Fluorescence Imaging-guided Photodynamic Therapy Research Articles

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

Rationally Designed Benzobisthiadiazole-Based Covalent Organic Framework for High-Performance NIR-II Fluorescence Imaging-Guided Photodynamic Therapy.

Although being applied as photosensitizers for photodynamic therapy, covalent organic frameworks (COFs) fail the precise fluorescence imaging in vivo and phototherapy in deep-tissue, due to short excitation/emission wavelengths. Herein, this work proposes the first example of NIR-II emissive and benzobisthiadiazole-based COF-980. Comparing to its ligands, the structure of COF-980 can more efficiently reducing the energy gap (ΔES1-T1) between the excited state and the triplet state to enhance photodynamic therapy efficiency. Importantly, COF-980 demonstrates high photostability, good anti-diffusion property, superior reactive oxygen species (ROS) generation efficiency, promising imaging ability, and ROS production in deep tissue (≈8mm). Surprisingly, COF-980 combined with laser irradiation could trigger larger amount of intracellular ROS to high efficiently induce cancer cell death. Notably, COF-980 NPs precisely enable PDT guided by NIR-II fluorescence imaging that effectively inhibit the 4T1 tumor growth with negligible adverse effects. This study provides a universal approach to developing long-wavelength emissive COFs and exploits its applications for biomedicine.

Anion-π+ AIEgens for Fluorescence Imaging and Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (PDT) has attracted extensive attention due to its potential of real-time monitoring the lesion locations and visualizing the treatment process with high sensitivity and resolution. Aggregation-induced emission luminogens (AIEgens) show enhanced fluorescence and reactive oxygen species (ROS) generation after cellular uptake, giving them significant advantages in bioimaging and PDT applications. However, most AIEgens are unfavorable for the application in organisms due to their severe hydrophobicity. Anion-π+ type AIEgens carry intrinsic charges that can effectively alleviate their hydrophobicity and improve their binding capability to cells, which is expected to enhance the bioimaging quality and PDT performance. This concept summarizes the applications of anion-π+ type AIEgens in fluorescence imaging, fluorescence imaging-guided photodynamic anticancer and antimicrobial therapy in recent years, hoping to provide some new ideas for the construction of robust photosensitizers. Finally, the current problems and future challenges of anion-π+ AIEgens are discussed.

Rational design of biodegradable semiconducting polymer nanoparticles for NIR-II fluorescence imaging-guided photodynamic therapy

Rational design of biodegradable semiconducting polymer nanoparticles for NIR-II fluorescence imaging-guided photodynamic therapy

Recent advances in aggregation-induced emission-active type I photosensitizers with near-infrared fluorescence: From materials design to therapeutic platform fabrication.

Near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) technology plays an important role in treating various diseases and still attracts increasing research interests for developing novel photosensitizers (PSs) with outstanding performances. Conventional PSs such as porphyrin and rhodamine derivatives have easy self-aggregation properties in the physiological environment due to their inherent hydrophobic nature caused by their rigid molecular structure that induces strong intermolecular stacking π-π interaction, leading to serious fluorescence quenching and cytotoxic reactive oxygen species (ROS) reduction. Meanwhile, hypoxia is an inherent barrier in the microenvironment of solid tumors, seriously restricting the therapeutic outcome of conventional PDT. Aforementioned disadvantages should be overcome urgently to enhance the therapeutic effect of PSs. Novel NIR fluorescence-guided type I PSs with aggregation-induced emission (AIE), which features the advantages of improving fluorescent intensity and ROS generation efficiency at aggregation as well as outstanding oxygen tolerance, bring hope for resolving aforementioned problems simultaneously. At present, plenty of research works fully demonstrates the advancement of AIE-active PDT based on type I PSs. In this review, cutting-edge advances focusing on AIE-active NIR type I PSs that include the aspects of the photochemical mechanism of type I ROS generation, various molecular structures of reported type I PSs with NIR fluorescence and their design strategies, and typical anticancer applications are summarized. Finally, a brief conclusion is obtained, and the underlying challenges and prospects of AIE-active type I PSs are proposed.

