Hypoxia Induced by Upconversion‐Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors

Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro‐drugs that can be activated at low‐oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica‐shelled upconversion nanoparticles (UCNPs) nanostructure capable of co‐delivering photosensitizer (PS) molecules and a bioreductive pro‐drug (tirapazamine, TPZ) were designed (TPZ‐UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC‐based (UC‐) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC‐PDT. Treatment with TPZ‐UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC‐PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much‐enhanced cytotoxicity of TPZ under PDT‐induced hypoxia.     

Luminescent Gold Nanorods To Enhance the Near-Infrared Emission of a Photosensitizer for Targeted Cancer Imaging and Dual Therapy: Experimental and Theoretical Approach

Strong plasmon absorption in the near-infrared (NIR) region renders gold nanorods (GNRs) amenable for biomedical applications, particularly for photothermal therapy. However, these nanostructures have not been explored for their imaging potential because of their weak emission profile. In this study, the weak fluorescence emission of GNRs is tuned to match that of the absorption of a photosensitizer (PS) molecule, and energy transfer from the GNR to PS enhances the emission profile of the GNR–PS combination. GNR complexes generally quench the fluorescence emission of nearby chromophores. However, herein, the complex retains or rather enhances the fluorescence through competition in energy transfer. Excitation-dependent energy transfer has been explained experimentally and theoretically by using DFT calculations, the CIE chromaticity diagram, and power spectrum. The final GNR–PS complex modified for tumor specificity serves as an excellent organ-specific theranostic probe for bioimaging and dual therapy both in vitro and in vivo. Principal component analysis designates photodynamic therapy a better candidate than that of photothermal therapy for long-term efficacy in vivo.     

Platelet‐Facilitated Photothermal Therapy of Head and Neck Squamous Cell Carcinoma

Here, we present a platelet‐facilitated photothermal tumor therapy (PLT‐PTT) strategy, in which PLTs act as carriers for targeted delivery of photothermal agents to tumor tissues and enhance the PTT effect. Gold nanorods (AuNRs) were first loaded into PLTs by electroporation and the resulting AuNR‐loaded PLTs (PLT‐AuNRs) inherited long blood circulation and cancer targeting characteristics from PLTs and good photothermal property from AuNRs. Using a gene‐knockout mouse model, we demonstrate that the administration of PLT‐AuNRs and localizing laser irradiation could effectively inhibit the growth of head and neck squamous cell carcinoma (HNSCC). In addition, we found that the PTT treatment augmented PLT‐AuNRs targeting to the tumor sites and in turn, improved the PTT effects in a feedback manner, demonstrating the unique self‐reinforcing characteristic of PLT‐PTT in cancer therapy.     

Dual‐Mode Antibacterial Conjugated Polymer Nanoparticles for Photothermal and Photodynamic Therapy

In this work, dual‐mode antibacterial conjugated polymer nanoparticles (DMCPNs) combined with photothermal therapy (PTT) and photodynamic therapy (PDT) are designed and explored for efficient killing of ampicillin‐resistant Escherichia coli (Amp^r E. coli). The DMCPNs are self‐assembled into nanoparticles with a size of 50.4 ± 0.6 nm by co‐precipitation method using the photothermal agent poly(diketopyrrolopyrrole‐thienothiophene) (PDPPTT) and the photosensitizer poly[2‐methoxy‐5‐((2‐ethylhexyl)oxy)‐p‐phenylenevinylene] (MEH‐PPV) in the presence of poly(styrene‐co‐maleic anhydride) which makes nanoparticles disperse well in water via hydrophobic interactions. Thus, DMCPNs simultaneously possess photothermal effect and the ability of sensitizing oxygen in the surrounding to generate reactive oxygen species upon the illumination of light, which could easily damage resistant bacteria. Under combined irradiation of near‐infrared light (550 mW cm^?2, 5 min) and white light (65 mW cm^?2, 5 min), DMCPNs with a concentration of 9.6 × 10^?4 µm could reach a 93% inhibition rate against Amp^r E. coli, which is higher than the efficiency treated by PTT or PDT alone. The dual‐mode nanoparticles provide potential for treating pathogenic infections induced by resistant microorganisms in clinic.     

Two‐Dimensional Nanomaterials for Photothermal Therapy

Two‐dimensional (2D) nanomaterials are currently explored as novel photothermal agents because of their ultrathin structure, high specific surface area, and unique optoelectronic properties. In addition to single photothermal therapy (PTT), 2D nanomaterials have demonstrated significant potential in PTT‐based synergistic therapies. In this Minireview, we summarize the recent progress in 2D nanomaterials for enhanced photothermal cancer therapy over the last five years. Their unique optical properties, typical synthesis methods, and surface modification are also covered. Emphasis is placed on their PTT and PTT‐synergized chemotherapy, photodynamic therapy, and immunotherapy. The major challenges of 2D photothermal agents are addressed and the promising prospects are also presented.     

