A Self-Assembly-Induced Exciton Delocalization Strategy for Converting a Perylene Diimide Derivative from a Type-II to Type-I Photosensitizer.

Type-I photosensitizers have shown advantages in addressing the shortcomings of traditional oxygen-dependent type-II photosensitizers for the photodynamic therapy (PDT) of hypoxic tumors. However, developing type-I photosensitizers is yet a huge challenge because the type-II energy transfer process is much faster than the type-I electron transfer process. Herein, from the fundamental point of view, an effective approach is proposed to improve the electron transfer efficiency of the photosensitizer by lowering the internal reorganization energy and exciton binding energy via self-assembly-induced exciton delocalization. An example proof is presented by the design of a perylene diimide (PDI)-based photosensitizer (PDIMp) that can generate singlet oxygen (1O2) via a type-II energy transfer process in the monomeric state, but induce the generation of superoxide anion (O2˙-) via a type-I electron transfer process in the aggregated state. Significantly, with the addition ofcucurbit[6]uril (CB[6]), the self-assembled PDIMp can convert back to the monomeric state via host-guest complexation and consequently recover the generation of 1O2. The biological evaluations reveal that supramolecular nanoparticles (PDIMp-NPs) derived from PDIMp show superior phototherapeutic performance via synergistic type-I PDT and mild photothermal therapy (PTT) against cancer under either normoxia or hypoxia conditions.

Type I Photosensitizer Targeting Glycans: Overcoming Biofilm Resistance by Inhibiting the Two-Component System, Quorum Sensing, and Multidrug Efflux.

Stubborn biofilm infections pose serious threats to human health due to the persistence, recurrence, and dramatically magnified antibiotic resistance. Photodynamic therapy has emerged as a promising approach to combat biofilm. Nevertheless, how to inhibit the bacterial signal transduction system and the efflux pump to conquer biofilm recurrence and resistance remains a challenging and unaddressed issue. Herein, a boric acid-functionalized lipophilic cationic type I photosensitizer, ACR-DMP, is developed, which efficiently generates •OH to overcome the hypoxic microenvironment and photodynamically eradicates methicillin-resistant Staphylococcus aureus (MRSA) and biofilms. Furthermore, it not only alters membrane potential homeostasis and osmotic pressure balance due to its strong binding ability with plasma membrane but also inhibits quorum sensing and the two-component system, reduces virulence factors, and regulates the activity of the drug efflux pump attributed to the glycan-targeting ability, helping to prevent biofilm recurrence and conquer biofilm resistance. In vivo, ACR-DMP successfully obliterates MRSA biofilms attached to implanted medical catheters, alleviates inflammation, and promotes vascularization, thereby combating infections and accelerating wound healing. This work not only provides an efficient strategy to combat stubborn biofilm infections and bacterial multidrug resistance but also offers systematic guidance for the rational design of next-generation advanced antimicrobial materials.

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.

Selenium-Containing Type-I Organic Photosensitizers with Dual Reactive Oxygen Species of Superoxide and Hydroxyl Radicals as Switch-Hitter for Photodynamic Therapy.

Organic type-I photosensitizers (PSs) which produce aggressive reactive oxygen species (ROS) with less oxygen-dependent exhibit attractive curative effect for photodynamic therapy (PDT), as they adapt better to hypoxia microenvironment in tumors. However, the reported type-I PSs are limited and its exacted mechanism of oxygen dependence is still unclear. Herein, new selenium-containing type-I PSs of Se6 and Se5 with benzoselenadiazole acceptor has been designed and possessed aggregation-induced emission characteristic. Benefited from double heavy-atom-effect of selenium and bromine, Se6 shows a smaller energy gap (ΔEST ) of 0.03 eV and improves ROS efficiency. Interestingly, type-I radicals of both long-lived superoxide anion (O2 •‾ ) and short-lived hydroxyl (• OH) are generated from them upon irradiation. This may provide a switch-hitter of dual-radical with complementary lifetimes for PDT. More importantly, simultaneous processes to produce • OH are revealed, including disproportionation of O2 •‾ and reaction between excited PS and water. Actually, Se6 displays superior in-vitro PDT performance to commercial chlorin e6 (Ce6), under normoxia or hypoxia. After intravenous injection, a significantly in-vivo PDT performance is demonstrated on Se6, where tumor growth inhibition rates of 99% is higher than Ce6. These findings offer new insights about both molecular design and mechanism study of type-I PSs.

