Aggregation-enhanced photothermal therapy of organic dyes.

Photothermal therapy (PTT) represents a groundbreaking approach to targeted disease treatment by harnessing the conversion of light into heat. The efficacy of PTT heavily relies on the capabilities of photothermal agents (PTAs). Among PTAs, those based on organic dyes exhibit notable characteristics such as adjustable light absorption wavelengths, high extinction coefficients, and high compatibility in biological systems. However, a challenge associated with organic dye-based PTAs lies in their efficiency in converting light into heat while maintaining stability. Manipulating dye aggregation is a key aspect in modulating non-radiative decay pathways, aiming to augment heat generation. This review delves into various strategies aimed at improving photothermal performance through constructing aggregation. These strategies including protecting dyes from photodegradation, inhibiting non-photothermal pathways, maintaining space within molecular aggregates, and introducing intermolecular photophysical processes. Overall, this review highlights the precision-driven assembly of organic dyes as a promising frontier in enhancing PTT-related applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

A Light-Triggered J-Aggregation-Regulated Therapy Conversion: from Photodynamic/Photothermal Therapy to Long-Lasting Chemodynamic Therapy for Effective Tumor Ablation.

Reactive oxygen species (ROS) have become an effective tool for tumor treatment. The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) takes advantage of various ROS and enhances therapeutic effects. However, the activation of CDT usually occurs before PDT, which hinders the sustained maintenance of hydroxyl radicals (⋅OH) and reduces the treatment efficiency. Herein, we present a light-triggered nano-system based on molecular aggregation regulation for converting cancer therapy from PDT/photothermal therapy (PTT) to a long-lasting CDT. The ordered J-aggregation enhances the photodynamic properties of the cyanine moiety while simultaneously suppressing the chemodynamic capabilities of the copper-porphyrin moiety. Upon light irradiation, Cu-PCy JNPs demonstrate strong photodynamic and photothermal effects. Meanwhile, light triggers a rapid degradation of the cyanine backbone, leading to the destruction of the J-aggregation. As a result, a long-lasting CDT is sequentially activated, and the sustained generation of ⋅OH is observed for up to 48 hours, causing potent cellular oxidative stress and apoptosis. Due to their excellent tumor accumulation, Cu-PCy JNPs exhibit effective in vivo tumor ablation through the converting therapy. This work provides a new approach for effectively prolonging the chemodynamic activity in ROS-based cancer therapy.

A Terrylene-Anthraquinone Dyad as a Chromophore for Photothermal Therapy in the NIR-II Window.

A terrylenedicarboximide-anthraquinone dyad, FTQ, with absorption in the second near-infrared region (NIR-II) is obtained as a high-performance chromophore for photothermal therapy (PTT). The synthetic route proceeds by C-N coupling of amino-substituted terrylenedicarboximide (TMI) and 1,4-dichloroanthraquinone followed by alkaline-promoted dehydrocyclization. FTQ with extended π-conjugation exhibits an optical absorption band peaking at 1140 nm and extending into the 1500 nm range. Moreover, as determined by dielectric spectroscopy in dilute solutions, FTQ achieves an ultrastrong dipole moment of 14.4 ± 0.4 Debye due to intense intramolecular charge transfer. After encapsulation in a biodegradable polyethylene glycol (DSPE-mPEG2000), FTQ nanoparticles (NPs) deliver a high photothermal conversion efficiency of 49% under 1064 nm laser irradiation combined with excellent biocompatibility, photostability, and photoacoustic imaging capability. In vitro and in vivo studies reveal the great potential of FTQ NPs in photoacoustic-imaging-guided photothermal therapy for orthotopic liver cancer treatment in the NIR-II window.

Regulating steric hindrances of perylenediimide to construct NIR photothermal J-aggregates with a large red-shift.

