Amphiphilic Single-Chain Polymer Nanoparticles as Imaging and Far-Red Photokilling Agents for Photodynamic Therapy in Zebrafish Embryo Xenografts.

This work introduces rationally designed, improved amphiphilic single-chain polymer nanoparticles (SCNPs) for imaging and photodynamic therapy (PDT) in zebrafish embryo xenografts. SCNPs are ultrasmall polymeric nanoparticles with sizes similar to proteins, making them ideal for biomedical applications. Amphiphilic SCNPs result from the self-assembly in water of isolated synthetic polymeric chains through intrachain hydrophobic interactions, mimicking natural biomacromolecules and, specially, proteins (in size and when loaded with drugs, metal ions or fluorophores also in function). These ultrasmall, soft nanoparticles have various applications, including catalysis, sensing, and nanomedicine. Initial in vitro experiments with nonfunctionalized, amphiphilic SCNPs loaded with a photosensitizing Zn phthalocyanine with four nonperipheral isobutylthio substituents, ZnPc, showed promise for PDT. Herein, the preparation of improved, amphiphilic SCNPs containing ZnPc as highly efficient photosensitizer encapsulated within the nanoparticle and surrounded by anthracene units is disclosed. The amount of anthracene groups and ZnPc molecules within each single-chain nanoparticle controls the imaging and PDT properties of these nanocarriers. Critically, this work opens the way to improved PDT applications based on amphiphilic SCNPs as a first step toward ideal, long-term artificial photo-oxidases (APO).

Nanoencapsulation of a Far-Red Absorbing Phthalocyanine into Poly(benzylmalate) Biopolymers and Modulation of Their Photodynamic Efficiency.

Two different poly(benzylmalate) biopolymers, a hydrophobic non-PEGylated (PMLABe73) and an amphiphilic PEGylated derivative (PEG42-b-PMLABe73), have been used to encapsulate a phthalocyanine chosen for its substitution pattern that is highly suitable for photodynamic therapy. Different phthalocyanine/(co)polymers ratios have been used for the nanoprecipitation. A set of six nanoparticles has been obtained. If the amphiphilic PEGylated copolymer proved to be slightly more efficient for the encapsulation and to lower the aggregation of the phthalocyanine inside the nanoparticles, it is, however, the hydrophobic PMLABe73-based nanoparticles that exhibited the best photodynamic efficiency.

Comparing PVP and Polymeric Micellar Formulations of a PEGylated Photosensitizing Phthalocyanine by NMR and Optical Techniques.

Phthalocyanines are ideal candidates as photosensitizers for photodynamic therapy (PDT) of cancer due to their favorable chemical and photophysical properties. However, their tendency to form aggregates in water reduces PDT efficacy and poses challenges in obtaining efficient forms of phthalocyanines for therapeutic applications. In the current work, polyvinylpyrrolidone (PVP) and micellar formulations were compared for encapsulating and monomerizing a water-soluble zinc phthalocyanine bearing four non-peripheral triethylene glycol chains (Pc1). 1H NMR spectroscopy combined with UV-vis absorption and fluorescence spectroscopy revealed that Pc1 exists as a mixture of regioisomers in monomeric form in dimethyl sulfoxide but forms dimers in an aqueous buffer. PVP, polyethylene glycol castor oil (Kolliphor RH40), and three different triblock copolymers with varying proportions of polyethylene and polypropylene glycol units (termed P188, P84, and F127) were tested as micellar carriers for Pc1. 1H NMR chemical shift analysis, diffusion-ordered spectroscopy, and 2D nuclear Overhauser enhancement spectroscopy was applied to monitor the encapsulation and localization of Pc1 at the polymer interface. Kolliphor RH40 and F127 micelles exhibited the highest affinity for encapsulating Pc1 in the micellar core and resulted in intense Pc1 fluorescence emission as well as efficient singlet oxygen formation along with PVP. Among the triblock copolymers, efficiency in binding and dimer dissolution decreased in the order F127 > P84 > P188. PVP was a strong binder for Pc1. However, Pc1 molecules are rather surface-attached and exist as monomer and dimer mixtures. The results demonstrate that NMR combined with optical spectroscopy offer powerful tools to assess parameters like drug binding, localization sites, and dynamic properties that play key roles in achieving high host-guest compatibility. With the corresponding adjustments, polymeric micelles can offer simple and easily accessible drug delivery systems optimizing phthalocyanines' properties as efficient photosensitizers.