Self-Assembly Induced Photosensitization of Long-Tailed Heavy-Atom-Free BODIPY Derivatives for Photodynamic Therapy.

Type I photosensitizers (PSs) are a promising approach for photodynamic therapy (PDT) since they can generate radicals that are tolerant to hypoxia. Thus, the development of highly efficient type I PSs is essential. Self-assembly is a promising strategy for developing novel PSs with desirable properties. Here, a simple and effective approach is developed to create heavy-atom-free PSs for PDT by self-assembling long-tailed boron dipyrromethene dyes (BODIPYs). The resulting aggregates BY-I16 and BY-I18 can efficiently convert their excited energy to the triplet state, producing reactive oxygen species that are essential for PDT. Furthermore, the aggregation and PDT performance can be regulated by adjusting the length of the tailed alkyl chains. As proof of concept, the efficacy of these heavy-atom-free PSs both in vitro and in vivo under both normoxic and hypoxic conditions is demonstrated.

Manipulating the Subcellular Localization and Anticancer Effects of Benzophenothiaziniums by Minor Alterations of N-Alkylation.

Cationic, water-soluble benzophenothiaziniums have been recognized as effective type I photosensitizers (PSs) against hypoxic tumor cells. However, the study of the structure-property relationship of this type of PS is still worth further exploration to achieve optimized photodynamic effects and minimize the potential side effects. Herein, we synthesized a series of benzophenothiazine derivatives with minor N-alkyl alteration to study the effects on the structure-property relationships. The cellular uptake, subcellular organelle localization, reactive oxygen species (ROS) generation, and photocytotoxicity performances were systematically investigated. NH2NBS and EtNBS specifically localized in lysosomes and exhibited high toxicity under light with a moderate phototoxicity index (PI) due to the undesirable dark toxicity. However, NMe2NBS with two methyl substitutions accumulated more in mitochondria and displayed an excellent PI value with moderate light toxicity and negligible dark toxicity. Without light irradiation, NH2NBS and EtNBS could induce lysosomal membrane permeabilization (LMP), while NMe2NBS showed no obvious damage to lysosomes. After irradiation, NH2NBS and EtNBS were released from lysosomes and relocated into mitochondria. All compounds could induce mitochondria membrane potential (MMP) loss and nicotinamide adenine dinucleotide phosphate (NADPH) consumption under light to cause cell death. NMe2NBS exhibited remarkable in vivo photodynamic therapy (PDT) efficacy in a xenograft mouse tumor (inhibition rate, 89%) with no obvious side effects. This work provides a valuable methodology to investigate the structure-property relationships of benzophenothiazine dyes, which is of great importance in the practical application of PDT against hypoxia tumor cells.

Bioactive AIEgens Tailored for Specific and Sensitive Theranostics of Gram-Positive Bacterial Infection.

Diseases caused by bacterial infections are increasingly threatening human health. As a major part of the microbial family, Gram-positive bacteria induce severe infections in hospitals and communities. Therefore, developing antibacterial materials that can recognize bacteria and specifically kill them is significant to cope with fatal bacterial infection. To this end, we designed and prepared a series of positively charged photosensitizers with an aggregation-induced emission feature and a type I reactive oxygen species (ROS) generation ability. Based on a molecular engineering strategy, the PS abbreviated to MTTTPy that owns a superior ROS generation ability and red emission in aggregation is obtained by adjusting bridging groups. Due to the unique molecular structure, MTTTPy can sensitively and specifically recognize and light up Gram-positive bacteria through electrostatic adsorption and void permeability. In addition, it can kill 95% of the recognized bacteria at a low concentration of 0.5 µM by generating oxygen-independent ROS under white light irradiation. Both in vitro and in vivo studies verify the sensitive and specific recognition and killing effect of MTTTPy toward Gram-positive bacteria. This work provides superior material-integrated diagnosis and treatment for Gram-positive bacteria-caused infectious diseases and shows potential for addressing bacterial resistance.

