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).

Imidazo[1,2-a]pyridine and Imidazo[1,5-a]pyridine: Electron Donor Groups in the Design of D-π-A Dyes.

This work investigates the electron-donating capabilities of two 10-π electron nitrogen bridgehead bicyclic [5,6]-fused ring systems, imidazo[1,2-a]pyridine and imidazo[1,5-a]pyridine rings. Eight compounds with varying positions of electron-withdrawing moieties (TCF or DCI) coupled to the imidazopyridine ring were synthesized and studied. DCI-containing compounds (Ib-IVb) exhibited a purely dipolar nature with broad absorption bands, weak fluorescence, large Stokes shifts, and strong solvatochromism. In contrast, TCF-containing compounds (Ia-IVa) demonstrated diverse properties. Imidazo[1,2-a]pyridine derivatives Ia and IIa were purely dipolar, while imidazo[1,5-a]pyridine derivatives IIIa and IVa displayed a cyanine-like character with intense absorption and higher quantum yields of emission. The observed gradual red shift in optical properties with changing electron-donor groups (IIb < Ib < IIIb < IVb) and (IIa < Ia < IIIa < IVa) underscores the stronger electron-donor character of imidazo[1,5-a]pyridine compared to that of imidazo[1,2-a]pyridine. Furthermore, crystalline powders of imidazo[1,2-a]pyridine derivatives exhibited fluorescence despite minimal emission in solution. Two compounds (Ib and IVa) were successfully formulated into nanoparticles for potential in vivo imaging applications in zebrafish embryos.

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.

Engineered therapeutic antibodies with mannose 6-phosphate analogues as a tool to degrade extracellular proteins.

Inducing the degradation of pathological soluble antigens could be the key to greatly enhancing the efficacy of therapeutic monoclonal antibodies (mAbs), extensively used in the treatment of autoimmune and inflammatory disorders or cancer. Lysosomal targeting has gained increasing interest in recent years due to its pharmaceutical applications far beyond the treatment of lysosomal diseases, as a way to address proteins to the lysosome for eventual degradation. Mannose 6-phosphonate derivatives (M6Pn), called AMFA, are unique glycovectors that can significantly enhance the cellular internalization of the proteins conjugated to AMFA via the cation-independent mannose 6-phosphate receptor (M6PR) pathway. AMFA engineering of mAbs results in the generation of a bifunctional antibody that is designed to bind both the antigen and the M6PR. The improvement of the therapeutic potential by AMFA engineering was investigated using two antibodies directed against soluble antigens: infliximab (IFX), directed against tumor necrosis factor α (TNF-α), and bevacizumab (BVZ), directed against the vascular endothelial growth factor (VEGF). AMFA conjugations to the antibodies were performed either on the oligosaccharidic chains of the antibodies or on the lysine residues. Both conjugations were controlled and reproducible and provided a novel affinity for the M6PR without altering the affinity for the antigen. The grafting of AMFA to mAb increased their cellular uptake through an M6PR-dependent mechanism. The antigens were also 2.6 to 5.7 times more internalized by mAb-AMFA and rapidly degraded in the cells. Additional cell culture studies also proved the significantly higher efficacy of IFX-AMFA and BVZ-AMFA compared to their unconjugated counterparts in inhibiting TNF-α and VEGF activities. Finally, studies in a zebrafish embryo model of angiogenesis and in xenografted chick embryos showed that BVZ-AMFA was more effective than BVZ in reducing angiogenesis. These results demonstrate that AMFA grafting induces the degradation of soluble antigens and a significant increase in the therapeutic efficacy. Engineering with mannose 6-phosphate analogues has the potential to develop a new class of antibodies for autoimmune and inflammatory diseases.

Exceptional anticancer photodynamic properties of [1,4-Bis(3,6,9,12-Tetraoxatridec-1-yloxy)phthalocyaninato]zinc(II).

