Uptake and Removal of Uranium by and from Human Teeth.

Uranium-238 (238U), a long-lived radiometal, is widespread in the environment because of both naturally occurring processes and anthropogenic processes. The ingestion or inhalation of large amounts of U is a major threat to humans, and its toxicity is considered mostly chemical rather than radiological. Therefore, a way to remove uranium ingested by humans from uranium-contaminated water or from the air is critically needed. This study investigated the uranium uptake by hydroxyapatite (HAP), a compound found in human bone and teeth. The uptake of U by teeth is a result of U transport as dissolved uranyl (UO22+) in contaminated water, and U adsorption has been linked to delays in both tooth eruption and development. In this present work, the influence of pH, contact time, initial U concentration, and buffer solution on the uptake and removal of U in synthetic HAP was investigated and modeled. The influence of pH (pH of human saliva, 6.7-7.4) on the uptake of uranyl was negligible. Furthermore, the kinetics were extremely fast; in one second of exposure, 98% of uranyl was uptaken by HAP. The uptake followed pseudo-second-order kinetics and a Freundlich isotherm model. A 0.2 M sodium carbonate solution removed all the uranyl from HAP after 1 h. Another series of in vitro tests were performed with real teeth as targets. We found that, for a 50 mg/L U in PBS solution adjusted to physiological pH, ∼35% of the uranyl was uptaken by the tooth after 1 h, following pseudo-first-order kinetics. Among several washing solutions tested, a commercially available carbonate, as well as a commercially available fluoride solution, enabled removal of all the uranyl taken up by the teeth.

Distorted Phthalocyanines by Click Chemistry: Photoacoustic, Photothermal, and Surface-Enhanced Resonance Raman Studies.

Distortion of nominally planar phthalocyanine macrocycles affects the excited state dynamics in that most of the excited-state energy decays through internal conversion. A click-type annulation reaction on a perfluorophthalocyanine platform appending a seven-membered ring to the ß-positions on one or more of the isoindoles distorts the macrocycle and modulates solubility. The distorted derivative enables photoacoustic imaging, photothermal effects, and strong surface-enhanced resonance Raman signals.

Improved synthesis of the bifunctional chelator p-SCN-Bn-HOPO.

The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.4%. Herein we report an improved and efficient synthesis of p-SCN-Bn-HOPO in four steps with 14.3% overall yield which will improve its availability for further biological studies and wider application in PET imaging. The new synthetic route also allows variation in linker length and chemistries which may be helpful in modifying in vivo clearance behaviors of future agents.

A Structural Model of Nitro-Porphyrin Dyes Based on Spectroscopy and Density Functional Theory.

Nitro-porphyrins are an important class of commercial dyes with a range of potential applications. The nitro group is known to dramatically affect the photophysics of the porphyrin, but there are few systematic investigations of the contributing factors. To address this deficiency, we present spectroscopic studies of a series of nitro-porphyrins, accompanied by density functional theory calculations to elucidate their structures. In particular, we explore how the positions of the substituents affect the energy levels and nuclear geometry. As expected, nitro groups on the meso-phenyl rings cause small changes to the orbital energies by induction, while those at the ß-pyrrole positions more strongly conjugate into the aromatic system. In addition, however, we find evidence that ß-pyrrole nitro groups distort the porphyrin, creating two non-planar conformations with distinct properties. This unexpected result helps explain the anomalous photophysics of nitro-porphyrins reported throughout the literature, including inhomogeneous line broadening and biexponential fluorescence decay. © 2017 Wiley Periodicals, Inc.

Carbon-1 versus Carbon-3 Linkage of d-Galactose to Porphyrins: Synthesis, Uptake, and Photodynamic Efficiency.