Type I Photosensitizers Based on Aggregation-Induced Emission: A Rising Star in Photodynamic Therapy.

Photodynamic therapy (PDT), emerging as a minimally invasive therapeutic modality with precise controllability and high spatiotemporal accuracy, has earned significant advancements in the field of cancer and other non-cancerous diseases treatment. Thereinto, type I PDT represents an irreplaceable and meritorious part in contributing to these delightful achievements since its distinctive hypoxia tolerance can perfectly compensate for the high oxygen-dependent type II PDT, particularly in hypoxic tissues. Regarding the diverse type I photosensitizers (PSs) that light up type I PDT, aggregation-induced emission (AIE)-active type I PSs are currently arousing great research interest owing to their distinguished AIE and aggregation-induced generation of reactive oxygen species (AIE-ROS) features. In this review, we offer a comprehensive overview of the cutting-edge advances of novel AIE-active type I PSs by delineating the photophysical and photochemical mechanisms of the type I pathway, summarizing the current molecular design strategies for promoting the type I process, and showcasing current bioapplications, in succession. Notably, the strategies to construct highly efficient type I AIE PSs were elucidated in detail from the two aspects of introducing high electron affinity groups, and enhancing intramolecular charge transfer (ICT) intensity. Lastly, we present a brief conclusion, and a discussion on the current limitations and proposed opportunities.

Cationization-Enhanced Type I and Type II ROS Generation for Photodynamic Treatment of Drug-Resistant Bacteria.

Photodynamic therapy as an emerging phototheranostic approach holds great potential for antibacterial treatment, but is limited by compromised reactive oxygen species (ROS) generation in an aggregate and hypoxic microenvironment. Herein, we report a molecular cationization approach to boost the ROS, especially type I ROS generation of aggregation-induced emission (AIE) photosensitizers for photodynamic treatment of drug-resistant bacteria. Such cationization reinforces the electron-accepting ability of the cationic moiety, promotes intersystem crossing (ISC), and increases electron separation and transfer processes. The resultant CTBZPyI exhibits largely enhanced ROS generation ability with predominant hydroxyl radical generation over its neutral counterpart in aggregate. Moreover, cationization also confers CTBZPyI with the bacterial binding ability and a moderate bacterial inactivation ability in the dark. Further light irradiation leads to superb antibacterial performance, which largely promotes the healing process of a MRSA-infected wound. Such a cationization strategy is expected to be a general strategy for the design of highly effective type I photosensitizers for bacterial infection treatment.

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.

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.

Achieving Efficient NIR-II Type-I Photosensitizers for Photodynamic/Photothermal Therapy upon Regulating Chalcogen Elements.