Perylene diimide (PDI)-based photothermal agents (PTAs) possess excellent stability and high photothermal conversion efficiency. However, developing PDIs with strong near-infrared absorption under biological conditions remains a challenge. In this study, we introduce a novel approach to facilitate the formation of J-aggregate-based PTAs with significantly red-shifted absorption by modulating steric hindrances of PDIs. PDIA, featuring larger steric hindrances at the bay position and smaller steric hindrances at the imide position, self-assembles into J-aggregates which exhibit a remarkable red-shift of over 100 nm. After encapsulation by DPSE-PEG, PDIA nanoparticles (PDIA-NPs) demonstrated a uniform and stable size, while retaining their significant red-shift. In vitro experiments demonstrated the great potential of PDIA-NPs in photothermal therapies for tumors and thrombi under 808 nm laser irradiation. This research provides valuable insights into the design of stable J-aggregates based on PDIs suitable for biological applications, paving the way for the development of more effective PTAs.

Perylenediimides with Enhanced Autophagy Inhibition for a Dual-Light Activatable Photothermal Gas Therapy.

Photothermal therapy (PTT) has emerged as a promising strategy for the treatment of tumors. However, the intrinsic self-repair mechanism of cells and the nonspecific photothermal effect of photothermal agents can result in poor treatment outcomes and normal tissue injury. To address this issue, we developed a dual light activatable perylenediimide derivative (P-NO) for nitric oxide-enhanced PTT. P-NO can self-assemble into nanoparticles in aqueous solutions. The P-NO nanoparticles are capable of releasing both NO and a photothermal molecule (P-NH) upon green light irradiation. The simultaneous release of NO and P-NH activates the photothermal effect and inhibits cell protection autophagy, thereby improving the therapeutic efficacy of PTT under near-infrared (NIR) light. Moreover, the switch on of NIR fluorescence allows real-time monitoring of the release of P-NH. Remarkably, in a mouse subcutaneous tumor model, significant tumor ablation can be achieved following dual light activated photothermal gas therapy. This work offers a promising and straightforward approach to constructing activatable perylenediimide-based photothermal agents for enhancing the effectiveness of photothermal gas therapy.

NIR-II Perylene Monoimide-Based Photothermal Agent with Strengthened Donor-Acceptor Conjugation for Deep Orthotopic Glioblastoma Phototheranostics.

Extensive efforts have been devoted to the design of organic photothermal agents (PTAs) that absorb in the second near-infrared (NIR-II) bio-window, which can provide deeper tissue penetration that is significant for phototheranostics of lethal brain tumors. Herein, the first example of NIR-II-absorbing small organic molecule (N1) derived from perylene monoamide (PMI) and its bio-application after nano-encapsulation of N1 to function as a nano-agent for phototheranostics of deep orthotopic glioblastoma (GBM) is reported. By adopting a dual modification strategy of introducing a donor-acceptor unit and extending π-conjugation, the obtained N1 can absorb in 1000-1400 nm region and exhibit high photothermal conversation due to the apparent intramolecular charge transfer (ICT). A choline analogue, 2-methacryloyloxyethyl phosphorylcholine, capable of interacting specifically with receptors on the surface of the blood-brain barrier (BBB), is used to fabricate the amphiphilic copolymer for the nano-encapsulation of N1. The obtained nanoparticles demonstrate efficient BBB-crossing due to the receptor-mediated transcytosis as well as the small nanoparticle size of approximately 26 nm. The prepared nanoparticles exhibit excellent photoacoustic imaging and significant growth inhibition of deep orthotopic GBM. The current study demonstrates the enormous potential of PMI-based NIR-II PTAs and provides an efficient phototheranostic paradigm for deep orthotopic GBM.

Tumor microenvironment-activated multi-functional nanodrug with size-enlargement for enhanced cancer phototheranostics.