Phthalocyanines have been described as effective photosensitizers for photodynamic therapy and are therefore, being studied for their biomedical applications. The metalation of photosensitizers can improve their photodynamic therapy potential. Here, we focus on the biological properties of [1,4-Bis(3,6,9,12-Tetraoxatridec-1-yloxy)phthalocyaninato]zinc(II) (ZnPc(αEG4)2) and demonstrate its exceptional anticancer activity upon light stimulation to kill preferentially cancer cells with a start of efficiency at 10 pM. Indeed, in this work we highlighted the high selectivity of ZnPc(αEG4)2 for cancer cells compared with healthy ones and we establish its mechanism of action, enabling us to conclude that ZnPc(αEG4)2 could be a powerful tool for cancer therapy.

Probing the Use of Triphenyl Phosphonium Cation for Mitochondrial Nucleoside Delivery.

Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria.

Novel Antifouling Coatings by Zwitterionic Silica Grafting on Glass Substrates.

Zwitterionic silica coatings for surface functionalization are greatly prominent because of their simple and fast preparation, high availability, and effective antifouling properties. In this work, two zwitterionic sulfobetaine silane coatings, i.e., mono-SBSi and tris-SBSi, were deposited on glass surfaces and tested for antifouling of biological material and biofilm using human cancer cell and seawater, respectively. The used zwitterionic precursors mono-SBSi and tris-SBSi differ by the number of hydrolyzable silane groups: mono-SBSi contains one trimethoxysilane group, whereas tris-SBSi contains three of these functions. First, X-ray photoelectron spectroscopy indicates the successful grafting of zwitterionic coatings onto a glass surface. Characterization using atomic force microscopy shows the different morphologies and roughness of the two coatings. The glass surface became more hydrophilic after the grafting of zwitterionic coatings than the bare glass substrate. The antifouling properties of two coatings were evaluated via human cancer cell adsorption. Interestingly, the tris-SBSi coating displays a significantly lower level of cell adsorption compared to that of both mono-SBSi coating and the non-modified control surface. The same trend was observed for biofilm formation in seawater. Finally, the toxicity of mono-SBSi and tris-SBSi coatings was evaluated on zebrafish embryos, indicating the good biocompatibility of both coatings. Our results indicate interesting antifouling properties of zwitterionic coatings. The chemical constitution of the used precursor has an impact on the antifouling properties of the formed coating: the tris-SBSi-based zwitterionic silica coatings display improved antifouling properties compared to those of the mono-SBSi-based coating. Besides, the use of trisilylated precursors should result in the formation of more resistant and robust coatings due to the higher number of grafting functions. For all these reasons, we anticipate that tris-SBSi coatings will open new perspectives for antifouling applications for biological environments and implants.

Self-assembled porphyrin-peptide cages for photodynamic therapy.

The development of photodynamic therapy requires access to smart photosensitizers which combine appropriate photophysical and biological properties. Interestingly, supramolecular and dynamic covalent chemistries have recently shown their ability to produce novel architectures and responsive systems through simple self-assembly approaches. Herein, we report the straightforward formation of porphyrin-peptide conjugates and cage compounds which feature on their surface chemical groups promoting cell uptake and specific organelle targeting. We show that they self-assemble, in aqueous media, into positively-charged nanoparticles which generate singlet oxygen upon green light irradiation, while also undergoing a chemically-controlled disassembly due to the presence of reversible covalent linkages. Finally, the biological evaluation in cells revealed that they act as effective photosensitizers and promote synergistic effects in combination with Doxorubicin.

Upscale Synthesis of Magnetic Mesoporous Silica Nanoparticles and Application to Metal Ion Separation: Nanosafety Evaluation.