Second near-infrared (NIR-II) window type-I photosensitizers have intrinsic advantages in photodynamic/photothermal therapy (PDT/PTT) of some malignant tumors with deep infiltration, large size, complicated location, and low possibility of surgery/radiotherapy. Herein, three chalcogen-element-based donor-acceptor-type semiconducting polymers (poly[2,2″-((E)-4,4″-bis(2-octyldodecyl)-[6,6″-bithieno[3,2-b]pyrrolylidene]-5,5″(4H,4″H)-dione)-alt-2,5-(thiophene)] (PTS), poly[2,2″-((E)-4,4″-bis(2-octyldodecyl)-[6,6″-bithieno[3,2-b]pyrrolylidene]-5,5″(4H,4″H)-dione)-alt-2,5-(selenophene)] (PTSe), and poly[2,2″-((E)-4,4″-bis(2-octyldodecyl)-[6,6″-bithieno[3,2-b]pyrrolylidene]-5,5″(4H,4'H)-dione)-alt-2,5-(tellurophene)] (PTTe)) are synthesized and fully characterized, demonstrating strong absorption in the NIR-II region. Upon adjusting the chalcogen elements, the intramolecular charge-transfer characteristics and the heavy-atom effect are tuned to enhance the intersystem crossing rate, improving the photodynamic effect. Moreover, the energy levels and Gibbs free energies are tuned to facilitate the type-I photodynamic process. As a result, PTTe nanoparticles (NPs) produce superoxide anion radicals (O2 •- ) more efficiently and demonstrate higher photothermal conversion efficiency than PTS and PTSe NPs upon NIR-II (1064 nm) laser irradiation, exhibiting unprecedented NIR-II type-I PDT/PTT performance in vitro and in vivo. This work provides ideas for achieving high-performance NIR-II type-I PDT/PTT semiconducting polymers for hypoxic oncotherapy.

Type I Photosensitizers Revitalizing Photodynamic Oncotherapy.

Photodynamic therapy (PDT) has shown great potential for tumor treatment with merits of non-invasiveness, high selectivity, and minimal side effects. However, conventional type II PDT relying on 1 O2 presents poor therapeutic efficacy for hypoxic tumors due to the oxygen-dependent manner. Alternatively, emerging researches have demonstrated that type I PDT exhibits superiority over type II PDT in tumor treatment owing to its diminished oxygen-dependence. In this review, state-of-the-art studies concerning recent progress in type I photosensitizers are scrutinized, emphasizing the strategies to construct highly effective type I photosensitizers. As the foundation, basic principles of type I PDT are presented, and up-to-date type I photosensitizers are summarized and classified based on their attributes. Then, a literature review of representative type I photosensitizers (including nanomaterials and small molecules) is presented with impetus to delineate their novel designs, action mechanisms, as well as anticancer PDT applications. Finally, the remaining challenges and development directions of type I photosensitizers are outlined, highlighting key scientific issues toward clinical translations.

Photosensitizing anthraquinones from Heterophyllaea lycioides (Rubiaceae).

Seven anthraquinones were isolated from aerial parts of Heterophyllaea lycioides (Rusby) Sandwith (Rubiaceae), including three derivatives that have not been described before: a hetero-bianthraquinone identified as (R)-2-hydroxymethyl-2'methyl-1,1',6,6'-tetrahydroxy-5,5' bianthraquinone (lycionine), and two mono-chlorinated derivatives related to soranjidiol. One of them is a homo-bianthraquinone: (R)-7-chloro-2,2'-dimethyl-1,1',6,6'-tetrahydroxy-5,5' bianthraquinone (7-chlorobisoranjidiol), whereas the second halogenated derivative corresponds to a monomeric structure: 5-chloro-1,6-dihydroxy-2-methyl anthraquinone (5-chlorosoranjidiol). The four known compounds were already isolated from another species of this genus, H. pustulata, and they were identified as 5,5'-bisoranjidiol, soranjidiol, pustuline and heterophylline. Structural elucidation was performed by means of an extensive spectroscopic analysis, including 1D and 2D NMR data as well as by HRMS analysis. Chemical structures of 7-chlorobisoranjidiol and 5-chlorosoranjidiol were confirmed by their synthesis from 5,5'-bisoranjidiol and soranjidiol, respectively. Type I photosensitizing properties (superoxide anion radical generation, O2-) were assessed by using the nitroblue tetrazolium assay. When lycionine and chlorinated derivatives were irradiated, they enhanced the O2- production with respect to the control; 7-chlorobisoranjidiol stood out by generating an increase of 20%, whereas the other anthraquinones only produced a slight increase of 7%.