Phototheranostics that integrate diagnosis and treatment modalities have shown great promise in personalized cancer therapy. However, the "always on" characteristics often lead to suboptimal imaging quality and severe side effects. Herein, we report the construction of a perylenemonoimide based nanodrug CPMI NP with multi-functional activatable theranostic capability. The nanodrug is facilely co-assembled from a prodrug CPMI and DSPE-mPEG2000. In a tumor microenvironment (TME) with excessive glutathione (GSH), CPMI undergoes a cascade reaction to generate the phototheranostic molecule NPMI and the chemodrug chlorambucil, simultaneously switching on the near-infrared (NIR) fluorescence, photothermal effect, and drug release. The photothermal conversion efficiency is as high as 52.2%. Moreover, NPMI exhibits an enhanced intermolecular π-π stacking effect, leading to significant size-enlargement of the nanodrug and prolonged tumor retention. Due to TME-activation, the strong in vivo fluorescence signal of the tumor can be observed 144 h post injection with a high signal-to-noise ratio of up to 17. The enhanced tumor inhibition efficiency of the nanodrug is confirmed through activatable chemo-photothermal therapy. This work paves the way for the design of activatable phototheranostic agents for accurate cancer diagnosis and treatment.

A fluorescent nano vector for early diagnosis and enhanced Interleukin-33 therapy of thoracic aortic dissection.

Thoracic aortic dissection (TAD) is the most devastating complication of vascular disease. The accuracy of the clinical diagnosis and treatment of TAD at the early stage is still limited. Herein, we report a nano-delivery strategy for early diagnosis and the first case of interleukin-33 (IL-33) based therapy for the effective intervention of TAD. A targeted fluorescent nano vector (FNV) is designed to co-assemble with IL-33, which protects IL-33 and prolongs its half-life. With specific targeting ability to the thoracic aorta, FNV can diagnose TAD at its early stage through fluorescent imaging. FNV@IL-33 nanocomplex presents better therapeutic effects on mice TAD progression compared with that of IL-33 alone by reducing smooth muscle apoptosis. Administration of FNV@IL-33 two weeks before onset, the development of TAD is greatly intervened. Our study provides a novel approach for early diagnosis and effective IL-33 therapy of TAD, which opens attractive opportunities for clinical prevention of cardiovascular diseases.

Chronic exposure to the star polycation (SPc) nanocarrier in the larval stage adversely impairs life history traits in Drosophila melanogaster.

BACKGROUND: Nanomaterials are widely used as pesticide adjuvants to increase pesticide efficiency and minimize environmental pollution. But it is increasingly recognized that nanocarrier is a double-edged sword, as nanoparticles are emerging as new environmental pollutants. This study aimed to determine the biotoxicity of a widely applied star polycation (SPc) nanocarrier using Drosophila melanogaster, the fruit fly, as an in vivo model. RESULTS: The lethal concentration 50 (LC50) value of SPc was identified as 2.14 g/L toward third-instar larvae and 26.33 g/L for adults. Chronic exposure to a sub lethal concentration of SPc (1 g/L) in the larval stage showed long-lasting adverse effects on key life history traits. Exposure to SPc at larval stage adversely impacted the lifespan, fertility, climbing ability as well as stresses resistance of emerged adults. RNA-sequencing analysis found that SPc resulted in aberrant expression of genes involved in metabolism, innate immunity, stress response and hormone production in the larvae. Orally administrated SPc nanoparticles were mainly accumulated in intestine cells, while systemic responses were observed. CONCLUSIONS: These findings indicate that SPc nanoparticles are hazardous to fruit flies at multiple levels, which could help us to develop guidelines for further large-scale application.

Perylenemonoimide-Based Colorimetric Probe with High Contrast for Naked-Eye Detection of Fluoride Ions.

Excessive fluoride ions (F-) in drinking water are harmful to the environment and human health. However, most reported probes of F- can only detect fluorocarbons rather than aqueous F-. Herein, a colorimetric and fluorescent probe (PMI-OH) based on perylenemonoimide is designed and synthesized for the detection of aqueous F-, with high sensitivity, good selectivity, and reversibility. The F- causes deprotonation of PMI-OH, leading to a significant red shift of 222 nm (from 520 to 742 nm) of the absorption band. Upon the addition of fluorocarbons, the fluorescence intensities of PMI-OH show good linearity against the concentrations of F-, realizing the quantitative detection of fluorocarbons with a limit of detection as low as 0.495 µM. Finally, PMI-OH is applied to detect F- in drinking water. The color of PMI-OH solution shows remarkable response from pink to green when the concentrations of F- exceed the upper limit set by the World Health Organization (WHO), realizing rapid and naked-eye detection of aqueous F-.