Efficient type Ⅰ and type Ⅱ ROS generated aggregation-induced emission photosensitizer for mitochondria targeted photodynamic therapy

Fluorescence imaging-guided photodynamic therapy (PDT) is considered as an ideal alternative strategy to treat tumors. However, insufficient supply of oxygen in solid tumor tissue, aggregation-caused quenching (ACQ) of photosensitizers (PSs), poor targeting-specificity of cancer cells and short wavelengths of emission are representative obstacles for effective PDT. In this paper, three D-π-A structured PSs TSB-OH, TSBPy-OH, TSBPy-DNT with aggregation induced emission (AIE) properties and integrated type I and type II ROS generation were synthesized by modulating distinct acceptor units. Among them, TSBPy-OH is optimal with multiple advantages including near-infrared emission, good biocompatibility, remarkably intracellular ROS production ability, mitochondria targeting capability inducing cell apoptosis and enhancing PDT, and long-term tumor retention ability for imaging-guided photodynamic therapy. More importantly, efficient in vitro cancer cells damage, in vivo tumor ablation and ignorable damage in major organs during PDT are demonstrated, suggesting potential capability of TSBPy-OH in safe and effective fluorescence imaging-guided PDT. This successful example of AIE theranostics design would provide a reference for the modification of D-π-A structure organic AIEgens.

FRET-based two-photon benzo[a] phenothiazinium photosensitizer for fluorescence imaging-guided photodynamic therapy

To overcome the conflict between the long-wavelength excitation and high singlet oxygen quantum yield of photosensitizers, we conjugated a two-photon fluorophore, tetrahydroquinoxaline coumarin (TQ), and an efficient photodynamic therapeutic agent, benzo[a]phenothiazinium (NBS-NH2), through a hexamethylene linker to build a two-photon photosensitizer, TQ-NBS. In TQ-NBS, TQ served as an energy donor and NBS-NH2 acted as an energy acceptor; and TQ-NBS was a Förster resonance energy transfer (FRET) cassette with a 92.8% efficiency. The large two-photon absorption cross-section of TQ allowed photosensitizer TQ-NBS to work in a 900 nm two-photon excitation (TPE) mode, which greatly benefited the deep tissue penetration in PDT treatment. Meanwhile, the excellent phototoxicity and near-infrared fluorescence of NBS-NH2 was kept in TQ-NBS under a TPE mode via a FRET process. Photosensitizer TQ-NBS exhibited a high phototoxic efficacy in living cells and tumor-bearing mice.

Multifunctional DNA nanosphere platform for real-time monitoring and fluorescence imaging-guided photodynamic therapy

The DNA nanosphere (DNS) is constructed through the assembly of multifunctional Y-scaffold DNA monomers, which encompass aptamers, RNA interferences, and photodynamic therapy agents. The DNS nanoplatform facilitates efficient cellular uptake via aptamer-mediated delivery. The RNA interferences inhibit the microRNA-21 and microRNA-155, thereby enabling precise imaging guidance for photodynamic therapy, ultimately leading to apoptosis in MCF-7 cells. The platform allows for real-time monitoring of the therapeutic process, presenting a more comprehensive approach to cancer treatment. The results of in vitro and in vivo studies suggest the potential of this multifunctional DNS platform as a promising approach for cancer therapy that can be tailored to individual patients based on their specific cancer type.

An aggregation-induced emission photosensitizer with efficient singlet oxygen generation capacity for mitochondria targeted photodynamic therapy

A family of near-infrared (NIR) aggregation-induced emission (AIE) photosensitizers (PSs) were designed and synthesized to modulate the spectroscopic and photochemical properties of the contained donor-acceptor (D-A) units. Stronger intermolecular charge transfer (ICT) states were promoted by the synergistic action of benzothiadiazoles and quinolines, which accelerates intersystem crossing (ISC). The best NIR AIE-PS, BTQ, showed an extremely high 1O2 generation rate (5.6-fold of Rose Bengal) and highly efficient photodynamic killing of cancer cells. Furthermore, the mechanism by which mitochondria-targeted PSs produce large amounts of reactive oxygen species (ROS) triggering calcium ion (Ca2+) overload and opening of the mitochondrial permeability transition pore (mPTP), thereby disrupting mitochondria and leading to apoptosis, was demonstrated for the first time. This work provides an exciting benchmark for the molecular engineering of AIE-PSs targeting mitochondria and presented new insights of the development of fluorescence imaging guided photodynamic therapy (FL-G-PDT).

