Imaging-guided Photodynamic Therapy Research Articles

Coupling Chlorin e6 to the surface of Nanoscale Gas Vesicles strongly enhances their intracellular delivery and photodynamic killing of cancer cells

Protein-based nanobubbles such as halophilic archaeabacterial gas vesicles (GVs) represent a new class of stable, homogeneous nanoparticles with acoustic properties that allow them to be visualized by ultrasound (US) waves. To design GVs as theranostic agents, we modified them to respond to light, with a view to locally generate reactive oxygen species that can kill cancer cells. Specifically, up to 60,000 photoreactive chlorin e6 (Ce6) molecules were chemically attached to lysine ε-amino groups present on the surface of each purified Halobacterium sp. NRC-1 GV. The resulting fluorescent NRC-1 Ce6-GVs have dimensions comparable to that of native GVs and were efficiently taken up by human breast [MCF-7] and human hypopharyngeal [FaDu-GFP] cancer cells as monitored by confocal microscopy and flow cytometry. When exposed to light, internalized Ce6-GVs were 200-fold more effective on a molar basis than free Ce6 at killing cells. These results demonstrate the potential of Ce6-GVs as novel and promising nanomaterials for image-guided photodynamic therapy.

Aggregation-Induced Emission Photosensitizers: From Molecular Design to Photodynamic Therapy.

Photodynamic therapy (PDT) has emerged as a promising noninvasive treatment option for cancers and other diseases. The key factor that determines the effectiveness of PDT is the photosensitizers (PSs). Upon light irradiation, the PSs would be activated, produce reactive oxygen species (ROS), and induce cell death. One of the challenges is that traditional PSs adopt a large flat disc-like structure, which tend to interact with the adjacent molecules through strong π-π stacking that reduces their ROS generation ability. Aggregation-induced emission (AIE) molecules with a twisted configuration to suppress strong intermolecular interactions represent a new class of PSs for image-guided PDT. In this Miniperspective, we summarize the recent progress on the design rationale of AIE-PSs and the strategies to achieve desirable theranostic applications in cancers. Subsequently, approaches of combining AIE-PS with other imaging and treatment modalities, challenges, and future directions are addressed.

Synthesis of AIE-Active Materials with Their Applications for Antibacterial Activity, Specific Imaging of Mitochondrion and Image-Guided Photodynamic Therapy.

In comparison with fluorescence molecules with aggregation-caused quenching (ACQ), fluorescence molecules with aggregation-induced emission (AIE) have great advantages in cell imaging, image-guided photodynamic therapy (PDT), and antibacterial activity. However, the reasonable design and synthesis of related molecules are still of great challenges. Herein, a consecutive strategy via several reliable reactions to prepare a series of AIE-active luminogens by adjusting their structures is reported. Having concentrated on the factors for the principle purpose of 1O2 generation, TPA-18 is picked out within all triphenylamine (TPA) derivatives according to its longer emission wavelength (640 nm in solid), the lowest energy gap between HOMO and LUMO (calculated as 2.04 eV), the totally separated orbital distributions of HOMO and LUMO, and typical AIE characteristics. Meanwhile, owing to the presence of the positive structural charge and the bright emission color, TPA-18 in aggregated form is detected as an impressive probe for the mitochondria-targeted imaging and living zebrafish embryos imaging in vivo. Accordingly, TPA-18 can effectively generate 1O2 reactive oxygen species; it provides an effective application for image-guided photodynamic cancer treatment and antibacterial activity. Therefore, this study not only synthesized AIE photosensitizer with tunable emission wavelength (from blue to red color) but also raised a new concept for the constructing AIEgens with versatile applications in cell imaging, antibacterial activity, and image-guided PDT.

Tetraphenylporphine-Modified Polymeric Nanoparticles Containing NIR Photosensitizer for Mitochondria-Targeting and Imaging-Guided Photodynamic Therapy.

Near-infrared (NIR) photodynamic therapy (PDT) is a promising antitumor strategy under NIR light irradiation to kill cancer cells. Mitochondria has a critical function in sustaining cellular viability and death, which is the ideal organelle for PDT. Here, we reported a tetraphenylporphine (TPP)-conjugated amphiphilic copolymer and an iodinated boron dipyrromethene photosensitizer (BDPI) with high singlet oxygen yield to form nanoparticles (PBDPI-TPP), which could realize mitochondria-targeting and improve the NIR imaging-guided PDT. The as-prepared mitochondria-targeting nanoplatform could show effective subcellular localization and bring about significant irreversible mitochondrial injury for enhanced PDT. Both in vitro and in vivo experiments revealed that the mitochondria-targeting PDT system could achieve a remarkable therapeutic effect, indicating that it is a promising nanoplatform for NIR imaging-guided PDT in cancer therapeutics.

