Ring Transformation of Cyclopropenes to Benzo-Fused Five-Membered Oxa- and Aza-Heterocycles via a Formal [4+1] Cyclization.

In the context of the growing importance of heterocyclic compounds across various disciplines, numerous strategies for their construction have emerged. Exploiting the distinctive properties of cyclopropenes, this study introduces an innovative approach for the synthesis of benzo-fused five-membered oxa- and aza-heterocycles through a formal [4+1] cyclization and subsequent acid-catalyzed intramolecular O- to N- rearrangement. These transformations exhibit mild reaction conditions and a wide substrate scope. The applications in the late-stage modification of complex molecules and in the synthesis of a potential PD-L1 gene down-regulator, make this method highly appealing in related fields. Combined experimental mechanistic studies and DFT calculations demonstrate Rh(III)-mediated sequential C─H coupling/π-allylation/dynamically favorable O-attack route.

Hydrogen Sulfide Delivery System Based on Salting-Out Effect for Enhancing Synergistic Photothermal and Photodynamic Cancer Therapies.

The simultaneous application of photothermal therapy (PTT) and photodynamic therapy (PDT) offers substantial advantages in cancer treatment. However, their synergistic anticancer efficacy is often limited by tumor hypoxia, and thermotolerance induced by high expression of heat shock proteins (HSP). Fortunately, hydrogen sulfide (H2S), known for its direct cytotoxic effect on tumor cells, has been recognized for its ability to enhance PTT and PDT. The effectiveness of H2S in these therapies is challenged by its low loading efficiency, poor stability, and short diffusion distance. To address these issues, a nanoscale emulsion drop template created through the salting-out effect is employed to construct a robust H2S delivery system. Polydopamine (PDA), chosen for its interfacial polymerization tendency and excellent photothermal conversion rate, is utilized as a carrier for the H2S donor (ADT) and Zinc phthalocyanine (ZnPc) to fabricate a novel nanomedicine termed APZ NPs. The temperature-responsive APZ NPs are designed to release H2S during the PTT process. Elevated H2S levels promoted vasodilation, thereby enhancing the enhanced permeability and retention effect (EPR) of APZ NPs within solid tumors. This strategy effectively alleviated tumor hypoxia by disrupting the mitochondrial respiratory chain and mitigated tumor cell heat tolerance by inhibiting HSP expression.

Homologous polydopamine ameliorates haemolysis of melittin for enhancing its anticancer efficacy.

Despite exhibiting potent anticancer activity, the strong hemolytic properties of melittin (MEL) significantly restrict its delivery efficiency and clinical applications. To address this issue, we have devised a strategy wherein homologous dopamine (DA), an essential component of bee venom, is harnessed as a vehicle for the synthesis of MEL-polydopamine (PDA) nanoparticles (MP NPs). The ingenious approach lies in the fact that MEL is a basic polypeptide, and the polymerization of DA is also conducted under alkaline conditions, indicating the distinctive advantages of PDA in MEL encapsulation. Furthermore, MP NPs are modified with folic acid to fabricate tumor-targeted nanomedicine (MPF NPs). MPF NPs can ameliorate the hemolysis of MEL in drug delivery and undergo degradation triggered by high levels of reactive oxygen species (ROS) within solid tumors, thereby facilitating MEL release and subsequent restoration of anticancer activity. After cellular uptake, MPF NPs induce cell apoptosis through the PI3K/Akt-mediated p53 signaling pathway. The tumor growth inhibitory rate of MPF NPs in FA receptor-positive 4T1 and CT26 xenograft mice reached 78.04% and 81.66%, which was significantly higher compared to that in FA receptor-negative HepG2 xenograft mice (45.79%). Homologous vehicles provide a new perspective for nanomedicine design.

Oxygen-evolving hollow polydopamine alleviates tumour hypoxia for enhancing photodynamic therapy in cancer treatment.

Hypoxia, a characteristic hallmark of solid tumours, restricts the therapeutic effect of photodynamic therapy (PDT) for cancer treatment. To address this issue, a facile and nanosized oxygen (O2) bubble template is established by mixing oxygenated water and water-soluble solvents for guiding hollow polydopamine (HPDA) synthesis, and O2 is encapsulated in the cavity of HPDA. HPDA with abundant catechol is designed as a carrier for zinc phthalocyanine (ZnPc, a boronic acid modified photosensitizer) via borate ester bonds to fabricate nanomedicine (denoted as HZNPs). The in vitro and in vivo results indicate that O2-evolving HZNPs could alleviate tumour hypoxia and enhance PDT-anticancer efficiency. Melanin-like HPDA with a photothermal conversion rate (η) of 38.2% shows excellent synergistic photothermal therapy (PTT) efficiency in cancer treatment.

Multiple Functions Integrated inside a Single Molecule for Amplification of Photodynamic Therapy Activity.

Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO-), by NO and superoxide anions (O2•-), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O2•-. Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O2•- and NO generation in the same place at the same time to guarantee effective ONOO- formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO- formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.

Oxyhemoglobin nano-recruiter preparation and its application in biomimetic red blood cells to relieve tumor hypoxia and enhance photodynamic therapy activity.

Photodynamic therapy (PDT) is strongly O2 dependent. Therefore, its therapeutic effects are seriously hindered in hypoxic tumors. Red blood cells are responsible for delivering O2 in the blood. In this manuscript, biomimetic red blood cells (BRBCs) were exploited using a layer-by-layer assembly method, using Fe3O4@CuO, oxyhemoglobin (OxyHb), a photosensitizer and a photo-cross linked acrylate modified hyaluronic acid (HA) gel shell. The Fe3O4@CuO core has very high OxyHb loading efficiency (the adsorption capacity of Fe3O4@CuO for OxyHb is derived to be 0.99 mg mg-1) to ensure a sufficient O2 supply. OxyHb was protected well by the HA shell in order to avoid O2 release during the delivery process in blood before arrival at the tumor tissue. The HA shell protection can be eliminated in position at the tumor to trigger O2 release through hyaluronidase (HAase) triggered HA degradation. Furthermore, Fe3O4 in the nanosystem can provide magnetic field assisted tumor targeting and magnetic resonance imaging of the tumor. Therefore, this work presents a highly efficient all-in-one biomimetic nanomedicine approach to overcome hypoxia and achieve tumor targeting theranostics.

Drug-Controlled Release Based on Complementary Base Pairing Rules for Photodynamic-Photothermal Synergistic Tumor Treatment.

Controlled drug release systems can enhance the safety and availability but avoid the side effect of drugs. Herein, the concept of DNA complementary base pairing rules in biology is used to design and prepare a photothermal-triggered drug release system. Adenine (A) modified polydopamine nanoparticles (A-PDA, photothermal reagent) can effectively bind with thymine (T) modified Zinc phthalocyanine (T-ZnPc, photosensitizer) forming A-PDA = T-ZnPc (PATP) complex based on A = T complementary base pairing rules. Similar to DNA, whose base pairing in double strands will break by heating, T-ZnPc can be effectively released from A-PDA after near infrared irradiation-triggered light-thermal conversion to obtain satisfactory photodynamic-photothermal synergistic tumor treatment. In addition, PDA can carry abundant Gd3+ to provide magnetic resonance imaging guided delivery and theranostic function.

Design and synthesis of thymine modified phthalocyanine for Aß protofibrils photodegradation and Aß peptide aggregation inhibition.

The formation and accumulation of toxic amyloid beta (Aß) protofibrils in brain is recognized as the pathological hallmark of alzheimer's disease (AD). Recent research indicated that photodynamic therapy (PDT) has potential to treat AD because reactive oxygen species (ROS) generated by photosensitizers (PS) could degrades Aß protofibrils. Al3+ and Fe3+ were found at markedly high levels on and around Aß protofibrils comparing with the normal part of brain. Based on this, a thymine modified Zn phthalocyanine (T-ZnPc), which can specific recognize and has strong affinity with Fe3+ and Al3+, was designed and synthesized. The recognize, affinity, Aß protofibrils degradation and neuro protection process were monitored via ultraviolet absorption spectrometry (UV), fluorescence emission spectrum, transmission electron microscopy (TEM), flow cytometer and thiazolyl blue tetrazolium bromide (MTT) assay. The results revealed that such affinity effect greatly increases the molar extinction coefficient (from 1.70 × 104 to 4.67 × 104 and 3.30 × 104 after forming Fe-T-ZnPc and Al-T-ZnPc) and activates PDT activity of T-ZnPc to generate abundant ROS to degrade Aß protofibrils (62% and 81% degradation by Al-T-ZnPc and Fe-T-ZnPc) and prevent its neurotoxicity based on the statistical differences analysis. Besides, T-ZnPc could inhibit new Aß protofibrils formation and the chelation effect could reduce the free Fe3+ and Al3+ concentration in brain, which could be also helpful for AD treatment.

Breaking the reduced glutathione-activated antioxidant defence for enhanced photodynamic therapy.

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROSs) to kill cancer cells. However, a high concentration of reduced glutathione (GSH) is present in cancer cells and can consume ROSs and sharply reduce the PDT activity. To address this problem, herein, we synthesized a thymine modified Zn phthalocyanine (ZnPc, a monomer and an active form for PDT) and prepared its nanoparticle form (an aggregator and an inactive form) with Hg2+ providing the driving force for the "thymine-Hg2+-thymine" interaction. The nanoparticles could remain in the inactive form during the delivery process in blood. Once endocytosed by cancer cells, the nanoparticles are disintegrated, and deprived of Hg2+ by intracellular GSH, which decreases the level of GSH. Simultaneously, the activity of the released monomer ZnPc is recovered and high PDT activity is observed.