A heptamethine cyanine with meso-N-induced rearrangement for acid-activated tumour imaging and photothermal therapy.

Photothermal therapy has been developed as one of the most attractive strategies for tumour therapy. However, most of the reported photothermal probes still suffer from poor selectivity or specificity for the tumour region during treatment. Herein, a tumour acidic microenvironment activated heptamethine cyanine-based nanoprobe (Cy-TPA NPs) is constructed for fluorescence imaging-guided photothermal therapy with enhanced tumour specificity. Taking advantage of the pH-dependent molecular rearrangement, Cy-TPA NPs under weak acidic conditions exhibit enhanced near-infrared absorption and "turn on" fluorescence and photothermal performance. The "turn on" fluorescence signal in tumour tissues can improve the signal-to-background ratio, providing precise in vivo fluorescence imaging. Moreover, tumour-specific PTT can effectively ablate tumours with reduced damage to the surrounding tissue. Thus, our work presents a promising strategy for significantly improving the precision and specificity of tumour imaging and therapy.

A facile design of thio-perylenediimides with controllable fluorescent, photodynamic and photothermal effects towards cancer theranostics.

A series of thionated perylenediimides with modulating phototheranostic modalities have been synthesized by a one-pot method for multiple anti-cancer applications. Compared to the initial and 4-tert-butyl phenol-substituted fluorescent perylenediimide, the obtained monothionated perylenediimide became photodynamic. With the increase of thionation degree, tetrathionated perylenediimide changed into an optimal photothermal agent.

Dually Crosslinked Supramolecular Hydrogel for Cancer Biomarker Sensing.

Lysophosphatidic acid (LPA) as the biomarker of early stage ovarian cancer is essentially difficult to detect due to lack of target spots. A dually crosslinked supramolecular hydrogel (DCSH) was developed to achieve sensing of LPA, which acts as a competitive guest molecule triggering the responsive crosslinking of the DCSH. Through this strategy, the surface plasmon resonance combined with optical waveguide spectroscopy could be used to quantitatively detect LPA with a responsive range covering physiological conditions (in pure form as well as mimicking LPA plasma solution) with high selectivity and sensitivity. LPA efficiently immerses into the host molecule ß-cyclodextrin (ß-CD) up to a 1:2 ratio by the competitive interaction mechanism, confirmed by one-dimensional nuclear overhauser effect spectroscopy (1D NOESY), high-resolution mass spectrometry (HRMS), isothermal titration calorimetry (ITC), and computational simulation. Our method opens a new strategy to detect biomarkers without target spots and provides a platform for surface plasmon resonance (SPR)-based sensors measuring small molecules.

Enzyme-Triggered Disassembly of Perylene Monoimide-based Nanoclusters for Activatable and Deep Photodynamic Therapy.

Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide-based nanocluster capable of enzyme-triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)-responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate-decorated albumins into a nanocluster (FHP) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor-specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP. Furthermore, such enzyme-triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8-fold) and elevated singlet oxygen generation ability (ca. 4-fold), enabling in situ near-infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging-guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme-triggered molecular disassembly is an effective strategy for precise cancer theranostics.

Immunological Responses Induced by Blood Protein Coronas on Two-Dimensional MoS2 Nanosheets.