Irradiation-free photodynamic therapy in vivo induced by enhanced deep red afterglow within NIR-I bio-window

In situ precise anti-cancer therapeutics, such as imaging-guided photodynamic therapy (PDT), is one of the major efforts in reducing the mortality caused by tumor proliferation. Up to now, PDT can only be executed in hospital because of the restriction of relevant facilities and PDT specialists, e.g. lasers whose power density needs to be adjusted to a patient tolerable level on time. Therefore, an irradiation-free and long-term PDT is highly desirable in precision medicine, which may help for the realization of PDT at home for cancer patients. Herein, based on the facilitated tunneling process induced by Bi substitution in Cr doped zinc gallogermanate (ZGGO:Cr,Bi) deep red persistent luminescent nanoparticles (DRPLNPs) within NIR-I bio-window (650–950 nm), an irradiation-free PDT nanoplatform was constructed by loading zinc phthalocyanine (ZnPc) molecules into mesoporous silica coated on the surface of ZGGO:Cr,Bi DRPLNPS (ZGGO:Cr,Bi@mSiO2-ZnPc). It was demonstrated in vitro and in vivo that Bi substitution can effectively improve the afterglow intensity to such that the production of 1O2 is sufficient to have an apparent irradiation-free PDT. The inhibition factor of cancer growth two weeks after the injection of the nanocomposites was as high as ~80%. This work exhibits the interesting potential of the new generation of afterglow nanomaterials in precision medicine.

Efficient near-infrared photosensitizer with aggregation-induced emission characteristics for mitochondria-targeted and image-guided photodynamic cancer therapy

A highly efficient near-infrared photosensitizer with aggregation-induced emission characteristics was developed for mitochondria-targeted and image-guided photodynamic cancer therapy.

Activatable molecular agents for cancer theranostics.

Theranostics that integrates diagnosis and treatment modalities has attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome. Such a theranostic paradigm requires agents to simultaneously possess the capabilities of targeting, imaging, and treatment. Activatable molecular agents (AMAs) are promising for cancer theranostics, as they show a higher signal-to-noise ratio (SNR), real-time detection of cancer-associated biomarkers, lower normal tissue toxicity, and a higher therapeutic effect. This perspective summarizes the recent advancements of AMAs, which include imaging-guided chemotherapy, imaging-guided photodynamic therapy, and imaging-guided photothermal therapy. The molecular design principles, theranostic mechanisms, and biomedical applications of AMAs are described, followed by a discussion of potential challenges of AMAs in cancer theranostics.

Highly efficient singlet oxygen generation, two-photon photodynamic therapy and melanoma ablation by rationally designed mitochondria-specific near-infrared AIEgens.

Photosensitizers (PSs) with multiple characteristics, including efficient singlet oxygen (1O2) generation, cancer cell-selective accumulation and subsequent mitochondrial localization as well as near-infrared (NIR) excitation and bright NIR emission, are promising candidates for imaging-guided photodynamic therapy (PDT) but rarely concerned. Herein, a simple rational strategy, namely modulation of donor–acceptor (D–A) strength, for molecular engineering of mitochondria-targeting aggregation-induced emission (AIE) PSs with desirable characteristics including highly improved 1O2 generation efficiency, NIR emission (736 nm), high specificity to mitochondria, good biocompatibility, high brightness and superior photostability is demonstrated. Impressively, upon light irradiation, the optimal NIR AIE PS (DCQu) can generate 1O2 with efficiency much higher than those of commercially available PSs. The excellent two-photon absorption properties of DCQu allow two-photon fluorescence imaging of mitochondria and subsequent two-photon excited PDT. DCQu can selectively differentiate cancer cells from normal cells without the aid of extra targeting ligands. Upon ultralow-power light irradiation at 4.2 mW cm−2, in situ mitochondrial photodynamic activation to specifically damage cancer cells and efficient in vivo melanoma ablation are demonstrated, suggesting superior potency of the AIE PS in imaging-guided PDT with minimal side effects, which is promising for future precision medicine.