Phthalocyanines prepared from 4,5-dihexylthiophthalonitrile, a popular building block.

Phthalocyanines are tetrapyrrolic artificial porphyrinoids that play major roles in advanced biological and technological applications. Research on this family of dyes is particularly active in Türkiye, with many derivatives being prepared from 4,5-dihexylthiophthalonitrile DiSHexPN, which is one of the most popular noncommercially available building blocks for phthalocyanines. This review summarizes the phthalocyanines and their versatile properties and applications that have been published since 1994, when the synthesis of DiSHexPN was first described, to emphasize the importance of this building block in plentiful applications, all with biomedical or technological impact.

Far-red triplet sensitized Z-to-E photoswitching of azobenzene in bioplastics.

We report the first example of direct far-red triplet sensitized molecular photoswitching in a condensed phase wherein a liquid azobenzene derivative (Azo1) co-assembled within a liquid surfactant-protein film undergoes triplet sensitized Z-to-E photoswitching upon far-red/red light excitation in air. The role of triplet sensitization in photoswitching has been confirmed by quenching of sensitizer phosphorescence by Z-Azo1 and temperature-dependent photoswitching experiments. Herein, we demonstrate new biosustainable fabrication designs to address key challenges in solid-state photoswitching, effectively mitigating chromophore aggregation and requirement of high energy excitations by dispersing the photoswitch in the trapped liquid inside the solid framework and by shifting the action spectrum from blue-green light (450-560 nm) to the far-red/red light (740/640 nm) region.

Nanoscaled PAMAM Dendrimer Spacer Improved the Photothermal-Photodynamic Treatment Efficiency of Photosensitizer-Decorated Confeito-Like Gold Nanoparticles for Cancer Therapy.

A critical factor in developing an efficient photosensitizer-gold nanoparticle (PS-AuNP) hybrid system with improved plasmonic photosensitization is to allocate a suitable space between AuNPs and PS. Poly(amidoamine) (PAMAM) dendrimer is selected as a spacer between the PS and confeito-like gold nanoparticles (confeito-AuNPs), providing the required distance (≈2.5-22.5 nm) for plasmon-enhanced singlet oxygen generation and heat production upon 638-nm laser irradiation and increase the cellular internalization of the nanoconjugates. The loading of the PS, tetrakis(4-carboxyphenyl) porphyrin (TCPP), and modified zinc phthalocyanine (ZnPc1) onto PAMAM-confeito-AuNPs demonstrate better in vitro cancer cell-killing efficacy, as the combined photothermal-photodynamic therapies (PTT-PDTs) outperforms the single treatment modalities (PTT or PDT alone). These PS-PAMAM-confeito-AuNPs also demonstrate higher phototoxicity than photosensitizers directly conjugated to confeito-AuNPs (TCPP-confeito-AuNPs and ZnPc1-confeito-AuNPs) against all breast cancer cell lines tested (MDA-MB-231, MCF7, and 4T1). In the in vivo studies, TCPP-PAMAM-confeito-AuNPs are biocompatible and exhibit a selective tumor accumulation effect, resulting in higher antitumor efficacy than free TCPP, PAMAM-confeito-AuNPs, and TCPP-confeito-AuNPs. In vitro and in vivo evaluations confirm PAMAM effectiveness in facilitating cellular uptake, plasmon-enhanced singlet oxygen and heat generation. In summary, this study highlights the potential of integrating a PAMAM spacer in enhancing the plasmon effect-based photothermal-photodynamic anticancer treatment efficiency of PS-decorated confeito-AuNPs.

