鲜红斑痣光动力治疗的模型仿真初步研究

为了研究光敏剂特性对光动力疗法(PDT)治疗鲜红斑痣(PWS)疗效的影响，帮助临床采取有效的治疗方案，建立了光动力治疗鲜红斑痣的数学模型。建立了卟啉类光敏剂受光激发产生单线态氧的数学模型以及光敏剂自身漂白过程和组织中扩散过程的数学模型，以国产光敏剂血啉甲醚(HMME)的实验数据为例，用蒙特卡罗方法仿真组织中的光分布，应用建立的单线态氧产生过程的数学模型，仿真光动力治疗鲜红斑痣过程中，组织内单线态氧产量的分布。对比不同的光敏剂漂白速度对组织中单线态氧产量的影响，发现漂白速率越快，破坏血管的同时对表皮和真皮组织的保护作用越好。这些结果为光动力疗法治疗鲜红斑痣的临床应用提供了具有针对性的指导。     

鲜红斑痣光动力治疗数学模型及临床验证

为了研究光动力治疗(PDT)中各个因素作用的规律,帮助临床采取有效的治疗方案,针对鲜红斑痣(PWS)组织特性,将光动力治疗中组织光分布、单线态氧产生、光敏剂漂白过程和光敏剂扩散过程结合起来,建立适合于光动力治疗鲜红斑痣病变的系统模型。利用建立的模型,对临床中出现的第二光斑治疗效果差的问题进行仿真研究,发现影响其治疗效果的因素,并通过仿真实验提出改进其治疗效果的新方案。通过临床实验,证明了新方案的有效性和模型的有效性。研究结果说明,针对特定的病例条件建立仿真模型,通过仿真实验可以为临床和理论研究提供一种有效的分析方法。     

Fluorination-Induced Multi-Enhancement of a Nano-Photosensitizer for Deep Photodynamic Therapy against Hypoxia Tumor

Organic dyes hold great promise for application in photodynamic therapy (PDT). However, they currently face challenges such as inadequate photodynamic activity, limited tumor penetration, and constraints imposed by tumor hypoxia. Here, a facile and efficient strategy is presented for multi-enhanced PDT through the fluorination of a squarylium indocyanine dye-based photosensitizer (FCy). The amphiphilic FCy features perfluorooctane and PEG-biotin moieties conjugated to a squarylium indocyanine core. In aqueous environments, FCy spontaneously self-assembles into stable nano-sized photosensitizers (FCy NPs), demonstrating a high oxygen loading ability attributable to the presence of perfluoroalkyl groups. Consequently, the aggregation of squarylium indocyanine dyes remarkably boosts the photodynamic effect, yielding a 15-fold improvement in singlet oxygen quantum yield. Owing to the perfluoroalkyl group, FCy NPs exhibit increased endoplasmic reticulum (ER)- accumulating abilities, which further induce ER stress upon laser irradiation and enhance the PDT effect. Furthermore, the superior deep tumor penetration ability of FCy NPs is confirmed through both in vitro and in vivo studies. With efficient oxygen supply to the deep tumor regions, FCy NPs demonstrate potent imaging-guided PDT against hypoxia tumors. The study substantiates the enhanced ER-accumulating ability of the perfluoroalkyl group and presents a facile fluorination strategy for the multi-enhancement of photosensitizers.     

Application of diode lasers in light-oxygen cancer therapy

Singlet oxygen is the lowest energy electronic excited state of the oxygen molecule which is able to damage living cells. This property has long been used for the sensitized destruction of tumors in photodynamic cancer therapy. Here it is shown that similar results can be achieved without photosensitizers by using the light-oxygen effect. High-power continuous-wave (cw) diode lasers emitting within the absorption bands of dissolved molecular oxygen are most appropriate for light-oxygen cancer therapy.     