Biomineralized Bimetallic Oxide Nanotheranostics for Multimodal Imaging-Guided Combination Therapy

The hypoxia of the tumor microenvironment (TME) often hinders the effectiveness of cancer treatments, especially O2-dependent photodynamic therapy (PDT).Methods: An integrated iridium oxide (IrO2)-manganese dioxide (MnO2) nanotheranostic agent was fabricated through bovine serum albumin (BSA)-based biomineralization of Ir3+ and Mn2+. BSA was first covalently modified with chlorin e6 (Ce6), and used to fabricate multifunctional BSA-Ce6@IrO2/MnO2 nanoparticles (NPs) for computed X-ray tomography (CT) and photoacoustic (PA) imaging-guided PDT and photothermal (PTT) therapy of cancer. Extensive in vitro and in vivo studies were performed.Results: The theranostic agent produced can relieve tumor hypoxia by the decomposition of endogenous H2O2 in cancer cells to oxygen. The oxygen generated can be exploited for improved PDT. Paramagnetic Mn2+ released from the NPs in the acidic TME permits magnetic resonance imaging (MRI) to be performed. The exceptional photothermal conversion efficiency (65.3%) and high X-ray absorption coefficient of IrO2 further endow the NPs with the ability to be used in computed CT and PA imaging. Extensive antitumor studies demonstrated that the BSA-Ce6@IrO2/MnO2 nanoplatform inhibits cancer cell growth, particularly after combined PTT and PDT. Systematic in vivo biosafety evaluations confirmed the high biocompatibility of the nanoplatform.Conclusion: This work not only provides a novel strategy for designing albumin-based nanohybrids for theranostic applications but also provides a facile approach for extending the biomedical applications of iridium-based materials.

Designing a highly stable coordination-driven metallacycle for imaging-guided photodynamic cancer theranostics.

Coordination-driven self-assembly features good predictability and directionality in the construction of discrete metallacycles and metallacages with well-defined sizes and shapes, but their medicinal application has been limited by their low stability and solubility. Herein, we have designed and synthesized a highly stable coordination-driven metallacycle with desired functionality derived from a perylene-diimide ligand via a spontaneous deprotonation self-assembly process. Brilliant chemical stability and singlet oxygen production ability of this emissive octanuclear organopalladium macrocycle make it a good candidate toward biological studies. After cellular uptake by endocytosis, the metallacycle exhibits potent fluorescence cell imaging properties and cancer photodynamic therapeutic ability through enhancing ROS production, with high biocompatibility and safety. This study not only provides a rational design strategy for highly stable luminescent organopalladium metallacycles, but also sheds light on their application in imaging-guided photodynamic cancer therapy.

Photothermally Responsive Conjugated Polymeric Singlet Oxygen Carrier for Phase Change-Controlled and Sustainable Phototherapy for Hypoxic Tumor.

Hypoxia significantly compromises the therapeutic performance of photodynamic therapy (PDT) owing to the oxygen level which plays a key role in the production of singlet oxygen (1O2). Herein, the photothermally responsive phase change materials (PCM) are used to encapsulate 1,4-dimethylnaphthalene-functionalized platinum(II)-acetylide conjugated polymer (CP1) with intense near-infrared (NIR) absorption to prepare new 1O2 nanocarriers (CP1-NCs). The 1,4-dimethylnaphthalene moieties in CP1-NCs can trap the 1O2 produced from CP1 under irradiation and form a stable endoperoxide. Then, the endoperoxide undergoes cycloreversion to controllably release 1O2 via the NIR light-triggered photothermal effect of CP1 and controllable phase change of PCM, which can be used for oxygen-independent PDT for hypoxic tumor. Furthermore, the in vivo luminescence imaging-guided synergistic PDT and photothermal therapy showed better efficiency in tumor ablation. The smart design shows the potent promise of CP1-NCs in PCM-controlled and sustainable phototherapy under tumor hypoxic microenvironment, providing new insights for constructing oxygen-independent precise cancer phototherapeutic platform.

Cubic POSS engineering of photosensitizer-doped semiconducting polymer nanoparticles for enhanced fluorescence imaging and amplified photodynamic therapy

PorPOSSC12 -doped semiconducting polymer nanoparticles with simultaneously enhanced fluorescence brightness and amplified singlet oxygen generation ability were designed for imaging-guided photodynamic therapy.