Alkylthio-tetrasubstituted µ-Nitrido Diiron Phthalocyanines: Spectroelectrochemistry, Electrical Properties, and Heterojunctions for Ammonia Sensing.

Alkylthio-tetrasubstituted µ-nitrido diiron phthalocyanine complexes are synthesized with n-butyl, iso-butyl, tert-butyl, and n-hexadecyl alkyl moieties. For the first time, a spectroelectrochemical investigation of µ-nitrido diiron phthalocyanines is achieved at all the redox steps. The complexes are stable in all their redox states, unlike their unsubstituted analogues. The interest of the present complexes is to prepare sensing devices by a solution processing method. Films are characterized by electronic absorption and Raman spectroscopies. Electrical measurements on resistors show the highly resistive behavior of these complexes, whatever the chain length. However, when combined with the lutetium bisphthalocyanine, an intrinsic semiconductor, these complexes form heterojunctions that exhibit a high sensitivity to ammonia, with a very good signal over noise ratio, at room temperature and under atmospheric conditions.

Phthalocyanine-based mesoporous organosilica nanoparticles: NIR photodynamic efficiency and siRNA photochemical internalization.

Mesoporous organosilica nanoparticles (PHT-PMO) have been prepared from an octa-triethoxysilylated Zn phthalocyanine precursor. These PHT-PMO nanoparticles had no dark toxicity but high phototoxicity when irradiated at 650 nm, and remarkable near-infrared phototoxicity when excited at 760 and 810 nm. The PHT-PMO were then aminated to promote electrostatic complexation with siRNA. Transfection experiments were performed upon NIR irradiation and photochemical internalization was very efficient, leading to 65% luciferase extinction in MCF-7 cancer cells expressing stable luciferase.

CO2 electrochemical catalytic reduction with a highly active cobalt phthalocyanine.

Molecular catalysts that combine high product selectivity and high current density for CO2 electrochemical reduction to CO or other chemical feedstocks are urgently needed. While earth-abundant metal-based molecular electrocatalysts with high selectivity for CO2 to CO conversion are known, they are characterized by current densities that are significantly lower than those obtained with solid-state metal materials. Here, we report that a cobalt phthalocyanine bearing a trimethyl ammonium group appended to the phthalocyanine macrocycle is capable of reducing CO2 to CO in water with high activity over a broad pH range from 4 to 14. In a flow cell configuration operating in basic conditions, CO production occurs with excellent selectivity (ca. 95%), and good stability with a maximum partial current density of 165 mA cm-2 (at -0.92 V vs. RHE), matching the most active noble metal-based nanocatalysts. These results represent state-of-the-art performance for electrolytic carbon dioxide reduction by a molecular catalyst.

A Noble-Metal-Free Heterogeneous Photosensitizer-Relay Catalyst Triad That Catalyzes Water Oxidation under Visible Light.

An entirely earth-abundant chromophore-relay water oxidation catalyst triad system, which is robust and efficient at neutral pH, is presented. The synthesis involves the coordination of a porphyrin derivative to a bridging Fe(CN)5 group, which is then reacted with Co ions to prepare a covalently linked chromophore-Prussian blue analogue assembly. Light-driven water oxidation studies in the presence of an electron scavenger indicate that the triad is active and it maintains a steady activity for at least three hours. Transient absorption experiments and computational studies reveal that the Fe(CN)5 group is more than a linker as it takes part in electron-transfer and co-operates with porphyrin in the charge separation process.

Methylsulfonyl Zn phthalocyanine: A polyvalent and powerful hydrophobic photosensitizer with a wide spectrum of photodynamic applications.