铁掺杂的聚2-硝基-1,4-苯二胺纳米球的制备及在光热/光动力/化学动力学肿瘤治疗中的应用

肿瘤微环境(TME)的复杂性,使得单一治疗方式很难实现完全治愈。 为此,构建了一种负载吲哚菁绿(ICG)的铁掺杂的聚2-硝基-1,4-苯二胺多功能纳米球Fe-PNPD-ICG(FPIs),用于光热(PTT)/光动力(PDT)/化学动力学(CDT)的联合治疗。 在808 nm激光器照射下,ICG作为光敏剂可以产生单线态氧,铁掺杂的聚2-硝基-1,4-苯二胺纳米球作为光热剂具有36.65%的光热转换效率。 FPIs一旦内化到肿瘤内,由Fe³⁺/Fe²⁺转化引发Fenton反应产生·OH实现化学动力学治疗,反应过程中可以清除TME中过表达的谷胱甘肽(GSH),从而降低肿瘤中的抗氧化能力。 同时,产生的氧气可以改善TME中乏氧情况,增强PDT的治疗效果。 因此,FPIs是PTT/PDT/CDT联合治疗的一种理想材料,在肿瘤治疗中具有潜在的应用前景。     

Conjugated‐Polyelectrolyte‐Based Polyprodrug: Targeted and Image‐Guided Photodynamic and Chemotherapy with On‐Demand Drug Release upon Irradiation with a Single Light Source

Nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform are highly desirable for molecular medicine. Herein we report a novel theranostic platform based on a conjugated‐polyelectrolyte (CPE) polyprodrug that contains functionality for image, chemo‐ and photodynamic therapy (PDT), and on‐demand drug release upon irradiation with a single light source. Specifically, the PEGylated CPE serves as a photosensitizer and a carrier, and is covalently conjugated to doxorubicin through a linker that can be cleaved by reactive oxygen species (ROS). Under appropriate light irradiation, the CPE can generate ROS, not only for PDT, but also for on‐demand drug release and chemotherapy. This nanoplatform will offer on‐demand PDT and chemotherapy with drug release triggered by one light switch, which has great potential in cancer treatment.     

Development of a Novel Covalent Folate‐Albumin‐Photosensitizer Conjugate

There is considerable interest in the development of novel and more efficient delivery systems for improving the efficacy of photodynamic therapy (PDT). The authors in this highlighted issue describe the synthesis and the photobiological characterizations of two photosensitizer (PS) conjugates based on β‐carboline derivatives covalently conjugated to folic acid (FA) coupled to bovine serum albumin (BSA) as a carrier system specifically targeting cancer cells overexpressing FA receptor alpha (FRα). Accordingly, only the FA–BSA–β‐carboline conjugates are internalized specifically in FRα‐positive cells and are proved to be phototoxic. On the other hand, albumin–β‐carboline conjugates without FA or β‐carboline derivatives alone are not internalized and nontoxic. This conjugate is among the first to produce a conjugate composed of a PS and FA molecules that are directly conjugated to BSA. In addition, the in vitro studies are the first evidence that directly conjugated FA‐BSA can be used as carriers to selectively enhance cytotoxicity by PDT relative to unmodified PS or nontargeted BSA‐PS. This strategy is a positive step forward for the covalent design and construction of a photodynamic nanomedicine for FR‐positive tumors.     

GRP78‐Targeted HPMA Copolymer‐Photosensitizer Conjugate for Hyperthermia‐Induced Enhanced Uptake and Cytotoxicity in MCF‐7 Breast Cancer Cells

Photodynamic therapy (PDT) is a promising cancer treatment approach. However, the photosensitizers (PS) used for PDT are often limited by their poor solubility and selectivity for tumors. The goal of this study is to improve water solubility and delivery of the photosensitizer 2‐[1‐hexyloxyethyl]‐2‐divinyl pyropheophorbide‐a (HPPH) to breast cancer cells. An N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer–HPPH photosensitizer conjugate is synthesized with heat shock receptor glucose‐regulated protein 78 (GRP78), targeting to GRP78 receptors of MCF‐7 cells, which are upregulated under mild hyperthermia. It is found that the uptake of the GRP78 targeted pep‐HPMA‐HPPH copolymer conjugate in MCF‐7 cells is improved through heat induction. Under mild hyperthermia the targeted copolymers are more effective compared to free HPPH. These results show potential for the utility of mild hyperthermia and copolymer delivery vehicles to enhance the efficacy of photodynamic therapy.     