A NIR-I light-responsive superoxide radical generator with cancer cell membrane targeting ability for enhanced imaging-guided photodynamic therapy.

Photodynamic therapy (PDT), as an emerging treatment modality, which takes advantage of reactive oxygen species (ROS) generated upon light illumination to ablate tumours, has suffered from a limited treatment depth, strong oxygen dependence and short ROS lifespan. Herein, we developed a highly efficient NIR-I light (808 nm laser) initiated theranostic system based on a fluorescent photosensitizer (EBD-1) with cancer cell membrane targeting ability, which can realize large penetration depth in tissue, generate superoxide radicals (O2−˙) to relieve the oxygen-dependence, confine the ROS oxidation at the cell membrane, and self-report the cell viability during the PDT process. In vivo experiments demonstrated that EBD-1 under 808 nm light successfully accomplished remarkable cancer ablation. This work will be beneficial for the design of novel photosensitizers for PDT-based theranostic systems.

Fluorinated cryptophane-A and porphyrin-based theranostics for multimodal imaging-guided photodynamic therapy.

Herein, we developed fluorinated nanoemulsions with significantly enhanced in vitro and in vivo129Xe hyper-CEST MRI, 19F MRI and fluorescence imaging signals for selective and sensitive tumor detection and NIR-activated photodynamic therapy.

AIE based GSH activatable photosensitizer for imaging-guided photodynamic therapy.

A novel ferrocene decorated vinyl pyridinium-substituted tetraphenylethylene (TPEPY-S-Fc) linked by a disulfide bond was designed as a GSH activatable photosensitizer by aggregation-induced emission for imaging-guided photodynamic therapy of cancer cells.

Ultra-small Pyropheophorbide-a Nanodots for Near-infrared Fluorescence/Photoacoustic Imaging-guided Photodynamic Therapy.

Rationale: Nanoparticles (NPs) that are rapidly eliminated from the body offer great potential in clinical test. Renal excretion of small particles is preferable over other clearance pathways to minimize potential toxicity. Thus, there is a significant demand to prepare ultra-small theranostic agents with renal clearance behaviors.Method: In this work, we report a facile method to prepare NPs with ultra-small size that show renal clearable behavior for imaging-guided photodynamic therapy (PDT). Pyropheophorbide-a (Pa), a deep red photosensitizer was functionalized with polyethylene glycol (PEG) to obtain Pa-PEG. The prepared NPs formed ultra-small nanodots in aqueous solution and showed red-shifted absorbance that enabling efficient singlet oxygen generation upon light irradiation.Results: In vitro studies revealed good photodynamic therapy (PDT) effect of these Pa-PEG nanodots. Most of the cancer cells incubated with Pa-PEG nanodots were destroyed after being exposed to the irradiated light. Utilizing the optical properties of such Pa-PEG nanodots, in vivo photoacoustic (PA) and fluorescence (FL) imaging techniques were used to assess the optimal time for PDT treatment after intravenous (i.v.) injection of the nanodots. As monitored by the PA/FL dual-modal imaging, the nanodots could accumulate at the tumor site and reach the maximum concentration at 8 h post injection. Finally, the tumors on mice treated with Pa-PEG nanodots were effectively inhibited by PDT treatment. Moreover, Pa-PEG nanodots showed high PA/FL signals in kidneys implying these ultra-small nanodots could be excreted out of the body via renal clearance.Conclusion: We demonstrated the excellent properties of Pa-PEG nanodots that can be an in vivo imaging-guided PDT agent with renal clearable behavior for potential future clinical translation.

Fine-tuning the electronic structure of heavy-atom-free BODIPY photosensitizers for fluorescence imaging and mitochondria-targeted photodynamic therapy.