BACKGROUND: The biomedical photodynamic principle is based on the light-induced and photosensitizer-mediated killing of unwanted or harmful cells by overproduction of reactive oxygen species. Motivated by the success of photodynamic therapy (PDT) against several types of tumors, further applications of this approach are constantly identified which require the design and synthesis of novel photosensitizers with specifically tailored properties for a particular clinical application. METHODS: Hydrophobic photosensitizers are currently gaining attention and hence a tetramethylsulfonyl Zn(II) phthalocyanine (2) was designed with respect to the desired photoproperties. The photodynamic potential of 2 was assessed by the determination of its photophysical and photochemical properties, and by a large range of biological tests including its phototoxicity against cancer cells and Gram(+) bacteria. Unsubstituted ZnPc was used as a reference compound for comparison purposes. RESULTS: Phthalocyanine 2 has a better oxygen generation and is more photostable than ZnPc. 2 is a polyvalent and powerful hydrophobic photosensitizer with a wide spectrum of photodynamic applications against cancer (tested on A431 cells) and for Gram(+) PDI. Against Staphylococcus aureus, a maximum photokilling efficiency of more than 6 log10 steps was induced by a 5µM concentration of 2, outperforming the 3 log10 criterion for an antimicrobial effect (according to the recommendation of the American Society for Microbiology) by more than three orders of magnitude. CONCLUSIONS: Phthalocyanine 2 has attractive photophysical and -chemical characteristics. Initial evaluation of its application in anti-tumor PDT and PDI suggest potential for further pre-clinical and clinical development of this compound.

1,4,8,11,15,18,22,25-Alkylsulfanyl phthalocyanines: effect of macrocycle distortion on spectroscopic and packing properties.

The effect of phthalocyanine macrocycle distortion on its spectroscopic and packing properties is studied, by comparing two phthalocyanines octa-non-peripherally substituted by alkanethiols of different bulkiness (n-hexyl and tert-butyl). Their X-ray structures evidence their core shape, respectively planar and strongly distorted, inducing a 55 nm shift of their maximum absorption wavelength. Comparison of frontier orbital energies revealed that this distortion decreases the conjugation potency of the benzo rings to the central pyrrolic rings. Also the tert-butyl derivative presents a MOF-like porous crystalline assembly with 22.2% void.

Site-selective formation of an iron(iv)-oxo species at the more electron-rich iron atom of heteroleptic µ-nitrido diiron phthalocyanines.

Iron(iv)-oxo species have been identified as the active intermediates in key enzymatic processes, and their catalytic properties are strongly affected by the equatorial and axial ligands bound to the metal, but details of these effects are still unresolved. In our aim to create better and more efficient oxidants of H-atom abstraction reactions, we have investigated a unique heteroleptic diiron phthalocyanine complex. We propose a novel intramolecular approach to determine the structural features that govern the catalytic activity of iron(iv)-oxo sites. Heteroleptic µ-nitrido diiron phthalocyanine complexes having an unsubstituted phthalocyanine (Pc1) and a phthalocyanine ligand substituted with electron-withdrawing alkylsulfonyl groups (PcSO2R) were prepared and characterized. A reaction with terminal oxidants gives two isomeric iron(iv)-oxo and iron(iii)-hydroperoxo species with abundances dependent on the equatorial ligand. Cryospray ionization mass spectrometry (CSI-MS) characterized both hydroperoxo and diiron oxo species in the presence of H2O2. When m-CPBA was used as the oxidant, the formation of diiron oxo species (PcSO2R)FeNFe(Pc1)[double bond, length as m-dash]O was also evidenced. Sufficient amounts of these transient species were trapped in the quadrupole region of the mass-spectrometer and underwent a CID-MS/MS fragmentation. Analyses of fragmentation patterns indicated a preferential formation of hydroperoxo and oxo moieties at more electron-rich iron sites of both heteroleptic µ-nitrido complexes. DFT calculations show that both isomers are close in energy. However, the analysis of the iron(iii)-hydroperoxo bond strength reveals major differences for the (Pc1)FeN(PcSO2R)FeIIIOOH system as compared to (PcSO2R)FeN(Pc1)FeIIIOOH system, and, hence binding of a terminal oxidant will be preferentially on more electron-rich sides. Subsequent kinetics studies showed that these oxidants are able to even oxidize methane to formic acid efficiently.

