Dan Ding

Highly Stable Organic Small Molecular Nanoparticles as an Advanced and Biocompatible Phototheranostic Agent of Tumor in Living Mice

Near-infrared (NIR)-absorbing organic small molecules hold great promise as the phototheranostic agents for clinical translation by virtue of their intrinsic advantages such as well-defined chemical structure, high purity, and good reproducibility. However, most of the currently available ones face the challenges in varying degrees in terms of photothermal instability, and photobleaching/reactive oxygen nitrogen species (RONS) inresistance, which indeed impair their practical applications in precise diagnosis and treatment of diseases. Herein, we developed highly stable and biocompatible organic nanoparticles (ONPs) for effective phototheranostic application by design and synthesis of an organic small molecule (namely TPA-T-TQ) with intensive absorption in the NIR window. The TPA-T-TQ ONPs with no noticeable in vivo toxicity possess better capacities in photothermal conversion and photoacoustic imaging (PAI), as well as show far higher stabilities including thermal/photothermal stabilities, and photobleaching/RONS resistances, when compared with the clinically popularly used indocyanine green. Thanks to the combined merits, the ONPs can serve as an efficient probe for in vivo PAI in a high-contrast manner, which also significantly causes the stoppage of tumor growth in living mice through PAI-guided photothermal therapy. This study thus provides an insight into the development of advanced NIR-absorbing small molecules for practical phototheranostic applications.

Regulating Near-Infrared Photodynamic Properties of Semiconducting Polymer Nanotheranostics for Optimized Cancer Therapy

Development of optical nanotheranostics for the capability of photodynamic therapy (PDT) provides opportunities for advanced cancer therapy. However, most nanotheranostic systems fail to regulate their generation levels of reactive oxygen species (ROS) according to the disease microenvironment, which can potentially limit their therapeutic selectivity and increase the risk of damage to normal tissues. We herein report the development of hybrid semiconducting polymer nanoparticles (SPNs) with self-regulated near-infrared (NIR) photodynamic properties for optimized cancer therapy. The SPNs comprise a binary component nanostructure: a NIR-absorbing semiconducting polymer acts as the NIR fluorescent PDT agent, while nanoceria serves as the smart intraparticle regular to decrease and increase ROS generation at physiologically neutral and pathologically acidic environments, respectively. As compared with nondoped SPNs, the NIR fluorescence imaging ability of nanoceria-doped SPNs is similar due to the optically inactive nature of nanoceria; however, the self-regulated photodynamic properties of nanoceria-doped SPN not only result in dramatically reduced nonspecific damage to normal tissue under NIR laser irradiation but also lead to significantly enhanced photodynamic efficacy for cancer therapy in a murine mouse model. This study thus provides a simple yet effective hybrid approach to modulate the phototherapeutic performance of organic photosensitizers.

High performance photosensitizers with aggregation-induced emission for image-guided photodynamic anticancer therapy

A series of D–A′–π–A type photosensitizers, AP3 and AP4, were designed and synthesized to show strong aggregation-induced far red and near infrared emission and very effective 1O2 generation simultaneously. In comparison with the most widely used photosensitizer, Ce6 nanoparticles, AP4 nanoparticles showed over 10-fold higher fluorescence quantum yield, and more than 3-fold higher 1O2 generation efficiency, and have been successfully used for image-guided photodynamic anticancer therapy.

Topology dictates function: controlled ROS production and mitochondria accumulation via curved carbon materials

Both reactive oxygen species (ROS) and mitochondria are involved in many physiological and pathological processes. Herein, we employed curved corannulene with a large dipole moment for controlled ROS production and mitochondria targeting. Corannulene was solubilized in water via complexation with gamma-cyclodextrin (1u2009:u20092). The complex could produce type I ROS in water in a dose- and irradiation time-dependent manner. The curvature-induced dipole moment aids electron transfer and hence enables ROS generation. As a consequence of electron delocalization, which facilitates mitochondrial uptake due to the large negative membrane potential of mitochondria, mitochondrial accumulation of corannulene was demonstrated. However, this is not valid for the flat perylene control. This discovery not only presents a new tool for controlled ROS production as well as mitochondria targeting in basic biomedical research, but also opens an avenue for the potential application of curved carbon materials as therapeutic agents.

In vivo cancer research using aggregation-induced emission organic nanoparticles

Exploration of a nanoplatform that benefits precise cancer diagnosis and treatment in vivo is particularly valuable. In recent years, aggregation-induced emission luminogens (AIEgens) have emerged as advanced fluorescent materials for the design and preparation of organic nanoparticles (NPs); they also have unique advantages in biomedical applications, especially in cancer diagnosis and theranostics. In this review, we summarize the current status of the development of AIEgen-based NPs for in vivo cancer research, including in vivo tumor diagnosis, drug delivery, and photodynamic therapy. We hope that our review will inspire more exciting research in cross-disciplinary fields, contributing to precise cancer diagnostics and therapeutics.

