Type-I Photodynamic Therapy Induced by Pt-Coordination of Type-II Photosensitizers into Supramolecular Complexes.

Platinum supramolecular complexes based on photosensitizers have garnered great interest in photodynamic therapy (PDT) due to Pt (II) centers as chemotherapeutic agents to eliminate tumor cells completely, which greatly improve the antitumor efficacy of PDT. However, in comparison to precursor photosensitizer ligand, the formed platinum supramolecular complexes typically exhibit inferior outcomes in terms of reactive oxygen species (ROS) generation. How to boost ROS generation in the formed platinum supramolecular complexes for enhanced PDT is an enticing yet highly challenging task. Here we report a Pt-coordination-based dimeric photosensitizer complex (Cz-BTZ-Py)2Pt(OTf)2. It is found that comparing with photosensitizer ligand Cz-BTZ-Py, the formed supramolecular complex exhibit redshifts of absorption wavelength as well as enhanced ROS generation efficiency. Moreover, type-I ROS generation (O2⋅-) is produced in the formed platinum supramolecular complexes mainly due to a reduced energy gap ΔEST resulting from exciton coupling between two photosensitizer ligands. And type-I ROS (O2⋅-) generation significantly amplifies the photodynamic therapy (PDT) outcomes. In vitro evaluation shows excellent photochemotherapy performance of (Cz-BTZ-Py)2Pt(OTf)2 nanoparticles. We anticipate this work would provide a novel approach to design type-I photosensitizers for efficient PDT.

Metal-Coordination-Mediated H-Aggregates of Cyanine Dyes for Effective Photothermal Therapy.

Integration of cyanine dyes and metal ions into one nanoplatform via metal-coordination interactions is an effective strategy to build multimodality phototheranostics. The multifunctionalities of the formed nanoscale metal-organic particles (NMOPs) have been widely explored. However, the effect of metal-coordination interaction on the aggregation behavior of cyanine dyes is rarely reported. Herein, we reported the H-aggregation behavior of cyanine dye Cy-3COOH induced by different metal ions M (Fe2+ or Mn2+ ). Moreover, the extent of H-aggregates varied with different metal-coordination interactions. Upon NIR irradiation, H-aggregates of Cy-3COOH remarkably promoted photothermal conversion efficiency. Interestingly, we also find that H-aggregates of Cy-3COOH induced by metal ions can generate the reactive oxygen species (ROS) involving singlet oxygen (1 O2 ) and superoxide anion radical (O2 - ⋅) upon light irradiation. In addition, the ROS efficiency varies depending on the extent of H-aggregates. Additionally, the photoinduced ROS could disassemble aggregates and decompose cyanine dye Cy-3COOH, which limits the photothermal capability of Cy-3COOH/M NPs. Therefore, the photothermal performance of Cy-3COOH/M NPs could be manipulated by the degree of H-aggregation. This would provide a new insight to develop efficient phototheranostics NMOPs for cancer treatment.

A Selenium-Substituted Heptamethine Cyanine Photosensitizer for Near-Infrared Photodynamic Therapy.

Photodynamic therapy (PDT) is a relatively safe approach to cancer treatment without significant systemic side effects or drug resistance. However, the current PDT efficiency is unsatisfactory due to the lack of near-infrared (NIR) photosensitizers. Heptamethine cyanine (Cy7) dyes are well-known NIR fluorophores and are also used as photosensitizers. But their singlet oxygen quantum yields (ΦΔ ) are not ideal. Herein, we developed an NIR photosensitizer with a long-lived excited triplet state (τ=4.3 µs) by introducing a selenium atom into the structure of a Cy7 dye. The new NIR photosensitizer exhibits a significantly high singlet oxygen quantum yield (ΦΔ =0.11). Its good PDT effect was demonstrated in the living cells. Considering that the selenium-substituted photosensitizer has a very low dark cytotoxicity and good chemical stability, we conclude that it will have a promising future in biomedical and clinical applications.

Photothermal agents based on small organic fluorophores with intramolecular motion.

Photothermal therapy (PTT) has attracted great attention due to its noninvasive and low side effects. Photothermal agents (PTAs) which could convert absorbing light into heat play a critical role in PTT. For conventional small organic PTAs, the photothermal conversion ability is mainly achieved by intermolecular noncovalent interactions such as π-π interactions. However, in terms of organic fluorophores with rotator or vibrator segments, the balance between fluorescence emission and heat generation is mainly regulated by intramolecular motions which could be mediated by molecular engineering. Following this designing principle, various fluorophores with intramolecular motions for effective PTT have been reported. In this review, we highlight the recent progress of PTAs based on small organic fluorophores with intramolecular motions for enhanced PTT. Designing tactics of these fluorophores to afford long-wavelength absorption, high photothermal conversion ability, and effective accumulation capability are emphasized. Finally, one-for-all phototheranostics achieved by mediating intramolecular motions of these fluorophores are highlighted. We hope this review could pave a new avenue to developing fluorophores with intramolecular motion as PTAs to advance their clinical transition. STATEMENT OF SIGNIFICANCE: Recent progress of photothermal agents (PTAs) based on small organic fluorophores with intramolecular motion is summarized in this review. Molecular engineering of these small organic fluorophores to afford long-wavelength absorption, high photothermal conversion ability, and effective accumulation at tumor sites for enhanced photothermal therapy (PTT) is highlighted. Strategies to tune the intramolecular motions of these fluorophores to achieve multimodal phototherapy are emphasized as well.

