New Designs for Phototherapeutic Transition Metal Complexes

In this Minireview, we highlight recent advances in the design of transition metal complexes for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), and discuss the challenges and opportunities for the translation of such agents into clinical use. New designs for light‐activated transition metal complexes offer photoactivatable prodrugs with novel targeted mechanisms of action. Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side‐effects. The photophysical and photochemical properties of transition metal complexes can be controlled by the appropriate choice of the metal, its oxidation state, the number and types of ligands, and the coordination geometry.     

Planar AIEgens with Enhanced Solid‐State Luminescence and ROS Generation for Multidrug‐Resistant Bacteria Treatment

Planar luminogens have encountered difficulties in overcoming intrinsic aggregation‐caused emission quenching by intermolecular π‐π stacking interactions. Although excited‐state double‐bond reorganization (ESDBR) can guide us on designing planar aggregation‐induced emission (AIE) luminogens (AIEgens), its mechanism has yet been elucidated. Major challenges in the field include methods to efficiently restrict ESDBR and enhance AIE performance without using bulky substituents (e.g., tetraphenylethylene and triphenylamine). In this study, we rationally developed fluoro‐substituent AIEgens with stronger intermolecular H‐bonding interaction for restricted molecular motions and increased crystal density, leading to decreased nonradiative decay rate by one order of magnitude. The adjusted ESDBR properties also show a corresponding response to variation in viscosity. Furthermore, their aggregation‐induced reactive oxygen species (ROS) generations have been discovered. The application of such planar AIEgen in treating multidrug‐resistant bacteria has been demonstrated in a mouse model. The relationship between ROS generation and distinct E/Z‐configurational stacking behaviors have been further understood, providing a design principle for synthesizing planar AIEgen‐based photosensitizers.     

Mitochondrial‐DNA‐Targeted IrIII‐Containing Metallohelices with Tunable Photodynamic Therapy Efficacy in Cancer Cells

The development of DNA‐targeted photodynamic therapy (PDT) agents for cancer treatment has drawn substantial attention. Herein, the design and synthesis of dinuclear Ir^III‐containing luminescent metallohelices with tunable PDT efficacy that target mitochondrial DNA in cancer cells are reported. The metallohelices are fabricated using dynamic imine‐coupling chemistry between aldehyde end‐capped fac‐Ir(ppy)₃ handles and linear alkanediamine spacers, followed by reduction of the imine linkages. The length and odd–even character of the diamine alkyl linker determined the stereochemistry (helicates vs. mesocates). Compared to the helicates, the mesocates exhibit improved apoptosis‐induction upon white‐light irradiation. Molecular docking studies indicate that the mesocate with a proper length of diamine spacers shows stronger affinity for the minor groove of DNA. This study highlights the potential of DNA‐targeting Ir^III‐containing metallohelices as PDT agents.     

Peripheral RAFT Polymerization on a Covalent Organic Polymer with Enhanced Aqueous Compatibility for Controlled Generation of Singlet Oxygen

A covalent organic polymer (COP) is prepared by crosslinking the photosensitizer 4,4′,4′′,4′′′‐(porphyrin‐5,10,15,20‐tetrayl)tetraaniline (TAPP) with 4,4′‐(anthracene‐9,10‐diyl)dibenzoic acid (ADDA) via 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide/4‐dimethylaminopyridine coupling. The COP is further modified with a hydrophilic polymer, poly(poly(ethylene glycol) methyl ether methacrylate) by grafting‐from reversible‐addition‐fragmentation chain transfer (RAFT) polymerization to enhance its solubility in various solvents. The modified COP can bind singlet oxygen through the formation of endoperoxide by ADDA upon the exposure to red light irradiation. Singlet oxygen can be then released via the photodynamic mechanism or the cycloreversion by endoperoxide when heated at 110 °C. These results open new possibilities for simultaneous generation of singlet oxygen by the photodynamic route and singlet oxygen carriers, demonstrating promise for treating hypoxic tumors.     

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.     

四磺化酞菁锌与白蛋白复合物的制备、光谱性质与光动力活性研究

通过光谱法研究了四磺化酞菁锌(ZnPcPS4)与白蛋白(BSA和HSA)的相互作用。结果表明,白蛋白对ZnPcPS4的存在状态影响显著,两者存在较强的相互作用,结合常数为106数量级。结合位点竞争性实验表明,其相互作用的结合位点主要位于牛血清白蛋白的亚域ⅠB。进一步制备了ZnPcPS4-BSA和ZnPcPS4-HSA复合物,复合物中ZnPcPS4和白蛋白的摩尔比约为1∶1。光谱研究表明,复合物展现出比游离ZnPcPS4治疗更明显的单体特征吸收峰,且Q带最大吸收波长红移(从692 nm红移至696 nm),这有利于光动力治疗作用。光动力抗癌活性测试表明,ZnPcPS4-BSA具有较高的光动力抗癌活性,其IC_(50)值仅为1. 68μmol/L,活性明显高于其对应的游离ZnPcPS4(IC_(50)=2. 73μmol/L),可归因于复合物具有更高的癌细胞摄取率。     

A Size‐Reducible Nanodrug with an Aggregation‐Enhanced Photodynamic Effect for Deep Chemo‐Photodynamic Therapy

Fluorescent dyes with multi‐functionality are of great interest for photo‐based cancer theranostics. However, their low singlet oxygen quantum yield impedes their potential applications for photodynamic therapy (PDT). Now, a molecular self‐assembly strategy is presented for a nanodrug with a remarkably enhanced photodynamic effect based on a dye‐chemodrug conjugate. The self‐assembled nanodrug possesses an increased intersystem crossing rate owing to the aggregation of dye, leading to a distinct singlet oxygen quantum yield (Φ(¹O₂)). Subsequently, upon red light irradiation, the generated singlet oxygen reduces the size of the nanodrug from 90 to 10 nm, which facilitates deep tumor penetration of the nanodrug and release of chemodrug. The nanodrug achieved in situ tumor imaging and potent tumor inhibition by deep chemo‐PDT. Our work verifies a facile and effective self‐assembly strategy to construct nanodrugs with enhanced performance for cancer theranostics.     

Folate‐Conjugated and Dual Stimuli‐Responsive Mixed Micelles Loading Indocyanine Green for Photothermal and Photodynamic Therapy

A folic acid targeted mixed micelle system based on co‐assembly of poly(ε‐caprolactone)‐b‐poly(methoxytri(ethylene glycol) methacrylate‐co‐N‐(2‐methacrylamido)ethyl folatic amide) and poly(ε‐caprolactone)‐b‐poly(diethylene glycol monomethyl ether methacrylate) is developed to encapsulate indocyanine green (ICG) for photothermal therapy and photodynamic therapy. In this study, the use of folic acid is not only for specific cancer cell recognition, but also in virtue of the carboxylic acid on folic acid to regulate the pH‐dependent thermal phase transition of polymeric micelles for controlled drug release. The prepared ICG‐loaded mixed micelles possess several superior properties such as a preferable thermoresponsive behavior, excellent storage stability, and good local hyperthermia and reactive oxygen species generation under near‐infrared (NIR) irradiation. The photototoxicity induced by the ICG‐loaded micelles has efficiently suppressed the growth of HeLa cells (folate receptor positive cells) under NIR irradiation compared to that of HT‐29, which has low folate receptor expression. Hence, this new type of mixed micelles with excellent features could be a promising delivery system for controlled drug release, effective cancer cell targeting, and photoactivated therapy.