A novel BODIPY-based nano-photosensitizer with aggregation-induced emission for cancer photodynamic therapy

The discovery of aggregation-induced emission (AIE) effect provides opportunities for the rapid development of fluorescence imaging-guided photodynamic therapy (PDT). In this work, a boron dipyrromethene (BODIPY)-based photosensitizer (ET-BDP-O) with AIE characteristics was developed, in which the two linear arms of BODIPY group were linked with triphenylamine to form an electron Donor–Acceptor–Donor (D–A–D) architecture while side chain was equipped with triethylene glycol group. ET-BDP-O was able to directly self-assemble into nanoparticles (NPs) without supplement of any other matrices or stabilizers due to its amphiphilic property. The as-prepared ET-BDP-O NPs had an excellent colloid stability with the size of 125 nm. Benefiting from the AIE property, ET-BDP-O NPs could generate strong fluorescence and reactive oxygen species under light-emitting diode light irradiation (60[Formula: see text]mW/cm[Formula: see text]. After internalized in cancer cells, ET-BDP-O NPs were able to emit bright red fluorescence signal for bioimaging. In addition, the cell viability assay demonstrated that the ET-BDP-O NPs exhibited excellent photo-cytotoxicity against cancer cells, while negligible cytotoxicity under dark environment. Thus, ET-BDP-O NPs might be regarded as a promising photosensitizer for fluorescence imaging-guided PDT in future.

Novel selenium-containing photosensitizers for near-infrared fluorescence imaging-guided photodynamic therapy.

Benzopyran nitrile dyes cannot be used as qualified photosensitizers due to the low quantum yield of triplet state. The benzopyran derivatives containing selenium instead of oxygen atom based on the heavy atom effect are expected to become potential agents for photodynamic therapy. In this paper, a series of selenium-containing photosensitizers (PSX) were prepared according to this strategy. PSX can effectively produce both singlet oxygen and superoxide anions upon laser irradiation. PSX exhibited the emission wavelength at 500-800nm and near-infrared (NIR) fluorescence imaging in HeLa cells. Excellent biocompatibility and phototoxicity further indicated that PSX could be used as efficient photosensitizers for NIR fluorescence imaging and photodynamic therapy.

Single-walled carbon nanohorns-based smart nanotheranostic: From phototherapy to enzyme-activated fluorescence imaging-guided photodynamic therapy

Phototheranostics, a local non-invasive approach that integrates light-based diagnostics and therapeutics, enables precise treatment using nanotheranostic agents with minimal damage to normal tissues. However, ensuring high-efficiency ablation of cancer cells using phototheranostics for one time irradiation is highly challenging. Herein, we designed and synthesized a single-walled carbon nanohorns-based nanotheranostic agent, HA-IR808-SWNHs, by loading IR808, a photosensitizer, conjugated hyaluronic acid (HA) with an amide bond on the surface of single-walled carbon nanohorns (SWNHs) through noncovalent π−π interaction by the sonication method. The HA in HA-IR808-SWNHs improves the water dispersibility of SWNHs and endows SWNHs with targeting capabilities. Importantly, overexpressed endogenous hyaluronidase in cancer cells actively disassembles HA-IR808-SWNHs, forming small HA-IR808 fragments. The fragments exhibit a strong fluorescence signal and can be used to guide programmed photodynamic therapy for sequentially eliminating the residual living cancer cells. The current study confirms that HA-IR808-SWNHs is an endogenous enzyme-responsive nanotheranostic agent that can be employed to precisely track and ablate residual cancer cells in a spatiotemporal manner. The results strengthen the understanding of SWNH functionalization and expand its potential biomedical application, especially in cancer theranostics.