Sulfonamide-substituted iron phthalocyanine: design, solubility range, stability and oxidation of olefins.

4-tert-Butylbenzenesulfonamide was used as a substituent of tetra peripherally substituted Fe(ii) phthalocyanine, taking into account several parameters crucial for the design of potential oxidation catalysts such as solubility and stability. The resulting phthalocyanine exhibits a remarkable stability under oxidative conditions. The main product of the oxidation of cyclohexene using H2O2 as the oxidant is the allylic ketone, 2-cyclohexen-1-one. Styrene oxidation led mainly to the formation of benzaldehyde.

Expeditious selective access to functionalized platforms of A(7)B-type heteroleptic lanthanide double-decker complexes of phthalocyanine.

A one-step method to access to functionalized heteroleptic lanthanide double-decker complexes of phthalocyanine of A7B-type is reported. This optimized statistical method led to two hydroxylated model europium complexes, one of which was further converted into its mesylated and azido derivatives.

Modulation of the electronic and spectroscopic properties of Zn(II) phthalocyanines by their substitution pattern.

Four isomerically pure octasubstituted zinc phthalocyanines with variations in the attachment atom and positions of the substituents were selected for a systematic investigation of the effect of the substitution pattern on their electronic and spectroscopic properties. Effects which were investigated are the position, the electron donating and withdrawing properties, and the donating force of the substituent. The results are discussed and interpreted based on theoretical and experimental determination of the orbital levels. This work allows us to highlight which substitution patterns are the most suitable considering different common applications of phthalocyanines.

Axial binding and host-guest interactions of a phthalocyanine resorcinarene cavitand hybrid.

A Zn phthalocyanine-resorcinarene cavitand hybrid was prepared. The axial binding and host-guest interactions of this hybrid with a pyridinyl-pyrene were investigated by UV-vis and fluorescence spectroscopic means, revealing the encapsulation of the guest maintained by axial coordination to the Zn phthalocyanine. Energy transfer between the pyrene and the phthalocyanine was evidenced.

Preparation and characterization of mu-nitrido diiron phthalocyanines with electron-withdrawing substituents: application for catalytic aromatic oxidation.

Mu-nitrido-bis [tetra-(hexyl-sulfonyl)phthalocyaninatoiron] (3a) and mu-nitrido-bis [tetra-(tert-butylsulfonyl) phthalocyaninatoiron] (3b) complexes have been prepared and fully characterized by electrospray ionization mass spectrometry, UV-Vis, FTIR, EPR, Mössbauer techniques as well as by X-ray photoelectron and Fe K-edge X-ray absorption spectroscopies. Small changes at the periphery of the phthalocyanine ligand introduce a difference in the iron oxidation state. While 3b with tert-butyl substituents is a neutral complex with a mixed-valence Fe(3.5)-N-Fe(3.5) structural unit, 3a having n-hexyl substituents is an oxidized cationic Fe(IV)-N-Fe(IV) complex. The structural parameters of N-bridged diiron phthalocyanine with a Fe(3.5)-N-Fe(3.5) unit were determined for the first time. Iron atoms in 3b are displaced out of plane by 0.24 A and the Fe-N bond distance of the linear Fe-N-Fe fragment is equal to 1.67 A. Both complexes selectively catalyze benzylic oxidation of alkyl aromatic compounds by tBuOOH. Toluene was oxidized to benzoic acid with 80% selectivity, and the total turnover number was as high as 197. p-Toluic acid was the principal product of p-xylene oxidation. In this case the turnover number achieved 587 substrate molecules per molecule of catalyst. The described catalytic system is complementary to the recently reported system based on mu-nitrido diiron tetrabutylphthalocyanine-H2O2 which effectively oxidizes the benzene ring.