Tumor-Exocytosed Exosome/Aggregation-Induced Emission Luminogen Hybrid Nanovesicles Facilitate Efficient Tumor Penetration and Photodynamic Therapy

The development of novel photosensitizing agents with aggregation-induced emission (AIE) properties has fueled significant advances in the field of photodynamic therapy (PDT). An electroporation method was used to prepare tumor-exocytosed exosome/AIE luminogen (AIEgen) hybrid nanovesicles (DES) that could facilitate efficient tumor penetration. Dexamethasone was then used to normalize vascular function within the tumor microenvironment (TME) to reduce local hypoxia, thereby significantly enhancing the PDT efficacy of DES nanovesicles, and allowing them to effectively inhibit tumor growth. The hybridization of AIEgen and biological tumor-exocytosed exosomes was achieved for the first time, and combined with PDT approaches by normalizing the intratumoral vasculature as a means of reducing local tissue hypoxia. This work highlights a new approach to the design of AIEgen-based PDT systems and underscores the potential clinical value of AIEgens.     

Aggregation‐Induced Emission Gold Clustoluminogens for Enhanced Low‐Dose X‐ray‐Induced Photodynamic Therapy

The use of gold nanoparticles as radiosensitizers is an effective way to boost the killing efficacy of radiotherapy while drastically limiting the received dose and reducing the possible damage to normal tissues. Herein, we designed aggregation‐induced emission gold clustoluminogens (AIE‐Au) to achieve efficient low‐dose X‐ray‐induced photodynamic therapy (X‐PDT) with negligible side effects. The aggregates of glutathione‐protected gold clusters (GCs) assembled through a cationic polymer enhanced the X‐ray‐excited luminescence by 5.2‐fold. Under low‐dose X‐ray irradiation, AIE‐Au strongly absorbed X‐rays and efficiently generated hydroxyl radicals, which enhanced the radiotherapy effect. Additionally, X‐ray‐induced luminescence excited the conjugated photosensitizers, resulting in a PDT effect. The in vitro and in vivo experiments demonstrated that AIE‐Au effectively triggered the generation of reactive oxygen species with an order‐of‐magnitude reduction in the X‐ray dose, enabling highly effective cancer treatment.     

A Light‐Up Probe with Aggregation‐Induced Emission for Real‐Time Bio‐orthogonal Tumor Labeling and Image‐Guided Photodynamic Therapy

Bio‐orthogonal tumor labeling is more effective in delivering imaging agents or drugs to a tumor site than active targeting strategy owing to covalent ligation. However, to date, tumor‐specific imaging through bio‐orthogonal labeling largely relies on body clearance to differentiate target from the intrinsic probe signal owing to the lack of light‐up probes for in vivo bio‐orthogonal labeling. Now the first light‐up probe based on a fluorogen with aggregation‐induced emission for in vivo bio‐orthogonal fluorescence turn‐on tumor labeling is presented. The probe has low background fluorescence in aqueous media, showing negligible non‐specific interaction with normal tissues. Once it reacts with azide groups introduced to tumor cells through metabolic engineering, the probe fluorescence is lightened up very quickly, enabling rapid tumor‐specific imaging. The photosensitizing ability was also used to realize effective image‐guided photodynamic tumor therapy.     

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.     

Specific Light‐Up Bioprobe with Aggregation‐Induced Emission and Activatable Photoactivity for the Targeted and Image‐Guided Photodynamic Ablation of Cancer Cells

Activatable photosensitizers (PSs) have been widely used for the simultaneous fluorescence imaging and photodynamic ablation of cancer cells. However, the ready aggregation of traditional PSs in aqueous media can lead to fluorescence quenching as well as reduced phototoxicity even in the activated form. We have developed a series of PSs that show aggregation‐enhanced emission and phototoxicity and thus the exact opposite behavior to that of previously reported PSs. We further developed a dual‐targeted enzyme‐activatable bioprobe based on the optimized photosensitizer and describe simultaneous light‐up fluorescence imaging and activated photodynamic therapy for specific cancer cells. The design of smart probes should thus open new opportunities for targeted and image‐guided photodynamic therapy.     