BODIPY nanoparticles functionalized with lactose for cancer-targeted and fluorescence imaging-guided photodynamic therapy

A series of four lactose-modified BODIPY photosensitizers (PSs) with different substituents (-I, -H, -OCH3, and -NO2) in the para-phenyl moiety attached to the meso-position of the BODIPY core were synthesized; the photophysical properties and photodynamic anticancer activities of these sensitizers were investigated, focusing on the electronic properties of the different substituent groups. Compared to parent BODIPY H, iodine substitution (BODIPY I) enhanced the intersystem crossing (ISC) to produce singlet oxygen (1O2) due to the heavy atom effect, and maintained a high fluorescence quantum yield (ΦF) of 0.45. Substitution with the electron-donating methoxy group (BODIPY OMe) results in a significant perturbation of occupied frontier molecular orbitals and consequently achieves higher 1O2 generation capability with a high ΦF of 0.49, while substitution with the electron-withdrawing nitro group (BODIPY NO2) led a perturbation of unoccupied frontier molecular orbitals and induces a forbidden dark S1 state, which is negative for both fluorescence and 1O2 generation efficiencies. The BODIPY PSs formed water-soluble nanoparticles (NPs) functionalized with lactose as liver cancer-targeting ligands. BODIPY I and OMe NPs showed good fluorescence imaging and PDT activity against various tumor cells (HeLa and Huh-7 cells). Collectively, the BODIPY NPs demonstrated high 1O2 generation capability and ΦF may create a new opportunity to develop useful imaging-guided PDT agents for tumor cells.

Boost highly efficient singlet oxygen generation and accelerate cancer cell apoptosis for photodynamic therapy by logically designed mitochondria targeted near-infrared AIEgens

The aggregation-induced emission photosensitizers (AIE-PSs) manifest a multitude of notable superiorities in terms of high specificity to organelles, high-efficient singlet oxygen (1O2) generation as well as enhanced fluorescence intensity, which provides a feasible approach to overcome the problems such as the insufficient generation of reactive oxygen species (ROS) caused by grave aggregation-induced quenching (ACQ) and the lack of specific targeting existing in traditional PSs, but extremely challenging. Herein, a series of near-infrared (NIR) AIE luminogens (AIEgens) for targeting mitochondrial was devised and synthesized by regulating the D-A intensity assembly molecular engineering, which fabricating a progressively stronger intermolecular charge transfer (ICT) state to accelerate highly effective intersystem crossing (ISC) of excited electrons by the synergistic effect of thiophene and quinolinium. Impressively, the optimal NIR AIE-PS (DTTVQ-OH) revealed excellent photostability, biocompatibility, precise mitochondria targeting, extremely high generation yield of 1O2 (4.9-fold that of Rose Bengal) and superior phototoxicity in living HepG2 cells. Furthermore, apoptosis assay and cell migration experiment further demonstrated that DTTVQ-OH could efficaciously restrain cell proliferation and induce/speed up cancer cell death. Moreover, DTTVQ-OH can selectively distinguish cancer cells and normal cells by difference of fluorescence intensity in high resolution without the assist of any extra targeting ligands. As a consequence, this work provides a rational and practicable strategy for the specific targeted molecular engineering of AIE-PSs, which gives impetus to the development of fluorescence imaging-guided photodynamic therapy fields.

Novel Quinolizine AIE System: Visualization of Molecular Motion and Elaborate Tailoring for Biological Application.

Molecular motions are ubiquitous in nature and they immutably play intrinsic roles in all actions. However, exploring appropriate models to decipher molecular motions is an extremely important but very challenging task for researchers. Considering aggregation-induced emission (AIE) luminogens possess their unique merits to visualize molecular motions, it is particularly fascinating to construct new AIE systems as models to study molecular motion. Herein, a novel quinolizine (QLZ) AIE system was constructed based on the restriction intramolecular vibration (RIV) mechanism. It was demonstrated that QLZ could act as an ideal model to visualize single-molecule motion and macroscopic molecular motion via fluorescence change. Additionally, further elaborate tailoring of this impressive core achieved highly efficient reactive oxygen species production and realized fluorescence imaging-guided photodynamic therapy applications, which confirms the great application potential of this new AIE-active QLZ core. Therefore, this work not only provides an ideal model to visualize molecular motion but also opens a new way for the application of AIEgens.

Acceptor-donor-acceptor structured deep-red AIE photosensitizer: Lysosome-specific targeting, in vivo long-term imaging, and effective photodynamic therapy

Photosensitizers (PSs) with aggregation-induced emission (AIE) feature show promising applications in fluorescence imaging-guided photodynamic therapy (PDT) in virtue of their enhanced fluorescence and phototoxicity in aggregate state. Seeking the ideal AIE luminogens (AIEgens) with good capability of generating reactive oxygen species is still urgent. Here we rationally synthesized an acceptor-donor-acceptor (A-D-A) structured AIEgen (BTZPP) and then prepared it into nanoparticles (NPs) through a simple re-precipitation procedure. The obtained BTZPP NPs show a deep-red emission peaked at 635 nm, a large Stokes shift of 195 nm, and a high 1O2 generation quantum yield of 72.3%. Moreover, these NPs can selectively target lysosomes in live cells and image mouse tumor with a high contrast and long-term tracking (up to 14 days) capability. The high-efficiency imaging-guided PDT against cancer cells and tumors is successfully demonstrated in vitro and in vivo.