Rational design of a small organic photosensitizer for NIR-I imaging-guided synergistic photodynamic and photothermal therapy.

Developing a small molecular photosensitizer to achieve multimodal phototherapy has recently garnered attention as a promising strategy for efficient cancer treatment. However, synthesis of a multifunctional small molecular photosensitizer has remained challenging. Here we report an aggregation-induced-emission (AIE)-featured luminogen (AIEgen) TPA-BTZ decorated with long and branched alkyl chains. TPA-BTZ shows long-wavelength emission at ca. 800 nm in the NIR-I region. Moreover, upon laser irradiation, TPA-BTZ could produce O2˙- and 1O2via both type I and type II mechanisms for enhanced photodynamic therapy (PDT). The propeller-like structure triphenylamine (TPA) rotators not only endow TPA-BTZ with AIE characteristics but also facilitate heat generation by intramolecular rotation for photothermal therapy (PTT). More importantly, long and branched alkyl chains can create intermolecular spatial isolation in the fabricated TPA-BTZ@PEG2000 nanoparticles (NPs) to allow sufficient intramolecular motion for photothermal conversion. Due to these unique features, in vitro and in vivo evaluations demonstrate that the TPA-BTZ@PEG2000 NPs exhibited long-term NIR-imaging ability, superior tumoricidal activity, and suppressed tumor growth. This research provides new insights for developing new AIEgens for NIR imaging-guided multimodal phototherapy.

Open-Source and Reduced-Expenditure Nanosystem with ROS Self-Amplification and Glutathione Depletion for Simultaneous Augmented Chemodynamic/Photodynamic Therapy.

Reactive oxygen species (ROS)-induced cell apoptosis has emerged as an efficient strategy for cancer therapy. However, tumor hypoxia and insufficient amounts of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment are currently the main limitations of photodynamic therapy (PDT) and chemodynamic therapy (CDT). Moreover, the glutathione (GSH) scavenging effect on ROS further hinders the efficiency of ROS-mediated therapy. Here, a CaO2-based nanosystem (named as CF@CO@HC) with ROS self-amplification and GSH-depletion abilities was developed by a bottom-up approach. This hybrid nanoparticle consisted of a photosensitizer-doped calcium peroxide (CaO2) core (CaO2-FM), a hybrid organosilica framework (Cu-ONS) incorporated with Fenton reagents (Cu2+) and tetrasulfide groups, and a local hydrophobic cage (HC) shell. The photosensitizer was fluorescein derivative 4-FM with a thermally activated delayed fluorescence (TADF) property. The HC shell was built to protect the CaO2 and the photosensitizer from being attacked by water. Upon being internalized into cancer cells, the nanosystem was decomposed through the reduction reactions of Cu2+ and the tetrasulfide bond-doped silica shell by GSH, thus releasing Cu+ for Cu+-mediated CDT. Meanwhile, the exposed CaO2-FM can react with H2O to liberate photosensitizer 4-FM and generate H2O2 and O2 to overcome barriers in CDT and PDT. Thus, our study provided an open-source and reduced-expenditure strategy via GSH depletion and ROS self-amplification behaviors for ROS generation and significantly achieved an improved synergistic PDT/CDT for cancers.

Synthesis, self-assembly and drug release behaviors of a bottlebrush polymer-HCPT prodrug for tumor chemotherapy.

A bottlebrush polymer-cytotoxin prodrug, where a potent anticancer drug 10-hydroxycamptothecin (HCPT) and water-soluble methoxypolyethylene glycols (mPEG) were attached into the polyester backbone, was synthesized via thiol-ene reaction. The synthesized bottlebrush polymer-HCPT conjugate with drug loading content as high as ca. 20.4 wt% was characterized by NMR, IR, UV and fluorescence techniques. The prepared bottlebrush polymer-HCPT prodrug could self-assemble into nanosized micelles (ca. 153 nm), which were uniform and stable in aqueous solution. Moreover, when exposed to esterase, the formed prodrug micelles as stimuli-responsive nanomaterials could release HCPT. In the cellar uptake and cytotoxicity experiments, the formed prodrug micelles exhibited effective internalization into tumor cells and excellent anticancer efficacies.

Recent advances in ruthenium and platinum based supramolecular coordination complexes for antitumor therapy.

Since the discovery of cisplatin for antitumor activity, the platinum (Pt) based antitumor drugs have received significant attention and launched a new era to explore the transition metal complexes for therapy. However, these small Pt-based antitumor drugs have some limitations for their clinic application, such as short blood circulation time and limited accumulation at tumor site, which was mainly due to their poor water solubility and small molecule size. To overcome these obstacles, developing new generation of transition-metal based complexes as anticancer agents is urgently needed. For the unique properties, the ruthenium (Ru) based complexes have attractive significant attention and be expected to be a substitute for Pt-based anticancer agents. Due to the nanometer size, unique geometry, relatively high surface charge and unique photophysical properties, the transition-metal based supramolecular coordination complexes (SCCs) which exhibited excellent antitumor efficiency and possessed desirable bioapplications such as drug loading, bioimaging and biosensing have attracted great attention as anticancer agents. In this minireview, we will highlight the recent development of ruthenium (Ru) and Platinum (Pt) based SCCs as potential anticancer agents.