The synthesis of core-shell magnetic mesoporous nanoparticles (MMSNs) through a phase transfer process is usually performed at the 100-250 mg scale. At the gram scale, nanoparticles without cores or with multicore systems are observed. Iron oxide core nanoparticles (IO) were synthesized through a thermal decomposition procedure of α-FeO(OH) in oleic acid. A phase transfer from chloroform to water was then performed in order to wrap the IO nanoparticles with a mesoporous silica shell through the sol-gel procedure. MMSNs were then functionalized with DTPA (diethylenetriaminepentacetic acid) and used for the separation of metal ions. Their toxicity was evaluated. The phase transfer procedure was crucial to obtaining MMSNs on a large scale. Three synthesis parameters were rigorously controlled: temperature, time and glassware. The homogeneous dispersion of MMSNs on the gram scale was successfully obtained. After functionalization with DTPA, the MMSN-DTPAs were shown to have a strong affinity for Ni ions. Furthermore, toxicity was evaluated in cells, zebrafish and seahorse cell metabolic assays, and the nanoparticles were found to be nontoxic. We developed a method of preparing MMSNs at the gram scale. After functionalization with DTPA, the nanoparticles were efficient in metal ion removal and separation; furthermore, no toxicity was noticed up to 125 µg mL-1 in zebrafish.

Hybrid multifunctionalized mesostructured stellate silica nanoparticles loaded with ß-diketonate Tb3+/Eu3+ complexes as efficient ratiometric emissive thermometers working in water.

Despite the great effort made in recent years on lanthanide-based ratiometric luminescent nanothermometers able to provide temperature measurements in water, their design remains challenging. We report on the synthesis and properties of efficient ratiometric nanothermometers that are based on mesoporous stellate nanoparticles (MSN) of ca. 90 nm functionalized with an acetylacetonate (acac) derivative inside the pores and loaded with ß-diketonate-Tb3+/Eu3+ complexes able to work in water, in PBS or in cells. Encapsulating a [(Tb/Eu)9(acac)16(µ3-OH)8(µ4-O)(µ4-OH)] complex (Tb/Eu ratio = 19/1 and 9/1) led to hybrid multifunctionalized nanoparticles exhibiting a Tb3+ and Eu3+ characteristic temperature-dependent luminescence with a high rate Tb3+-to-Eu3+ energy transfer. According to theoretical calculations, the modifications of photoluminescence properties and the increase in the pairwise Tb3+-to-Eu3+ energy transfer rate by about 10 times can be rationalized as a change of the coordination number of the Ln3+ sites of the complex from 7 to 8 accompanied by a symmetry evolution from Cs to C4v and a slight shortening of intramolecular Ln3+-Ln3+ distances upon the effect of encapsulation. These nanothermometers operate in the 20-70 °C range with excellent photothermal stability, cyclability and repeatability (>95%), displaying a maximum relative thermal sensitivity of 1.4% °C-1 (at 42.7 °C) in water. Furthermore, they can operate in cells with a thermal sensitivity of 8.6% °C-1 (at 40 °C), keeping in mind that adjusting the calibration for each system is necessary to ensure accurate measurements.

Super-resolution imaging of antibody-conjugated biodegradable periodic mesoporous organosilica nanoparticles for targeted chemotherapy of prostate cancer.

Biodegradable periodic mesoporous organosilica nanoparticles (nanoPMOs) are widely used as responsive drug delivery platforms for targeted chemotherapy of cancer. However, the evaluation of their properties such as surface functionality and biodegradability is still challenging, which has a significant impact on the efficiency of chemotherapy. In this study, we have applied direct stochastic optical reconstruction microscopy (dSTORM), a single-molecule super-resolution microscopy technique, to quantify the degradation of nanoPMOs triggered by glutathione and the multivalency of antibody-conjugated nanoPMOs. Subsequently, the effect of these properties on cancer cell targeting, drug loading and release capability, and anticancer activity is also studied. Due to the higher spatial resolution at the nanoscale, dSTORM imaging is able to reveal the structural properties (i.e., size and shape) of fluorescent and biodegradable nanoPMOs. The quantification of nanoPMOs' biodegradation using dSTORM imaging demonstrates their excellent structure-dependent degradation behavior at a higher glutathione concentration. The surface functionality of anti-M6PR antibody-conjugated nanoPMOs as quantified by dSTORM imaging plays a key role in prostate cancer cell labeling: oriented antibody is more effective than random ones, while high multivalency is also effective. The higher biodegradability and cancer cell-targeting properties of nanorods conjugated with oriented antibody (EAB4H) effectively deliver the anticancer drug doxorubicin to cancer cells, exhibiting potent anticancer effects.