Theranostics that combines both diagnosis and therapy into a single platform has recently emerged as a promising biomedical approach for cancer treatment; however, the development of efficient theranostic agents with excellent optical properties remains a challenge. Here, we report novel mitochondria-targeting BODIPY photosensitizers (R-BODs) that possess considerable singlet oxygen generation capabilities and good fluorescence properties for imaging-guided photodynamic therapy (PDT). The incorporation of sulfur atoms into the π-conjugated skeleton of BODIPY along with the introduction of different functional groups at the meso-position of the BODIPY core is essential for tuning the photophysical and photosensitizing properties. Notably, the MeOPh-substituted thiophene-fused BODIPY (MeO-BOD, R = p-methoxyphenyl) displayed the highest singlet oxygen generation capability (ΦΔ ≈ 0.85 in air-saturated acetonitrile) and a moderate fluorescence quantum yield (Φf = 17.11). Furthermore, MeO-BOD showed good biocompatibility, low dark toxicity and superior fluorescence imaging properties in living cells. More importantly, the PDT efficacy of mitochondria-specific anchoring of MeO-BOD was remarkably amplified with an extremely low half-maximal inhibitory concentration (IC50) value of 95 nM. We believe that the incorporation of an electron-donating group at the meso-position of the thiophene-fused BODIPY platform may be an effective approach for developing theranostic agents for precision cancer therapy.

A tumour mRNA-triggered nanoassembly for enhanced fluorescence imaging-guided photodynamic therapy.

A multifunctional theranostic nanoplatform, which integrates diagnostic and therapeutic functions in a single nanosystem, holds great promise for guiding disease treatment and improving the corresponding therapy efficacy. We report the development of a novel g-C3N4 nanosheet-based theranostic nanoassembly for both enhanced imaging of cancer-relevant mRNA in living cells and imaging-guided on-demand photodynamic therapy (PDT) for tumors. The nanoassembly was constructed by using highly fluorescent and water-dispersible g-C3N4 nanosheets which act as nanocarriers, enabling efficient and self-tracking transfection of the DNA hairpin probes. The presence of intracellular mRNA will initiate the DNA hairpin probes, ultimately resulting in an amplified fluorescence signal via hybridization and displacement with mRNA. Moreover, enhanced fluorescence imaging-guided precise PDT for tumors in living cells was also demonstrated, allowing the selective ablation of tumors without any obvious side effects. Therefore, the developed theranostic approach can provide a promising platform for low-abundance biomarker discovery and early treatment of related diseases.

Metal-enhancement study of dual functional photosensitizers with aggregation-induced emission and singlet oxygen generation.

Photosensitizers with aggregation-induced emission (AIE-PS) are attractive for image-guided photodynamic therapy due to their dual functional role in generating singlet oxygen and producing high fluorescent signal in the aggregated state. However, their brightness and treatment efficiency maybe limited in current practice. Herein we report the first systematic investigation on the metal-enhanced fluorescence (MEF) and singlet oxygen generation (ME-SOG) ability of our newly synthesized AIE-photosensitizers. The Ag@AIE-PS of varied sizes were prepared via layer-by-layer assembly with controlled distance between silver nanoparticles (AgNPs) and AIE-PS. A maximum of 6-fold enhancement in fluorescence and 2-fold increment in SOG were observed for the 85nmAg@AIE-PS. Comprehensive characterization and simulation were conducted to unravel the plasmon-enhancement mechanisms of Ag@AIE-PS. Results show that MEF of AIE-PS is determined by the enhanced electric field around AgNPs, while ME-SOG is dictated by the scattering efficiency of the metal core, where bigger AgNPs would result in larger enhancement factor. Furthermore, the optimum distance between AgNPs and AIE-PS to achieve maximum SOG enhancement is shorter than that required for the highest MEF. The correlation of MEF and ME-SOG found in this study is useful for designing new a generation of AIE-photosensitizers with high brightness and treatment efficiency towards practical theranostic application in the future.

Boosting the photodynamic therapy efficiency by using stimuli-responsive and AIE-featured nanoparticles

Photosensitizers with aggregation-induced emission (AIE) characteristics are of great interest for cancer theranostics involving both fluorescence imaging and photodynamic therapy (PDT). However, in the purpose of clinical trials of PDT, the development of prominent drug delivery systems for boosting the PDT efficiency of AIE photosensitizers is highly desirable but still remain a challenging task. Herein, a novel strategy is designed and performed for boosting PDT effect based on stimuli-responsive nano-micelles as extraordinary carriers for an AIE photosensitizer, namely MeTTMN. Those presented stimuli-responsive nano-micelles loading MeTTMN exhibit good biocompatibility, excellent stability, appropriate nanoparticle size, high loading efficiency, outstanding imaging quality and significantly promoted PDT performance, eventually making them remarkably impressive and significantly superior to commercially available nano-micelles carried MeTTMN. This study thus offers an ideal template for fluorescence imaging-guided PDT, as well as a promising candidate for clinical trials.