Nanoscaled porphyrinic metal–organic framework for photodynamic/photothermal therapy of tumor

Nanoagents achieving photodynamic therapy (PDT) and photothermal therapy (PTT) combination treatment with improved therapeutic effect are highly desirable. However, the incorporation of both PDT and PTT into a single nanoagent often requires multistep fabrication process. Herein, we report that photoactive porphyrin ligands have been successfully introduced into Zn‐TCPP structure to construct the nanoagents that possesses photodynamic performance and photothermal performance simultaneously. Such a nanoagent enables the generation of single oxygen and heat under laser irradiation. Additionally, it exhibits satisfactory biocompatibility and high light toxicity against cancer cells. The current work provides a feasible approach to introduce both PDT and PTT into a single nanoplatform.     

Simultaneous Application of Photothermal Therapy and an Anti‐inflammatory Prodrug using Pyrene–Aspirin‐Loaded Gold Nanorod Graphitic Nanocapsules

Photothermal therapy (PTT) has been extensively developed as an effective approach against cancer. However, PTT can trigger inflammatory responses, in turn simulating tumor regeneration and hindering subsequent therapy. A therapeutic strategy was developed to deliver enhanced PTT and simultaneously inhibit PTT‐induced inflammatory response. 1‐Pyrene methanol was utilize to synthesize the anti‐inflammatory prodrug pyrene–aspirin (P‐aspirin) with a cleavable ester bond and also facilitate loading the prodrug on gold nanorod (AuNR)‐encapsulated graphitic nanocapsule (AuNR@G), a photothermal agent, through π–π interactions. Such AuNR@G‐P‐aspirin complexes were used for near‐infrared laser‐triggered photothermal ablation of solid tumor and simultaneous inhibition of PTT‐induced inflammation through the release of aspirin in tumor milieu. This strategy showed excellent effects in vitro and in vivo.     

Stimuli‐Responsive NO Release for On‐Demand Gas‐Sensitized Synergistic Cancer Therapy

Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state‐of‐the‐art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli‐responsive NO‐releasing nanomedicines and their biomedical applications for on‐demand NO‐sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area.     

Pheophytin Derived Near‐Infrared‐Light Responsive Carbon Dot Assembly as a New Phototheranotic Agent for Bioimaging and Photodynamic Therapy

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo‐induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg‐free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near‐infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (¹O₂) generation with a quantum yield of 0.62. The self‐assembled CDs from the as‐prepared CDs with DSPE‐mPEG2000 retained efficient ¹O₂ generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.     

Three‐Pronged Attack by Homologous Far‐red/NIR AIEgens to Achieve 1+1+1>3 Synergistic Enhanced Photodynamic Therapy

Photodynamic therapy (PDT) has long been shown to be a powerful therapeutic modality for cancer. However, PDT is undiversified and has become stereotyped in recent years. Exploration of distinctive PDT methods is thus highly in demand but remains a severe challenge. Herein, an unprecedented 1+1+1>3 synergistic strategy is proposed and validated for the first time. Three homologous luminogens with aggregation‐induced emission (AIE) characteristics were rationally designed based on a simple backbone. Through slight structural tuning, these far‐red/near‐infrared AIE luminogens are capable of specifically anchoring to mitochondria, cell membrane, and lysosome, and effectively generating reactive oxygen species (ROS). Notably, biological studies demonstrated combined usage of three AIE photosensitizers gives multiple ROS sources simultaneously derived from several organelles, which gives superior therapeutic effect than that from a single organelle at the same photosensitizers concentration. This strategy is conceptually and operationally simple, providing an innovative approach and renewed awareness of improving therapeutic effect through three‐pronged PDT.     

Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

Combinatorial antitumor therapies using different combinations of drugs and genes are emerging as promising ways to overcome drug resistance, which is a major cause for the failure of cancer treatment. However, dramatic pharmacokinetic differences of drugs greatly impede their combined use in cancer therapy, raising the demand for drug delivery systems (DDSs) for tumor treatment. By employing fluorescent dithiomaleimide (DTM) as a linker, we conjugate two paclitaxel (PTX) molecules with a floxuridine (FdU)‐integrated antisense oligonucleotide (termed chemogene) to form a drug–chemogene conjugate. This PTX–chemogene conjugate can self‐assemble into a spherical nucleic acid (SNA)‐like micellular nanoparticle as a carrier‐free DDS, which knocks down the expression of P‐glycoprotein and subsequently releases FdU and PTX to exert a synergistic antitumor effect and greatly inhibit tumor growth.     