NIR‐Induced Disintegration of CuS‐Loaded Nanogels for Improved Tumor Penetration and Enhanced Anticancer Therapy

Nanocarrier‐based cancer therapy suffers from poor tumor penetration and unsatisfied therapeutical efficacy, as its vascular extravasation efficiency is often compromised by the intrinsic physiological heterogeneity in tumor tissues. In this work, novel near infrared (NIR)‐responsive CuS‐loaded nanogels are prepared to deliver anticarcinogen into the tumor. These hybrid polymeric nanogels possess high photothermal conversion efficiency, and are able to load a large amount of antitumor drug (e.g., doxorubicin [DOX]). More importantly, the thermal heat could induce self‐destruction of the big‐size framework of hybrid nanogels into small nanoparticles, which greatly facilitates tumor penetration to release DOX deep inside the tumor, as validated by photoacoustic (PA) imaging which exhibits 26.3 times enhancement at the interior region compared to signals of groups without laser irradiation. Such structural alteration, combined with strong photothermal and chemotherapy effects, leads to remarkable inhibition of tumor growth in mice. As a result, this NIR‐induced disintegration of CuS‐loaded nanogels provides a novel drug delivery strategy and might open a new window for clinical cancer treatment.     

Molecular Design of Highly Efficient Heavy‐Atom‐Free Triplet BODIPY Derivatives for Photodynamic Therapy and Bioimaging

Novel BODIPY photosensitizers were developed for imaging‐guided photodynamic therapy. The introduction of a strong electron donor to the BODIPY core through a phenyl linker combined with the twisted arrangement between the donor and the BODIPY acceptor is essential for reducing the energy gap between the lowest singlet excited state and the lowest triplet state (ΔE_ST), leading to a significant enhancement in the intersystem crossing (ISC) of the BODIPYs. Remarkably, the BDP‐5 with the smallest ΔE_ST (ca. 0.44 eV) exhibited excellent singlet oxygen generation capabilities in both organic and aqueous solutions. BDP‐5 also displayed bright emission in the far‐red/near‐infrared region in the condensed states. More importantly, both in vitro and in vivo studies demonstrated that BDP‐5 NPs displayed a high potential for photodynamic cancer therapy and bioimaging.     

Highly Efficient,Conjugated‐Polymer‐Based Nano‐Photosensitizers for Selectively Targeted Two‐Photon Photodynamic Therapy and Imaging of Cancer Cells

Two‐photon photodynamic therapy (2P‐PDT) is a promising noninvasive treatment of cancers and other diseases with three‐dimensional selectivity and deep penetration. However, clinical applications of 2P‐PDT are limited by small two‐photon absorption (TPA) cross sections of traditional photosensitizers. The development of folate receptor targeted nano‐photosensitizers based on conjugated polymers is described. In these nano‐photosensitizers, poly{9,9‐bis[6′′‐(bromohexyl)fluorene‐2,7‐ylenevinylene]‐co‐alt‐1,4‐(2,5‐dicyanophenylene)}, which is a conjugated polymer with a large TPA cross section, acts as a two‐photon light‐harvesting material to significantly enhance the two‐photon properties of the doped photosensitizer tetraphenylporphyrin (TPP) through energy transfer. These nanoparticles displayed up to 1020‐fold enhancement in two‐photon excitation emission and about 870‐fold enhancement in the two‐photon‐induced singlet oxygen generation capability of TPP. Surface‐functionalized folic acid groups make these nanoparticles highly selective in targeting and killing KB cancer cells over NIH/3T3 normal cells. The 2P‐PDT activity of these nanoparticles was significantly improved, potentially up to about 1000 times, as implied by the enhancement factors of two‐photon excitation emission and singlet oxygen generation. These nanoparticles could act as novel two‐photon nano‐photosensitizers with combined advantages of low dark cytotoxicity, targeted 2P‐PDT with high selectivity, and simultaneous two‐photon fluorescence imaging capability; these are all required for ideal two‐photon photosensitizers.     

