Self-Adaptive Photodynamic-to-Photothermal Switch for Smart Antitumor Photoimmunotherapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.

A Cascade Strategy Boosting Hydroxyl Radical Generation with Aggregation-Induced Emission Photosensitizers-Albumin Complex for Photodynamic Therapy.

Effective photodynamic therapy (PDT) requires photosensitizers (PSs) to massively generate type I reactive oxygen species (ROS) in a less oxygen-dependent manner in the hypoxia tumor microenvironment. Herein, we present a cascade strategy to boost type I ROS, especially hydroxyl radical (OH·-), generation with an aggregation-induced emission (AIE) photosensitizer-albumin complex for hypoxia-tolerant PDT. The cationic AIE PS TPAQ-Py-PF6 (TPA = triphenylamine, Q = anthraquinone, Py = pyridine) contains three important moieties to cooperatively enhance free radical generation: the AIE-active TPA unit ensures the effective triplet exciton generation in aggregate, the anthraquinone moiety possesses the redox cycling ability to promote electron transfer, while the cationic methylpyridinium cation further increases intramolecular charge transfer and electron separation processes. Inserting the cationic TPAQ-Py-PF6 into the hydrophobic domain of bovine serum albumin nanoparticles (BSA NPs) could greatly immobilize its molecular geometry to further increase triplet exciton generation, while the electron-rich microenvironment of BSA ultimately leads to OH·- generation. Both experimental and theoretical results confirm the effectiveness of our molecular cationization and BSA immobilization cascade strategy for enhancing OH·- generation. In vitro and in vivo experiments validate the excellent antitumor PDT performance of BSA NPs, superior to the conventional polymeric encapsulation approach. Such a multidimensional cascade strategy for specially boosting OH·- generation shall hold great potential in hypoxia-tolerant PDT and related antitumor applications.

Pure Organic AIE Nanoscintillator for X-ray Mediated Type I and Type II Photodynamic Therapy.

X-ray induced photodynamic therapy (X-PDT) circumvents the poor penetration depth of conventional PDT with minimal radio-resistance generation. However, conventional X-PDT typically requires inorganic scintillators as energy transducers to excite neighboring photosensitizers (PSs) to generate reactive oxygen species (ROS). Herein, a pure organic aggregation-induced emission (AIE) nanoscintillator (TBDCR NPs) that can massively generate both type I and type II ROS under direct X-ray irradiation is reported for hypoxia-tolerant X-PDT. Heteroatoms are introduced to enhance X-ray harvesting and ROS generation ability, and AIE-active TBDCR exhibits aggregation-enhanced ROS especially less oxygen-dependent hydroxyl radical (HO•- , type I) generation ability. TBDCR NPs with a distinctive PEG crystalline shell to provide a rigid intraparticle microenvironment show further enhanced ROS generation. Intriguingly, TBDCR NPs show bright near-infrared fluorescence and massive singlet oxygen and HO•- generation under direct X-ray irradiation, which demonstrate excellent antitumor X-PDT performance both in vitro and in vivo. To the best of knowledge, this is the first pure organic PS capable of generating both 1 O2 and radicals (HO•- ) in response to direct X-ray irradiation, which shall provide new insights for designing organic scintillators with excellent X-ray harvesting and predominant free radical generation for efficient X-PDT.

Cationization to boost both type I and type II ROS generation for photodynamic therapy.

The pursuing of photosensitizers (PSs) with efficient reactive oxygen species (ROS) especially type I ROS generation in aggregate is always in high demand for photodynamic therapy (PDT) and photoimmunotherapy but remains to be a big challenge. Herein, we report a cationization molecular engineering strategy to boost both singlet oxygen and radical generation for PDT. Cationization could convert the neutral donor-acceptor (D-A) typed molecules with the dicyanoisophorone-triphenylamine core (DTPAN, DTPAPy) to their A-D-A' typed cationic counterparts (DTPANPF6 and DTPAPyPF6). Our experiment and simulation results reveal that such cationization could enhance the aggregation-induced emission (AIE) feature, promote the intersystem crossing (ISC) processes, and increase the charge transfer and separation ability, all of which work collaboratively to promote the efficient generation of ROS especially hydroxyl and superoxide radicals in aggregates. Moreover, these cationic AIE PSs also possess specific cancer cell mitochondrial targeting capability, which could further promote the PDT efficacy both in vitro and in vivo. Therefore, we expect this delicate molecular design represents an attractive paradigm to guide the design of type I AIE PSs for the further development of PDT.

Recent Progress in Type I Aggregation-Induced Emission Photosensitizers for Photodynamic Therapy.

In modern medicine, precision diagnosis and treatment using optical materials, such as fluorescence/photoacoustic imaging-guided photodynamic therapy (PDT), are becoming increasingly popular. Photosensitizers (PSs) are the most important component of PDT. Different from conventional PSs with planar molecular structures, which are susceptible to quenching effects caused by aggregation, the distinct advantages of AIE fluorogens open up new avenues for the development of image-guided PDT with improved treatment accuracy and efficacy in practical applications. It is critical that as much of the energy absorbed by optical materials is dissipated into the pathways required to maximize biomedical applications as possible. Intersystem crossing (ISC) represents a key step during the energy conversion process that determines many fundamental optical properties, such as increasing the efficiency of reactive oxygen species (ROS) production from PSs, thus enhancing PDT efficacy. Although some review articles have summarized the accomplishments of various optical materials in imaging and therapeutics, few of them have focused on how to improve the phototherapeutic applications, especially PDT, by adjusting the ISC process of organic optics materials. In this review, we emphasize the latest advances in the reasonable design of AIE-active PSs with type I photochemical mechanism for anticancer or antibacterial applications based on ISC modulation, as well as discuss the future prospects and challenges of them. In order to maximize the anticancer or antibacterial effects of type I AIE PSs, it is the aim of this review to offer advice for their design with the best energy conversion.

A novel near-infrared fluorescent probe for highly selective detection of cysteine and its application in living cells.

A novel red-emitting fluorescent probe (DDNA) for cysteine has been rationally designed and synthesized, which exhibited a low limit of detection to Cys (0.26 µM) as well as a favorable large stokes shift (λEm-λEx = 128 nm). This novel fluorophore (HDM), which features a large π-conjugation system and typical intramolecular charge transfer (ICT) process, has a long emission wavelength at 631 nm. Besides that, as a turn-on fluorescent probe, it shows high selectivity and sensitivity for Cys over other metal ions and amino acids including the similar structured homocysteine (Hcy) and glutathione (GSH). Finally, the probe DDNA was successfully applied to bioimage intracellular Cys in Hela cells with low cytotoxicity.

A novel benzothiazole-based fluorescent probe for cysteine detection and its application on test paper and in living cells.

A novel simple and readily synthesized turn-on fluorescent probe 4-(benzo[d]thiazol-2-yl)-1,3-phenylene bis(2-chloroacetate) (BPBC) for cysteine (Cys) was reported. This probe was designed based on an excited-state intramolecular proton transfer (ESIPT) dye: benzothiazole, and two chloroacetate groups present in benzothiazole as the reaction sites for Cys. It shows high selectivity and sensitivity for Cys over other amino acids including the similar structured homocysteine (Hcy) and glutathione (GSH). In addition, probe BPBC was successfully applied to bioimage intracellular Cys in living cells with low cytotoxicity. More importantly, a paper test strip system was developed with probe BPBC for Cys detection conveniently.