Superparamagnetic Spinel-Ferrite Nano-Adsorbents Adapted for Hg2+, Dy3+, Tb3+ Removal/Recycling: Synthesis, Characterization, and Assessment of Toxicity.

In the present work, superparamagnetic adsorbents based on 3-aminopropyltrimethoxy silane (APTMS)-coated maghemite (γFe2O3@SiO2-NH2) and cobalt ferrite (CoFe2O4@SiO2-NH2) nanoparticles were prepared and characterized using transmission-electron microscopy (TEM/HRTEM/EDXS), Fourier-transform infrared spectroscopy (FTIR), specific surface-area measurements (BET), zeta potential (ζ) measurements, thermogravimetric analysis (TGA), and magnetometry (VSM). The adsorption of Dy3+, Tb3+, and Hg2+ ions onto adsorbent surfaces in model salt solutions was tested. The adsorption was evaluated in terms of adsorption efficiency (%), adsorption capacity (mg/g), and desorption efficiency (%) based on the results of inductively coupled plasma optical emission spectrometry (ICP-OES). Both adsorbents, γFe2O3@SiO2-NH2 and CoFe2O4@SiO2-NH2, showed high adsorption efficiency toward Dy3+, Tb3+, and Hg2+ ions, ranging from 83% to 98%, while the adsorption capacity reached the following values of Dy3+, Tb3+, and Hg2+, in descending order: Tb (4.7 mg/g) > Dy (4.0 mg/g) > Hg (2.1 mg/g) for γFe2O3@SiO2-NH2; and Tb (6.2 mg/g) > Dy (4.7 mg/g) > Hg (1.2 mg/g) for CoFe2O4@SiO2-NH2. The results of the desorption with 100% of the desorbed Dy3+, Tb3+, and Hg2+ ions in an acidic medium indicated the reusability of both adsorbents. A cytotoxicity assessment of the adsorbents on human-skeletal-muscle derived cells (SKMDCs), human fibroblasts, murine macrophage cells (RAW264.7), and human-umbilical-vein endothelial cells (HUVECs) was conducted. The survival, mortality, and hatching percentages of zebrafish embryos were monitored. All the nanoparticles showed no toxicity in the zebrafish embryos until 96 hpf, even at a high concentration of 500 mg/L.

Periodic mesoporous ionosilica nanoparticles for dual cancer therapy: Two-photon excitation siRNA gene silencing in cells and photodynamic therapy in zebrafish embryos.

Photodynamic therapy (PDT) and photochemical internalization (PCI) are two methods that use light to provoke cell death or disturbance of cellular membranes, respectively, via excitation of a photosensitizer and the formation of reactive oxygen species (ROS). In this context, two-photon excitation (TPE) is of high interest for PCI and/or PDT due to spatiotemporal resolution of two-photon light and deeper penetration of near-infrared light in biological tissues. Here, we report that Periodic Mesoporous Ionosilica Nanoparticles (PMINPs) containing porphyrin groups allow the complexation of pro-apoptotic siRNA. These nano-objects were incubated with MDA-MB-231 breast cancer cells, and TPE-PDT led to significant cell death. Finally, MDA-MB-231 breast cancer cells were pre-incubated with the nanoparticles and then injected in the pericardial cavity of zebrafish embryos. After 24 h, the xenografts were irradiated with femtosecond pulsed laser and the size monitoring by imaging showed a decrease 24 h after irradiation. Pro-apoptotic siRNA was complexed with the nanoparticles and incubation with MDA-MB-231 cells did not lead to cancer cell death in dark conditions, but with two-photon irradiation, TPE-PCI was observed and a synergic effect between pro-apoptotic siRNA and TPE-PDT was noticed, leading to 90% of cancer cell death. Therefore, PMINPs represent an interesting system for nanomedicine applications.