NIR‐II Light Activated Photosensitizer with Aggregation‐Induced Emission for Precise and Efficient Two‐Photon Photodynamic Cancer Cell Ablation

Near infrared (NIR) light excitable photosensitizers are highly desirable for photodynamic therapy with deep penetration. Herein, a NIR‐II light (1200 nm) activated photosensitizer TQ‐BTPE is designed with aggregation‐induced singlet oxygen (¹O₂) generation for two‐photon photodynamic cancer cell ablation. TQ‐BTPE shows good two‐photon absorption and bright aggregation‐induced NIR‐I emission upon NIR‐II laser excitation. The ¹O₂ produced by TQ‐BTPE in an aqueous medium is much more efficient than that of commercial photosensitizer Ce6 under white light irradiation. Upon NIR‐II excitation, the two‐photon photosensitization of TQ‐BTPE is sevenfold higher than that of Ce6. The TQ‐BTPE molecules internalized by HeLa cells are mostly located in lysosomes as small aggregate dots with homogeneous distribution inside the cells, which favors efficient photodynamic cell ablation. The two‐photon photosensitization of TQ‐BTPE upon NIR‐I and NIR‐II excitation shows higher ¹O₂ generation efficiency than under NIR‐I excitation owing to the larger two‐photon absorption cross section at 920 nm. However, NIR‐II light exhibits better biological tissue penetration capability after passing through a fresh pork tissue, which facilitates stronger two‐photon photosensitization and better cancer cell ablation performance. This work highlights the promise of NIR‐II light excitable photosensitizers for deep‐tissue photodynamic therapy.     

Amplification of Cerenkov Luminescence Using Semiconducting Polymers for Cancer Theranostics

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation-induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross-sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have ≈100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, an optimized photosensitizer-doped SPN is investigated as a nanosystem to harness and amplify CL for cancer theranostics. It is found that semiconducting polymers significantly amplify CL energy transfer efficiency. Bimodal positron emission tomography (PET) and optical imaging studies show high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, it is found that photosensitizer-doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. This study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits.     

光动力抗菌纳米制剂研究进展

新兴的光动力抗菌疗法是一种无创激发式治疗手段,主要利用近红外光作为光源,激活富集在病灶部位的光敏剂并产生活性氧自由基,最终实现对目标病菌的杀伤。近年来,随着生物材料与纳米医学技术的发展,小分子光敏剂纳米功能化后其生物兼容性和生物安全性得到优化,量子产率和病灶部位富集率显著提升,在抗菌治疗方面有很大的临床应用前景。本文结合小分子光敏剂纳米化策略方法实例,综述了纳米技术在光动力抗菌疗法的应用和发展。     

X‐Ray‐Induced Persistent Luminescence Promotes Ultrasensitive Imaging and Effective Inhibition of Orthotopic Hepatic Tumors

Persistent luminescence imaging is accompanied by continuous illumination after the removal of excitation light, which can successfully prevent the generation of autofluorescence. In this study, a mesoporous silica template method is used to prepare uniform and monodisperse porous nanophosphors that can generate X‐ray‐excited persistent luminescence (XEPL). By loading photosensitizers, XEPL effectively excites the photosensitizers to produce reactive oxygen species for killing cancer cells. Imaging of orthotopic hepatic tumors in vivo shows that nanophosphors accumulate in the liver tumors through a passive targeting mechanism, as confirmed by the co‐imaging of bioluminescence and X‐ray‐excited luminescence. Under image‐guidance, X‐ray‐induced photodynamic therapy effectively inhibits the growth of orthotopic hepatic tumors with negligible side effects. Overall, X‐ray‐induced persistent luminescence promotes ultrasensitive imaging and effective inhibition of orthotopic hepatic tumors.     

An Iridium (III) Complex Bearing a Donor–Acceptor–Donor Type Ligand for NIR-Triggered Dual Phototherapy

Iridium(III) complexes are an important group of photosensitizers for photodynamic therapy (PDT). This work constructs a donor–acceptor–donor structure-based iridium(III) complex (IrDAD) with high reactive oxygen species (ROS) generation efficiency, negligible dark toxicity, and synergistic PDT and photothermal therapy (PTT) effect under near-infrared (NIR) stimulation. This complex self-assembles into metallosupramolecular aggregates with a unique aggregation-induced PDT behavior. Compared with conventional iridium(III) photosensitizers, IrDAD not only achieves NIR light deep tissue penetration but also shows highly efficient ROS and heat generation with ROS quantum yield of 14.6% and photothermal conversion efficiency of 27.5%. After conjugation with polyethylene glycol (PEG), IrDAD is formulated to a nanoparticulate system (IrDAD-NPs) with good solubility. In cancer phototherapy, IrDAD-NPs preferentially accumulate in tumor area and display a significant tumor inhibition in vivo, with 96% reduction in tumor volume, and even tumor elimination.     