An AIE‐Active Conjugated Polymer with High ROS‐Generation Ability and Biocompatibility for Efficient Photodynamic Therapy of Bacterial Infections

New, biocompatible materials with favorable antibacterial activity are highly desirable. In this work, we develop a unique conjugated polymer featuring aggregation‐induced emission (AIE) for reliable bacterial eradication. Thanks to the AIE and donor‐π‐acceptor structure, this polymer shows a high reactive oxygen species (ROS)‐generation ability compared to a low‐mass model compound and the common photosensitizer Chlorin E6. Moreover, the selective binding of pathogenic microorganisms over mammalian cells was found, demonstrating its biocompatibility. The effective growth inhibition of bacteria upon polymer treatment under light irradiation was validated in vitro and in vivo. Notably, the recovery from infection after treatment with our polymer is faster than that with cefalotin. Thus, this polymer holds great promise in fighting against bacteria‐related infections in practical applications.     

Diketopyrrolopyrrole‐Porphyrin Conjugates with High Two‐Photon Absorption and Singlet Oxygen Generation for Two‐Photon Photodynamic Therapy

Two‐photon photodynamic therapy is a promising therapeutic method which requires the development of sensitizers with efficient two‐photon absorption and singlet‐oxygen generation. Reported here are two new diketopyrrolopyrrole‐porphyrin conjugates as robust two‐photon absorbing dyes with high two‐photon absorption cross‐sections within the therapeutic window. Furthermore, for the first time the singlet‐oxygen generation efficiency of diketopyrrolopyrrole‐containing systems is investigated. A preliminary study on cell culture showed efficient two‐photon induced phototoxicity.     

Encapsulation of Photosensitizer into Multilayer Microcapsules by Combination of Spontaneous Deposition and Heat‐Induced Shrinkage for Photodynamic Therapy

Annealing of PDADMAC/PSS multilayer microcapsules assembled on PSS‐doped CaCO₃ particles at 80 °C for 30 min reduces their size dramatically from 6.9 ± 0.3 to 3.1 ± 0.5 µm. Methylene blue molecules are encapsulated by spontaneous deposition and post‐annealing with a concentration of 22 mg · mL^?1, which is 1000 times higher than the feeding value. The unreleased MB molecules are retained stably for a long time, which are then protected by the capsules against reductive enzymes and keep their photodynamic activity. The viability of HeLa cells incubated with the MB‐loaded capsules decreases sharply from ≈75 (dark cytotoxicity) to ≈20% after irradiation with a laser at 671 nm and 60 J · cm^?2 for 75 s.

     

Photochemical Properties and Activity of Water‐Soluble Polymer/C60 Nanohybrids for Photodynamic Therapy

Water‐soluble star‐like poly(vinyl alcohol)/C₆₀ and poly{[poly(ethylene glycol) acrylate]‐co‐(vinyl acetate)}/C₆₀ nanohybrids are prepared by grafting macroradicals onto C₆₀ and are assessed as photosensitizers for photodynamic therapy. The photophysical and biological properties of both nanohybrids highlight key characteristics influencing their overall efficiency. The macromolecular structure (linear/graft) and nature (presence/absence of hydroxyl groups) of the polymeric arms respectively impact the photodynamic activity and the stealthiness of the nanohybrids. The advantages of both nanohybrids are encountered in a third one, poly[(N‐vinylpyrrolidone)‐co‐(vinyl acetate)]/C₆₀, which has linear grafts without hydroxyl groups, and shows a better photodynamic activity.

     

Highly Efficient Far Red/Near‐Infrared Solid Fluorophores: Aggregation‐Induced Emission,Intramolecular Charge Transfer,Twisted Molecular Conformation,and Bioimaging Applications

The development of organic fluorophores with efficient solid‐state emissions or aggregated‐state emissions in the red to near‐infrared region is still challenging. Reported herein are fluorophores having aggregation‐induced emission ranging from the orange to far red/near‐infrared (FR/NIR) region. The bioimaging performance of the designed fluorophore is shown to have potential as FR/NIR fluorescent probes for biological applications.     

Highly Efficient Far Red/Near‐Infrared Solid Fluorophores: Aggregation‐Induced Emission,Intramolecular Charge Transfer,Twisted Molecular Conformation,and Bioimaging Applications

The development of organic fluorophores with efficient solid‐state emissions or aggregated‐state emissions in the red to near‐infrared region is still challenging. Reported herein are fluorophores having aggregation‐induced emission ranging from the orange to far red/near‐infrared (FR/NIR) region. The bioimaging performance of the designed fluorophore is shown to have potential as FR/NIR fluorescent probes for biological applications.