Wound Dressings Based on Sodium Alginate-Polyvinyl Alcohol-Moringa oleifera Extracts.

Biopolymers have significant pharmaceutical applications, and their blending has favorable characteristics for their pharmaceutical properties compared to the sole components. In this work, sodium alginate (SA) as a marine biopolymer was blended with poly(vinyl) alcohol (PVA) to form SA/PVA scaffolds through the freeze-thawing technique. Additionally, polyphenolic compounds in Moringa oleifera leaves were extracted by different solvents, and it was found that extracts with 80% methanol had the highest antioxidant activity. Different concentrations (0.0-2.5%) of this extract were successfully immobilized in SA/PVA scaffolds during preparation. The characterization of the scaffolds was carried out via FT-IR, XRD, TG, and SEM. The pure and Moringa oleifera extract immobilized SA/PVA scaffolds (MOE/SA/PVA) showed high biocompatibility with human fibroblasts. Further, they showed excellent in vitro and in vivo wound healing capacity, with the best effect noted for the scaffold with high extract content (2.5%).

Periodic Mesoporous Ionosilica Nanoparticles for BODIPY Delivery and Photochemical Internalization of siRNA.

Periodic Mesoporous Ionosilica Nanoparticles (PMINPs) made via co-condensation reactions starting from an ionosilica precursor and a porphyrin derivative were used for simultaneous BODIPY/siRNA delivery in cancer cells. We observed high BODIPY loading capacities and efficiencies of the PMINPs that are triggered by anion exchange. siRNA adsorption took place on the surface of the nanoparticles, whereas BODIPY was encapsulated within the core of the nanoparticles. BODIPY release was found to be pH-dependent. Our results indicate 94 % BODIPY release after 16 h at pH 4, whereas only 2 % were released at pH 7.4. Furthermore, complexation with siRNA against luciferase gene was observed at the surface of PMINPs and gene silencing through its delivery via photochemical internalization (PCI) mechanism was efficient in MDA-MB-231 breast cancer cells expressing stable luciferase.

Structure-Activity Relationships in Nucleic-Acid-Templated Vectors Based on Peptidic Dynamic Covalent Polymers.

The use of nucleic acids as templates, which can trigger the self-assembly of their own vectors represent an emerging, simple and versatile, approach toward the self-fabrication of tailored nucleic acids delivery vectors. However, the structure-activity relationships governing this complex templated self-assembly process that accompanies the complexation of nucleic acids remains poorly understood. Herein, the class of arginine-rich dynamic covalent polymers (DCPs) composed of different monomers varying the number and position of arginines were studied. The combinations that lead to nucleic acid complexation, in saline buffer, using different templates, from short siRNA to long DNA, are described. Finally, a successful peptidic DCP featuring six-arginine repeating unit that promote the safe and effective delivery of siRNA in live cancer cells was identified.

A Triazolium-Anchored Self-Immolative Linker Enables Self-Assembly-Driven siRNA Binding and Esterase-Induced Release.

The increased importance of RNA-based therapeutics comes with a need to develop next-generation stimuli-responsive systems capable of binding, transporting and releasing RNA oligomers. In this work, we describe triazolium-based amphiphiles capable of siRNA binding and enzyme-responsive release of the nucleic acid payload. In aqueous medium, the amphiphile self-assembles into nanocarriers that can disintegrate upon the addition of esterase. Key to the molecular design is a self-immolative linker that is anchored to the triazolium moiety and acts as a positively-charged polar head group. We demonstrate that addition of esterase leads to a degradation cascade of the linker, leaving the neutral triazole compound unable to form complexes and therefore releasing the negatively-charged siRNA. The reported molecular design and overall approach may have broad utility beyond this proof-of-principle study, because the underlying CuAAC "click" chemistry allows bringing together three groups very efficiently as well as cleaving off one of the three groups under the mild action of an esterase enzyme.