Assembly of Au Plasmonic Photothermal Agent and Iron Oxide Nanoparticles on Ultrathin Black Phosphorus for Targeted Photothermal and Photodynamic Cancer Therapy

Photodynamic therapy (PDT), as a minimally invasive and high‐efficiency anticancer approach, has received extensive research attention recently. Despite plenty of effort devoted to exploring various types of photodynamic agents with strong near‐infrared (NIR) absorbance for PDT and many encouraging progresses achieved in the area, effective and safe photodynamic photosensitizers with good biodegradability and biocompatibility are still highly expected. In this work, a novel nanocomposite has been developed by assembly of iron oxide (Fe₃O₄) nanoparticles (NPs) and Au nanoparticles on black phosphorus sheets (BPs@Au@Fe₃O₄), which shows a broad light absorption band and a photodegradable character. In vitro and in vivo assay indicates that BPs@Au@Fe₃O₄ nanoparticles are highly biocompatible and exhibit excellent tumor inhibition efficacy owing to a synergistic photothermal and photodynamic therapy mediated by a low‐power NIR laser. Importantly, BPs@Au@Fe₃O₄ can anticipatorily suppress tumor growth by visualized synergistic therapy with the help of magnetic resonance imaging (MRI). This work presents the first combination application of the photodynamic and photothermal effect deriving from black phosphorus nanosheets and plasmonic photothermal effect from Au nanoparticles together with MRI from Fe₃O₄ NPs, which may open the new utilization of black phosphorus nanosheets in biomedicine, optoelectronic devices, and photocatalysis.     

Tumor-Activated Prodrug with Synergistic Anti-Stemness Chemical and Photodynamic Therapies

Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS-triggered self-immolative therapeutic prodrug ( Mu-PS ) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS-responsive trigger, for the anti-stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu-PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME-related ROS, generating massive phototoxic ¹O₂ to kill most non-CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti-stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self-immolatative prodrug for combined CSCs-involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.     

Biofilm-Sensitive Photodynamic Nanoparticles for Enhanced Penetration and Antibacterial Efficiency

Efficient antimicrobials are urgently needed for the treatment of bacterial biofilms due to their resistance to traditional drugs. Photodynamic therapy (PDT) is a new strategy that has been used to combat bacteria and biofilms. Cationic photosensitizers, particularly cationic photodynamic nanoagents, are usually chosen to enhance photodynamic antimicrobial activity. However, positively charged nanoparticles (NPs) are beneficial to cellular internalization, which causes increased cell cytotoxicity. Herein, a pH-sensitive photodynamic nanosystem is designed. Rose Bengal (RB) polydopamine (PDA) NPs are decorated in a layer-by-layer fashion with polymyxin B (PMB) and gluconic acid (GA) to generate functionally adaptive NPs (RB@PMB@GA NPs). RB@PMB@GA NPs remain negative at physiological pH and exhibit good biocompatibility. When RB@PMB@GA NPs are exposed to an acidic infectious environment, the surface charge of the NPs is, in turn, positively charged as a result of pH-sensitive electrostatic interactions. This surface charge conversion allows the RB@PMB@GA to effectively bind to the surfaces of bacteria and enhance photoinactivation efficiency against gram-negative bacteria. Most importantly, RB@PMB@GA NPs exhibit good biofilm penetration and eradication under acidic conditions. Furthermore, RB@PMB@GA NPs efficiently eliminate biofilm infections in vivo. This study provides a promising strategy for safely treating biofilm-associated infections in vivo.     

酞菁类光敏剂单重态氧量子产额的激光诱导ESR研究

本文应用激光诱导ESR波谱法研究酞菁类光敏剂的光动力反应动力学过程,对几种酞菁的单重态氧(~1O_2)相对量子产额进行了测定比较。     

Molecular Engineering of Efficient Singlet Oxygen Generators with Near-Infrared AIE Features for Mitochondrial Targeted Photodynamic Therapy