Biomarker Displacement Activation: A General Host–Guest Strategy for Targeted Phototheranostics in Vivo

Activatable phototheranostics is highly appealing to meet the demand of precision medicine. However, although it displays efficacy in the construction of activatable photosensitizers (PSs), direct covalent decoration still shows some inevitable issues, such as complex molecular design, tedious synthesis, possible photoactivity changes, and potential toxicity. Herein, we propose a novel concept of biomarker displacement activation (BDA) using host-guest strategy. To exemplify BDA, we engineered a PS-loaded nanocarrier by utilizing a macrocyclic amphiphile, where the fluorescence and photoactivity of PS were completely annihilated by the complexation of macrocyclic receptor (OFF state). When nanocarriers were accumulated into tumor tissues via the enhanced permeability and retention effect, the overexpressed biomarker adenosine triphosphates displaced PSs, accompanied by their fluorescence and photoactivity recovered (ON state). These reinstallations are unattainable in normal tissues, allowing us to concurrently achieve selective tumor imaging and targeted therapy in vivo. Compared with widely used covalent approach, the present BDA strategy provides the following advantages: (1) employment of approved PSs without custom covalent decoration; (2) traceless release of PSs with high fidelity by biomarker displacement; (3) adaptability to different PSs for establishing a universal platform and promised facile combination of diverse PSs to enhance photon utility in light window. Such a host-guest BDA strategy is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged.

Direct visualization and real-time monitoring of dissipative self-assembly by synchronously coupled aggregation-induced emission

Dissipative self-assembly is a chemical process ubiquitous in and essential to living systems. Its dynamic nature makes it quite appealing to directly visualize and monitor in real-time, thus facilitating the understanding of this phenomenon. Herein, we have demonstrated for the first time a dissipative self-assembling system that in situ exhibits intrinsic fluorescence only in the assembly state by the employment of AIEgens, enabling its direct visualization and real-time monitoring using fluorescence microscopy and spectroscopy, respectively. Fluorescence assay, as a non-invasive and real-time monitoring technique with high sensitivity and resolution, represents a privileged way to disclose the kinetics of dissipative systems, which is on demand on account of their dynamic feature. Furthermore, transient Forster resonance energy transfer was validated as a proof-of-principle function and also to afford dual-channel monitoring.

Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDTs antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

Sequentially Programmable and Cellularly Selective Assembly of Fluorescent Polymerized Vesicles for Monitoring Cell Apoptosis

Abstract The introduction of controlled self‐assembly into living organisms opens up desired biomedical applications in wide areas including bioimaging/assays, drug delivery, and tissue engineering. Besides the enzyme‐activated examples reported before, controlled self‐assembly under integrated stimuli, especially in the form of sequential input, is unprecedented and ultimately challenging. This study reports a programmable self‐assembling strategy in living cells under sequentially integrated control of both endogenous and exogenous stimuli. Fluorescent polymerized vesicles are constructed by using cholinesterase conversion followed by photopolymerization and thermochromism. Furthermore, as a proof‐of‐principle application, the cell apoptosis involved in the overexpression of cholinesterase in virtue of the generated fluorescence is monitored, showing potential in screening apoptosis‐inducing drugs. The approach exhibits multiple advantages for bioimaging in living cells, including specificity to cholinesterase, red emission, wash free, high signal‐to‐noise ratio.

Enzyme-instructed self-assembly leads to the activation of optical properties for selective fluorescence detection and photodynamic ablation of cancer cells

Both fluorescence and photoactivity activatable probes are particularly valuable for cancer theranostics as they allow for sensitive fluorescence diagnosis and on-demand photodynamic therapy (PDT) against targeted cancer cells at the same time, which undoubtedly promote the diagnostic accuracy and reduce the side effects on normal tissues/cells. Here, we show that enzyme-instructed self-assembly (EISA) is an ideal strategy to develop a both fluorescence and reactive oxygen species (ROS) generation capability activatable probe with aggregation-induced emission (AIE) signature. As a proof-of-concept, we design and synthesize a precursor TPE-Py-FpYGpYGpY that consists of an AIE luminogen (TPE-Py) and a short peptide with three tyrosine phosphates (pY), which permits selective fluorescence visualization and PDT of alkaline phosphatase (ALP)-overexpressed cancer cells. TPE-Py-FpYGpYGpY has good aqueous solubility thanks to the hydrophilic phosphotyrosine residues and hence leads to weak fluorescence and negligible ROS generation ability. After ALP enzymatic dephosphorylation of the precursors, however, self-assembly of ALP-catalysed products occurs and the resultant nanostructures are activated to be highly emissive and efficiently produce ROS. Cellular studies reveal that TPE-Py-FpYGpYGpY is capable of differentiating cancer cells and normal cells, specifically pinpointing and suppressing ALP-overexpressed cancer cells. This study may inspire new insights into the design of advanced activatable molecular probes.