Simple Peptide‐Tuned Self‐Assembly of Photosensitizers towards Anticancer Photodynamic Therapy

Peptide‐tuned self‐assembly of functional components offers a strategy towards improved properties and unique functions of materials, but the requirement of many different functions and a lack of understanding of complex structures present a high barrier for applications. Herein, we report a photosensitive drug delivery system for photodynamic therapy (PDT) by a simple dipeptide‐ or amphiphilic amino‐acid‐tuned self‐assembly of photosensitizers (PSs). The assembled nanodrugs exhibit multiple favorable therapeutic features, including tunable size, high loading efficiency, and on‐demand drug release responding to pH, surfactant, and enzyme stimuli, as well as preferable cellular uptake and biodistribution. These features result in greatly enhanced PDT efficacy in vitro and in vivo, leading to almost complete tumor eradication in mice receiving a single drug dose and a single exposure to light.     

Cross‐linked Polymer‐Blend Gate Dielectrics through Thermal Click Chemistry

New cross‐linking reagents were synthesized and mixed with polystyrene (PS) in solution to form a blend. Thin‐films were spin‐coated from the blend and then cross‐linked by thermal activation at relatively low temperature (100 °C) to form cross‐linked gate dielectrics. This new method is compatible with plastic substrates in flexible electronics. The azide and alkyne cross‐linking reagents are kinetically stable at room temperature, so any premature cross‐linking is avoided during processing. This method also significantly improved the dielectric performances of PS thin films. Solution‐processed top‐gate organic field‐effect transistor devices with indacenodithiophene–benzothiadiazole copolymer as semiconductor layer and the cross‐linked PS blend as dielectric layer showed improved performances with lower gate leakages and higher operation stabilities than devices with neat PS film as dielectric layer.     

Upconverting Nanoparticles with a Mesoporous TiO2 Shell for Near‐Infrared‐Triggered Drug Delivery and Synergistic Targeted Cancer Therapy

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Herein, we report the synthesis of upconverting nanoparticles with a mesoporous TiO₂ (mTiO₂) shell for near‐infrared (NIR)‐triggered drug delivery and synergistic targeted cancer therapy. The NaGdF₄:Yb,Tm could convert NIR light to UV light, which activated the mTiO₂ to produce reactive oxygen species for photodynamic therapy (PDT). Due to the large surface area and porous structure, the mTiO₂ shell endowed the nanoplatform with another functionality of anticancer drug loading for chemotherapy. The hyaluronic acid modified on the surface not only promised controlled drug release but also conferred targeted ability of the system toward cluster determinant 44 overexpressed cancer cells. More importantly, cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or PDT.     

On‐Surface Synthesis and Characterization of Triply Fused Porphyrin–Graphene Nanoribbon Hybrids

On‐surface synthesis offers a versatile approach to prepare novel carbon‐based nanostructures that cannot be obtained by conventional solution chemistry. Graphene nanoribbons (GNRs) have potential for a variety of applications. A key issue for their application in molecular electronics is in the fine‐tuning of their electronic properties through structural modifications, such as heteroatom doping or the incorporation of non‐benzenoid rings. In this context, the covalent fusion of GNRs and porphyrins (Pors) is a highly appealing strategy. Herein we present the selective on‐surface synthesis of a Por–GNR hybrid, which consists of two Pors connected by a short GNR segment. The atomically precise structure of the Por–GNR hybrid has been characterized by bond‐resolved scanning tunneling microscopy (STM) and noncontact atomic force microscopy (nc‐AFM). The electronic properties have been investigated by scanning tunneling spectroscopy (STS), in combination with DFT calculations, which reveals a low electronic gap of 0.4 eV.     

A Supramolecular‐Based Dual‐Wavelength Phototherapeutic Agent with Broad‐Spectrum Antimicrobial Activity Against Drug‐Resistant Bacteria

With the ever‐increasing threat posed by the multi‐drug resistance of bacteria, the development of non‐antibiotic agents for the broad‐spectrum eradication of clinically prevalent superbugs remains a global challenge. Here, we demonstrate the simple supramolecular self‐assembly of structurally defined graphene nanoribbons (GNRs) with a cationic porphyrin (Pp4N) to afford unique one‐dimensional wire‐like GNR superstructures coated with Pp4N nanoparticles. This Pp4N/GNR nanocomposite displays excellent dual‐modal properties with significant reactive‐oxygen‐species (ROS) production (in photodynamic therapy) and temperature elevation (in photothermal therapy) upon light irradiation at 660 and 808 nm, respectively. This combined approach proved synergistic, providing an impressive antimicrobial effect that led to the complete annihilation of a wide spectrum of Gram‐positive, Gram‐negative, and drug‐resistant bacteria both in vitro and in vivo. The study also unveils the promise of GNRs as a new platform to develop dual‐modal antimicrobial agents that are able to overcome antibiotic resistance.