Aggregation-caused fluorescence quenching with insufficient production of reactive oxygen species (ROS) has limited the application of photosensitizers (PSs) in fluorescence-imaging-guided photodynamic therapy (PDT). Aggregation-induced emission PSs (AIE-PSs) exhibit enhanced fluorescence intensity and a high efficiency of ROS generation in the aggregation state, which provides an opportunity to solve the above problems. Herein, a series of AIE-PSs are successfully designed and synthesized by adjusting the D–A intensity through molecular engineering. The photophysical properties and theoretical calculations prove that the synergistic effect of 3,4-ethylenedioxythiophene and quinolinium increases the intramolecular charge transfer effect (ICT) of the whole molecule and promotes the intersystem crossing (ISC) from the lowest excited singlet state (S₁) to the lowest triplet state (T₁). Among these AIE-PSs, the optimal AIE-PS (TPA-DT-Qy) exhibits the highest generation yield of ¹O₂ (5.3-fold of Rose Bengal). Further PDT experiments show that the TPA-DT-Qy has a highly efficient photodynamic ablation of breast cancer cells (MCF-7 and MDA-MB-231) under white light irradiation. Moreover, the photodynamic antibacterial study indicates that TPA-DT-Qy has the discrimination and excellent photodynamic inactivation of S. aureus. This work provides a feasible strategy for the molecular engineering of novel AIE-PSs to improve the development of fluorescence-imaging-guided PDT.     

Dual Role of Subphthalocyanine Dyes for Optical Imaging and Therapy of Cancer

The family of subphthalocyanine (SubPc) macrocycles represents an interesting class of nonplanar aromatic dyes with promising features for energy conversion and optoelectronics. The use of SubPcs in biomedical research is, on the contrary, clearly underexplored, despite their documented high fluorescence and singlet oxygen quantum yields. Herein, for the first time it is shown that the interaction of these chromophores with light can also be useful for theranostic applications, which in the case of SubPcs comprise optical imaging and photodynamic therapy (PDT). In particular, the article evaluates, through a complete in vitro study, the dual‐role capacity of a novel series of SubPcs as fluorescent probes and PDT agents, where the macrocycle axial substitution determines their biological activity. The 2D and 3D imaging of various cancer cell lines (i.e., HeLa, SCC‐13, and A431) has revealed, for example, different subcellular localization of the studied photosensitizers (PS), depending on the axial substituent they bear. These results also show excellent photocytotoxicities, which are affected by the PS localization. With the best dual‐role PS, preliminary in vivo studies have demonstrated their therapeutic potential. Overall, the present paper sets the bases for an unprecedented biomedical use of these well‐known optoelectronic materials.     

Pegylated Composite Nanoparticles Containing Upconverting Phosphors and meso‐Tetraphenyl porphine (TPP) for Photodynamic Therapy

The utilization of upconverting nanophosphors (UCNP) for photodynamic therapy (PDT) has gained significant interests due to its ability to convert deep‐penetrating near‐infra red (NIR) light (i.e., 978 nm) to visible light. Previous attempts to co‐localize UCNPs with photosensitizers suffer from low photo­sensitizer loading and problems with nanoparticle aggregation. Here, the preparation of a novel composite nanoparticle formulation comprising 100 nm β?NaYF₄:Yb³⁺,Er³⁺ UCNPs, and meso‐tetraphenyl porphine (TPP) photo­sensitizer, stabilized by biocompatible poly(ethylene glycol‐block‐(dl )lactic acid) block copolymers (PEG‐b‐PLA) is presented. A photosensitizer loading of 10 wt% with respect to UCNP crystal was achieved via the Flash NanoPrecipitation (FNP) process. A sterically stabilizing PEG layer on the composite nanoparticle surface prevents nanoparticle aggregation and ensures nanoparticle stability in water, PBS buffer, and culture medium containing serum proteins, resulting in nanoparticle suitable for in vivo applications. Based on in vitro studies utilizing HeLa cervical cancer cell lines, the composite nanoparticles are shown to exhibit low dark toxicity and efficient cancer cell‐killing activity upon NIR excitation. Exposure with 134 W cm^?2 of 978 nm light for 45 min resulted in 75% HeLa cell death. This is the first quantification of the cell‐killing capabilities of the UCNP/TPP composite nanoparticles formulated for photodynamic therapy.     