Two-dimensional (2D) nanosheets (NSs) have a large surface area, high surface free energy, and ultrathin structure, which enable them to more easily penetrate biological membranes and promote adsorption of drugs and proteins. NSs are capable of adsorbing a large amount of blood proteins to form NSs-protein corona complexes; however, their inflammatory effects are still unknown. Therefore, we investigated the pro-inflammatory effect of 2D model nanosheet structures, molybdenum disulfide (MoS2), and the MoS2 NSs-protein complexes with four abundant proteins in human blood, i.e., human serum albumin (HSA), transferrin (Tf), fibrinogen (Fg), and immunoglobulin G (IgG). The interactions between the NSs and the proteins were analyzed by quantifying protein adsorption, determining binding affinity, and correlating structural changes in the protein corona with the uptake of NSs by macrophages and the subsequent inflammatory response. Although all of the NSs-protein complexes induced inflammation, IgG-coated and Fg-coated NSs triggered much stronger inflammatory effects by producing and releasing more cytokines. Among the four proteins, IgG possessed the highest proportion of ß-sheets and led to fewer secondary structure changes on the MoS2 nanosheets. This can facilitate uptake and produce a stronger pro-inflammatory response in macrophages due to the recognition of an NSs-IgG complex by Fc gamma receptors and the subsequent activation of the NF-κB pathways. Our results demonstrate that the blood protein components contribute to the inflammatory effects of nanosheets and provide important insights for the nanosafety evaluation and the rational design of nanomedicines in the future.

pH-responsive perylenediimide nanoparticles for cancer trimodality imaging and photothermal therapy.

Organic chromophores have been well developed for multimodality imaging-guided photothermal therapy (PTT) due to their outstanding optical properties and excellent designability. However, the theranostic efficiencies of most currently available organic chromophores are restricted intrinsically, owing to their poor photostability or complex synthesis procedures. These drawbacks not only increase their cost of synthesis, but also cause side effects in PTT. Method: We presented a facile strategy for constructing a near-infrared (NIR)-absorbing perylenediimide structured with pH-responsive piperazine ring at the bay region. The chromophore was conjugated with carboxyl-end-capped PEG as side chains that can self-assemble into nanoparticles (NPs) in aqueous solution. The NIR optical properties and photothermal conversation ability of PPDI-NPs were investigated. We then studied the imaging-guided PTT of PPDI-NPs under NIR light illumination in 4T1 cells and mice respectively. Results: The excellent photostable PPDI-NPs had near-infrared fluorescence (NIRF) emission and high photothermal conversion efficiency in acidic microenvironment. Importantly, PPDI-NPs can be utilized for the precise detection of tumors by NIRF/photoacoustic/thermal trimodality imaging. Efficient PTT of PPDI-NPs was applied in vitro and in vivo with high biosafety. Conclusion: In summary, we developed pH-responsive perylenediimide nanoparticles as multifunctional phototheranostic agent with high stability and simple synthesis procedures. This study offers a promising organic chromophore for developing phototheranostics in cancer therapy.

From Dyestuff Chemistry to Cancer Theranostics: The Rise of Rylenecarboximides.

Fighting cancer with the means of chemistry remains a tremendous challenge and defines a pressing societal need. Compounds based on synthetic organic dyes have long been recognized as vital tools for cancer diagnosis and therapy (theranostics). Fluorescence and photoacoustic imaging of cancer as well as cancer treatment protocols such as photodynamic and photothermal therapy are all photobased technologies that require chromophores. However, a serious drawback of most chromophoric molecules is photobleaching over the course of their use in biological environments, which severely compromises the desired theranostic effects. At this point, rylenecarboximide (RI) dyes with ultrahigh photostability hold enormous promise. RI stands for a homologous series of dyes consisting of an aromatic core and carboximide auxochromic groups. They possess high molar extinction coefficients and finely tunable photophysical properties. RIs such as perylenebiscarboxylic acid monoimide (PMI), perylenetetracarboxylic acid diimide (PDI), terrylenetetracarboxylic acid diimide (TDI), and quaterrylene tetracarboxylic acid diimide (QDI) have attracted great scientific attention as colorants, components of organic photovoltaics and organic field-effect transistors, as well as tools for biological applications. PDI has appeared as one of the most widely studied RI dyes for fluorescence bioimaging. Our recent breakthroughs including chemotherapy with PDI-based DNA intercalators and photothermal therapy guided by photoacoustic imaging using PDI, TDI, or QDI, define urgent needs for further scientific research and clinical translation. In this Account, we tackle the relationship between chemical structures and photophysical and pharmacologic properties of RIs aiming at new contrast and anticancer agents, which then lay the ground for further biomedical applications. First, we introduce the design concepts for RIs with a focus on their structure-property relationships. Chemical structure has an enormous impact on the fluorescent, chemotoxic, photodynamic, and photothermal performance of RIs. Next, based on the resulting performance criteria, we employ RIs for fluorescence and photoacoustic cancer imaging as well as cancer therapies. When carrying electron donating substituents, PDIs and PMIs possess high fluorescence quantum yield and red-shifted emission which qualifies them for use in cancer fluorescence imaging. Also, some fluorescent PDIs are combined with chemodrugs or developed into DNA intercalators for chemotherapy. PDI-based photosensitizers are prepared by "heavy atom" substitution, showing potential for photodynamic therapy. Further, photothermal agents using PDI, TDI, and QDI with near-infrared absorption and excellent photothermal conversion efficiency offer high promise in photothermal cancer therapy monitored by photoacoustic imaging. Finally, looking jointly at the outstanding properties of RIs and the demands of current biomedicine, we offer an outlook toward further modifications of RIs as a powerful and practical platform for advanced cancer theranostics as well as treatment of other diseases.