A near-infrared bioprobe with aggregation-induced emission feature for in vitro photodynamic therapy

Fluorescence imaging-guided photodynamic therapy (PDT) plays an important role in diagnosis and therapeutics. However, conventional photosensitizers (e.g. porphyrins and inorganic nanomaterials) often suffer from suppressed emission and decreased reactive oxygen species (ROS) production due to aggregates formation. In this study, a novel facile near-infrared aggregation-induced emission (AIE) fluorescent bioprobe (TPA-diCN-F127 NPs) with AIE molecules (TPA-diCN) as core and Pluronic F127 as shell was prepared. The structure and photophysical properties of TPA-diCN were verified by standard spectroscopic methods. Further experiments demonstrated that TPA-diCN-F127 NPs possess many desirable characteristics including near-infrared emission (maximum emission at 672 nm), a large Stokes shift (224 nm), good dispersibility, superior photosensitization efficiency and satisfactory biocompatibility. More importantly, upon white light irradiation, efficient in vitro cancer cells damage are demonstrated, suggesting potential capability of TPA-diCN-F127 NPs in imaging-guided PDT.

Aggregation-Induced Generation of Reactive Oxygen Species: Mechanism and Photosensitizer Construction.

Luminogens with aggregation-induced emission (AIEgens) have been widely applied in the field of photodynamic therapy. Among them, aggregation-induced emission photosensitizers (AIE–PSs) are demonstrated with high capability in fluorescence and photoacoustic bimodal imaging, as well as in fluorescence imaging-guided photodynamic therapy. They not only improve diagnosis accuracy but also provide an efficient theranostic platform to accelerate preclinical translation as well. In this short review, we divide AIE–PSs into three categories. Through the analysis of such classification and construction methods, it will be helpful for scientists to further develop various types of AIE–PSs with superior performance.

A DNA tetrahedron-loaded natural photosensitizer with aggregation-induced emission characteristics for boosting fluorescence imaging-guided photodynamic therapy

A natural AIE-active PS (PaH) is utilized to bind into DNA-T for cancer theranostics. The constructed PaH@DNA-T exhibits highly boosted fluorescence intensity and ROS generation, as well as much higher cell uptake efficiency.

Multifunctional aggregation-induced emission nanoparticle for high-fidelity imaging of lipid droplets in living cells and its application in photodynamic therapy

Near-infrared (NIR) aggregation-induced emission (AIE) nanomaterials, with organelles targeted-imaging ability and effective reactive oxygen species (ROS) generation nature, are highly desirable photosensitizers (PSs) for fluorescence imaging-guided photodynamic therapy (PDT), but it remains challenging. Herein, a NIR AIE luminogens (AIEgens, TTI) was designed and synthesized using three-fragmentary assembly molecular engineering, which was used for intracellular lipid droplets (LDs) high-fidelity dynamic tracking (Pearson’s coefficient of 0.95) due to its strong lipophilic nature (ClogP of 8.34), large Stokes shifts (170 nm), excellent photostability and good biocompatibility. Meanwhile, TTI self-assembled nanoparticles with an average diameter of 196.57 nm exhibited extremely high-efficient singlet oxygen (1O2) generation efficiency (with up to 85.16% of quantum yield) in PBS solution. In addition, the TTI as a desired PS revealed good phototoxicity for living HepG2 cells under white light irradiation. Moreover, the live/dead cells co-staining image, flow cytometry and scratch wound healing assays indicated that TTI could effectively inhibit the proliferation and cause/induce cells apoptosis, which eventually led to the death of HepG2 cells. Therefore, this work provides a useful strategy for LDs-targeting molecular engineering and highlights the potential of organic nanoparticles PSs drug in biomedical and fluorescence imaging-guided PDT fields.