Inverse Opal Photonic Hydrogels for Blue-Edge Slow Photon-Enhanced Photodynamic Antibacterial Therapy

Photodynamic therapy is promising for combating bacteria by reactive oxygen species. However, the therapeutic efficiency of photodynamic antibacterial therapy (PDAT) is largely hindered by limited photon absorption and the low quantum yield of photosensitizers. Herein, a novel light-harvesting platform is designed by decorating photosensitizer chlorine e6 (Ce6) into an inverse opal photonic hydrogel (Ce6/IOPG) framework for efficient light utilization to enhance PDAT. It is shown that the generating efficiency of singlet oxygen (¹O₂) can be tuned by the relative positions of the photonic bandgap (PBG) of IOPG and the absorption band of Ce6. The coupling of the slow photon effect with the efficient dispersion of Ce6 allows for a maximum generation of ¹O₂ of approximately 69.5-fold and markedly enhances PDAT activity upon low light irradiation when the blue edge of PBG overlaps with the absorption band of Ce6. Particularly, slow photons at the blue edge show advantages in improving ¹O₂ generation compared to those at the red edge. The variation in ¹O₂ generation by altering the incident angle of light provides direct evidence for the slow photon effect in Ce6/IOPG. This work provides insights into blue-edge slow photons in photodynamic enhancement and offers an advisable design principle for efficient antibacterial therapy.     

Development of Sulfonamide-Functionalized Charge-Reversal AIE Photosensitizers for Precise Photodynamic Therapy in the Acidic Tumor Microenvironment

Tumor-targeted photodynamic therapy (PDT) is desirable as it can achieve efficient killing of tumor cells with no or less harm to normal cells. Herein, a facile molecular engineering strategy is developed for photosensitizers (PSs) with aggregation induced emission (AIE) characteristics and responsive properties to the acidic tumor microenvironment (TME). By the marriage of pH-sensitive sulfonamide moieties with AIE PSs, two near-infrared AIE luminogens called DBP-SPy and DBP-SPh are designed and synthesized. Both luminogens can form negatively charged nanoaggregates in the aqueous medium at physiological pH. The DBP-SPy nanoaggregates undergo surface charge conversion to become positive at pH close to the signature pH of TME, while DBP-SPh nanoaggregates show no such property. The endowed response to acidic TME enables the enhanced cellular uptake of DBP-SPy at pH = 6.8. By contrast, its cellular uptake is much sacrificed at pH 7.4. As a result, under white light irradiation, DBP-SPy nanoaggregates demonstrate a considerable photodynamic therapeutic effect on cancer cells in vitro and excellent tumor growth inhibition in vivo. Hence, this study not only provides an acidic TME-responsive AIE PS for precise PDT, but also inspires new design strategies for AIE-based theragnostic systems with targeting characteristics.     

MC在大肠癌PDT中增效规律研究

目的：探讨超低浓度的丝裂霉素在大肠癌细胞光动力学疗法增效作用中对癌细胞杀伤作用规律。方法：在癌细胞培养的基础上,用超低浓度的丝裂霉素增效;光动力学疗法后采用荧光光地和ＭＴＴ法对癌细胞内光敏剂含量与激光照射后细胞存活率呈显著负相关;光动力学疗法后癌细胞存活率曲线明显左移,在８、１６小时细胞存活率显著降低;癌细胞与光敏剂作用８￣１６小时激光照射可达到最佳杀伤效果。结论：单独超低浓度的丝裂霉素对癌细胞无     

Lighting the Path: Light Delivery Strategies to Activate Photoresponsive Biomaterials In Vivo

Photoresponsive biomaterials are experiencing a transition from in vitro models to in vivo demonstrations that point toward clinical translation. Dynamic hydrogels for cell encapsulation, light-responsive carriers for controlled drug delivery, and nanomaterials containing photosensitizers for photodynamic therapy are relevant examples. Nonetheless, the step to the clinic largely depends on their combination with technologies to bring light into the body. This review highlights the challenge of photoactivation in vivo, and presents strategies for light management that can be adopted for this purpose. The authors’ focus is on technologies that are materials-driven, particularly upconversion nanoparticles that assist in “direct path” light delivery through tissue, and optical waveguides that “clear the path” between external light source and in vivo target. The authors’ intention is to assist the photoresponsive biomaterials community transition toward medical technologies by presenting light delivery concepts that can be integrated with the photoresponsive targets. The authors also aim to stimulate further innovation in materials-based light delivery platforms by highlighting needs and opportunities for in vivo photoactivation of biomaterials.