Photosensitivity of Different Nanodiamond-PMO Nanoparticles in Two-Photon-Excited Photodynamic Therapy.

BACKGROUND: In addition to their great optical properties, nanodiamonds (NDs) have recently proved useful for two-photon-excited photodynamic therapy (TPE-PDT) applications. Indeed, they are able to produce reactive oxygen species (ROS) directly upon two-photon excitation but not with one-photon excitation; Methods: Fluorescent NDs (FNDs) with a 100 nm diameter and detonation NDs (DNDs) of 30 nm were compared. In order to use the gems for cancer-cell theranostics, they were encapsulated in a bis(triethoxysilyl)ethylene-based (ENE) periodic mesoporous organosilica (PMO) shell, and the surface of the formed nanoparticles (NPs) was modified by the direct grafting of polyethylene glycol (PEG) and amino groups using PEG-hexyltriethoxysilane and aminoundecyltriethoxysilane during the sol-gel process. The NPs' phototoxicity and interaction with MDA-MB-231 breast cancer cells were evaluated afterwards; Results: Transmission electronic microscopy images showed the formation of core-shell NPs. Infrared spectra and zeta-potential measurements confirmed the grafting of PEG and NH2 groups. The encapsulation of the NDs allowed for the imaging of cancer cells with NDs and for the performance of TPE-PDT of MDA-MB-231 cancer cells with significant mortality. CONCLUSIONS: Multifunctional ND@PMO core-shell nanosystems were successfully prepared. The NPs demonstrated high biocompatibility and TPE-PDT efficiency in vitro in the cancer cell model. Such systems hold good potential for two-photon-excited PDT applications.

The Anti-Obesity Potential of Superparamagnetic Iron Oxide Nanoparticles against High-Fat Diet-Induced Obesity in Rats: Possible Involvement of Mitochondrial Biogenesis in the Adipose Tissues.

BACKGROUND: Obesity is a pandemic disease that is rapidly growing into a serious health problem and has economic impact on healthcare systems. This bleak image has elicited creative responses, and nanotechnology is a promising approach in obesity treatment. This study aimed to investigate the anti-obesity effect of superparamagnetic iron oxide nanoparticles (SPIONs) on a high-fat-diet rat model of obesity and compared their effect to a traditional anti-obesity drug (orlistat). METHODS: The obese rats were treated daily with orlistat and/or SPIONs once per week for 8 weeks. At the end of the experiment, blood samples were collected for biochemical assays. Then, the animals were sacrificed to obtain white adipose tissues (WAT) and brown adipose tissues (BAT) for assessment of the expression of thermogenic genes and mitochondrial DNA copy number (mtDNA-CN). RESULTS: For the first time, we reported promising ameliorating effects of SPIONs treatments against weight gain, hyperglycemia, adiponectin, leptin, and dyslipidemia in obese rats. At the molecular level, surprisingly, SPIONs treatments markedly corrected the disturbed expression and protein content of inflammatory markers and parameters controlling mitochondrial biogenesis and functions in BAT and WAT. CONCLUSIONS: SPIONs have a powerful anti-obesity effect by acting as an inducer of WAT browning and activator of BAT functions.

D-Mannose-appended 5,15-diazaporphyrin for photodynamic therapy.

5,15-Diazaporphyrin appended with D-mannose moieties was prepared through Suzuki-Miyaura cross-coupling reaction and SN2 alkylation. The resultant diazaporphyrin was hydrophilic enough to exhibit sufficient solubility in aqueous media. Because of the photosensitizing ability of diazaporphyrins, the in vitro activity of the D-mannose-appended diazaporphyrin in photodynamic therapy (PDT) was investigated. The specific internalization of the functionalized diazaporphyrin into human breast adenocarcinoma (MDA-MB-231) cells through mannose receptors was confirmed by confocal microscopy imaging. We also demonstrated the strong PDT activity of the functionalized diazaporphyrin at a nanomolar level with short light irradiation time.