Dually Cross-Linked Supramolecular Hydrogel as Surface Plasmon Resonance Sensor for Small Molecule Detection.

Dually cross-linked supramolecular hydrogels (DCSH) are designed to show responsive properties while maintaining the gel structure by introducing two different kinds of cross-links. This is realized by utilizing a photo-cross-linker for permanent cross-linking and ß-cyclodextrin (ß-CD) and ferrocene (Fc) as host-guest recognition pair. The DCSH shows increased swelling in the presence of the small target molecule adamantane amine (Ada). Ada can break the non-covalent bonding between ß-CD and Fc through competitive molecular guest interaction with ß-CD. By using a combination of surface plasmon resonance and optical waveguide spectroscopy, it is possible to use this behavior to construct a reversible sensor for specific small molecule detection.

Green-Light-Triggered Phase Transition of Azobenzene Derivatives toward Reversible Adhesives.

Studies on the azobenzene derivative based phase transitions mostly rely on photoisomerization, which require a long time to spontaneously revert back. Here we show a photothermal-driven solid-to-liquid transition and fast reversion of azobenzene derivatives. Owing to the aggregation of suitably substituted azobenzenes, solid-to-liquid transitions can be induced by photothermal effects under irradiation with green light. The liquid-state azobenzene derivatives spontaneously solidify again within 2 min due to heat release in a purely physical fashion. One thus obtains a perfectly reversible adhesion with a strength as high as that of commercial materials. Our work affords a novel concept to construct reversible adhesives via phase transitions of organic compounds induced by light.

Perylene-Based Fluorescent Nanoprobe for Acid-Enhanced Detection of Formaldehyde in Lysosome.

Formaldehyde (FA), as a reactive carbonyl species, is extremely hazardous to human health if its concentration is above normal level. In live cells, lysosome is a main organelle to generate endogenous FA. Thus, the design of facile, stable, and sensitive probes for the detection of FA in lysosome is essential. Herein, a self-assembled fluorescent nanoprobe based on homoallylamino substituted perylene (P-FA) has been developed for FA detection in lysosome. P-FA can react with FA along with emission color change from blue to green. P-FA exhibited high sensitivity and selectivity to FA in DMSO solution. In aqueous solution, P-FA self-assembled into uniform sphere-like nanoparticle as a fluorescent nanoprobe. Furthermore, the reaction between the nanoprobe and FA was greatly facilitated at pH 4-5, which led to a lower detection limit (0.96 µM at pH 5) than that in DMSO. In live cells, P-FA nanoprobe achieved long-term tracking of lysosome (over 12 h). The fluorescent nanoprobe was then used for both exogenous and endogenous FA detection. Our work provides a facile and effective strategy for the detection of FA in lysosome.