分子与材料研究进展

光笼(photocage)是一种用于光控释放的光敏物质,是以物理和化学等方法将目标释放物与光敏基团及其他功能基团结合形成的对光敏感的物质,在指定波段的光照射线下,光笼能够实现目标物的可控释放.因其具备时空调控、操作简单、易于控制、可修饰性强和对机体损伤小等优点,使其广泛应用在化学、生物学、材料学和医学等领域.本综述介绍...     

Near‐Infrared Light‐Mediated Photoactivation of a Platinum Antitumor Prodrug and Simultaneous Cellular Apoptosis Imaging by Upconversion‐Luminescent Nanoparticles

Platinum‐based drugs are among the most active antitumor reagents in clinical practice; their application is limited by side effects and drug resistance. A novel and personalized near‐infrared (NIR) light‐activated nanoplatform is obtained by combining a photoactivatable platinum(IV) prodrug and a caspase imaging peptide conjugated with silica‐coated upconversion‐luminescent nanoparticles (UCNPs) for the remote control of antitumor platinum prodrug activation, and simultaneously for real‐time imaging of apoptosis induced by activated cytotoxicity. Upon NIR light illumination, the Pt^IV prodrug complex is activated at the surface of the nanoparticle and active components are selectively released which display cytotoxicity against human ovarian carcinoma A2780 cells and its cisplatin‐resistant variant A2780cis cells. More importantly, the caspases enzymes triggered by cytotoxicity would effectively cleave the probe peptide, thereby allowing the direct imaging of apoptosis in living cells.     

Near‐Infrared Optogenetic Genome Engineering Based on Photon‐Upconversion Hydrogels

Photon upconversion (UC) from near‐infrared (NIR) light to visible light has enabled optogenetic manipulations in deep tissues. However, materials for NIR optogenetics have been limited to inorganic UC nanoparticles. Herein, NIR‐light‐triggered optogenetics using biocompatible, organic TTA‐UC hydrogels is reported. To achieve triplet sensitization even in highly viscous hydrogel matrices, a NIR‐absorbing complex is covalently linked with energy‐pooling acceptor chromophores, which significantly elongates the donor triplet lifetime. The donor and acceptor are solubilized in hydrogels formed from biocompatible Pluronic F127 micelles, and heat treatment endows the excited triplets in the hydrogel with remarkable oxygen tolerance. Combined with photoactivatable Cre recombinase technology, NIR‐light stimulation successfully performs genome engineering resulting in the formation of dendritic‐spine‐like structures of hippocampal neurons.     

Far‐Red and Near‐IR AIE‐Active Fluorescent Organic Nanoprobes with Enhanced Tumor‐Targeting Efficacy: Shape‐Specific Effects

The rational design of high‐performance fluorescent materials for cancer targeting in vivo is still challenging. A unique molecular design strategy is presented that involves tailoring aggregation‐induced emission (AIE)‐active organic molecules to realize preferable far‐red and NIR fluorescence, well‐controlled morphology (from rod‐like to spherical), and also tumor‐targeted bioimaging. The shape‐tailored organic quinoline–malononitrile (QM) nanoprobes are biocompatible and highly desirable for cell‐tracking applications. Impressively, the spherical shape of QM‐5 nanoaggregates exhibits excellent tumor‐targeted bioimaging performance after intravenously injection into mice, but not the rod‐like aggregates of QM‐2.     

Recent development in near infrared light-responsive polymeric materials for smart drug-delivery systems

Stimuli-responsive drug delivery systems (DDS) may overcome the drawbacks of conventional chemotherapy for cancer treatment. In particular, light-responsive polymer-based DDS may ensure spatio and temporal control in drug delivery. In this regard, near infrared (NIR) light triggered drug nanocarriers present several advantages when compared to UV–visible light triggered nanocarriers. This review surveys the recent development on the design, synthesis, functions, and applications of NIR photo-sensitive compounds in the development of long-wavelength light-responsive nanocarriers. Diverse NIR light responsive groups such as coumarin (CM), ortho-nitrobenzyl (ONB), 2-diazo-1,2-naphthoquinone (DNQ) and spiropyran (SP) derivatives and their photo-cleavage reaction mechanisms are discussed, as well as the use of indocyanine green (ICG) and its photo-thermal application. The loading into polymeric nanocarriers of up converting nanoparticles (UCNPs) which can convert NIR light into UV or visible light is also discussed. The described DDS are classified on the basis on the photo responsive groups. In details, the behavior of different polymeric materials such as micelles, hydrogels bearing photo responsive groups linked to bioactive molecules which are released under NIR light irradiation is reviewed and discussed. A section relative to commonly used instrument setup for drug release studies by NIR light irradiation is also presented for better understanding how the light has been used to irradiate in various experimental situations.     

An Efficient Near‐Infrared Emissive Artificial Supramolecular Light‐Harvesting System for Imaging in the Golgi Apparatus

Light‐harvesting systems are an important way for capturing, transferring and utilizing light energy. It remains a key challenge to develop highly efficient artificial light‐harvesting systems. Herein, we report a supramolecular co‐assembly based on lower‐rim dodecyl‐modified sulfonatocalix[4]arene (SC4AD) and naphthyl‐1,8‐diphenyl pyridinium derivative (NPS) as a light‐harvesting platform. NPS as a donor shows significant aggregation induced emission enhancement (AIEE) after assembling with SC4AD. Upon introduction of Nile blue (NiB) as an acceptor into the NPS‐SC4AD co‐assembly, the light‐harvesting system becomes near‐infrared (NIR) emissive (675 nm). Importantly, the NIR emitting NPS‐SC4AD‐NiB system exhibits an ultrahigh antenna effect (33.1) at a high donor/acceptor ratio (250:1). By co‐staining PC‐3 cells with a Golgi staining reagent, NBD C₆‐ceramide, NIR imaging in the Golgi apparatus has been demonstrated using these NIR emissive nanoparticles.     

Thiol-Responsive Gold Nanodot Swarm with Glycol Chitosan for Photothermal Cancer Therapy

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.