The use of glycosylated compounds is actively pursued as a therapeutic strategy for cancer due to the overexpression of various types of sugar receptors and transporters on most cancer cells. Conjugation of saccharides to photosensitizers such as porphyrins provides a promising strategy to improve the selectivity and cell uptake of the photosensitizers, enhancing the overall photosensitizing efficacy. Most porphyrin-carbohydrate conjugates are linked via the carbon-1 position of the carbohydrate because this is the most synthetically accessible approach. Previous studies suggest that carbon-1 galactose derivatives show diminished binding since the hydroxyl group in the carbon-1 position of the sugar is a hydrogen bond acceptor in the galectin-1 sugar binding site. We therefore synthesized two isomeric porphyrin-galactose conjugates using click chemistry: one linked via the carbon-1 of the galactose and one linked via carbon-3. Free base and zinc analogs of both conjugates were synthesized. We assessed the uptake and photodynamic therapeutic (PDT) activity of the two conjugates in both monolayer and spheroidal cell cultures of four different cell lines. For both the monolayer and spheroid models, we observe that the uptake of both conjugates is proportional to the protein levels of galectin-1 and the uptake is suppressed after preincubation with an excess of thiogalactose, as measured by fluorescence spectroscopy. Compared to that of the carbon-1 conjugate, the uptake of the carbon-3 conjugate was greater in cell lines containing high expression levels of galectin-1. After photodynamic activation, MTT and lactate dehydrogenase assays demonstrated that the conjugates induce phototoxicity in both monolayers and spheroids of cancer cells.

One-Pot Synthesis of Four Chlorin Derivatives by a Divergent Ylide.

Chlorins have unique photophysical properties that are exploited in diverse biological and materials applications. De novo chlorin synthesis with specific exocyclic motifs can be challenging and many are not stable to photobleaching and/or oxidation. A facile approach to a stable synthetic chlorin with a fused N-methyl pyrrolidine uses cyclo addition of a sarcosine-based azomethine ylide on 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)-porphyrin (TPPF20) is reported, but this approach has limitations. We report the synthesis of stable chlorin scaffolds starting with TPPF20 using a new glycine-based N-(hydroxymethyl)- N-methelenemethanideaminium ylide. Careful control of the 1,3-dipolar cycloaddition reaction allows a divergent use of the glycine derived ylide to yield four new chlorins, including the fused NH-pyrrolidine, two dimers, and the same N-methyl chlorin product from the sarcosine ylide reaction. The mechanism begins with the formation of a bis(hydroxymethyl)glycine, which then dehydrates and decarboxylates to form the active N-(hydroxymethyl)- N-methelenemethanideaminium ylide, which then reacts with TPPF20 to form a key N-(hydroxymethyl)-17,18-pyrrolidinyl-chlorin intermediate. Deformylation of this intermediate affords the (17,18-pyrrolidinyl)-chlorin, whereas a Cannizzaro-type reaction promotes a hydride attack to an imine chlorin cation to yield the N-methyl chlorin. The exocyclic NH-pyrrolidine provides a unique mode of attaching chiral moieties that avoids formation of diasteromers at the bridgehead carbons.

Compromising the plasma membrane as a secondary target in photodynamic therapy-induced necrosis.

Photodynamic therapy (PDT) is a non-invasive treatment widely applied to different cancers. The goal of PDT is the photo-induced destruction of cancer cells by the activation of different cell death mechanisms, including apoptosis and/or necrosis. Recent efforts focusing on understanding the mechanisms of cell death activated by PDT find that it depends on the type of photosensitizer (PS), targeted organelles, and nature of the light used. It is generally accepted that very short incubation times are required to direct the PS to the plasma membrane (PM), while longer periods result in the accumulation of the PS in internal compartments such as the endoplasmic reticulum or mitochondria. Glycosylation of the PS targets cancer via saccharide receptors on the cell surface, and is generally assumed that these compounds rapidly internalize and accumulate, e.g. in the endoplasmic reticulum. Herein we demonstrate that a minor fraction of a glycosylated chlorin compound residing at the PM of cancer cells can activate necrosis upon illumination by compromising the PM independently of the length of the incubation period. The results presented here show that the PM can also be targeted by glycosylated PS designed to accumulate in internal organelles. PS activation to induce necrosis by compromising the plasma membrane has the benefits of fast cell death and shorter irradiation times. The findings described here expand our understanding of the cellular damage induced by phototherapies, presenting the possibility of activating another cell death mechanism based on the incubation time and type of light used.

Practical, high-yield synthesis of thiol-terminated diacetylenes for formation of conductive monolayers.

Self-assembled monolayers of thiol terminated conjugated diacetylenes can be cross-linked using ultraviolet light to form highly conjugated polydiacetylenic conductive monolayers1; however, the reported syntheses of the diacetylene monomers present numerous problems that prevent the wide spread application of these in functional materials. We report a redesigned four-step synthesis that proceeds in 75-80 % overall yields and allows gram scale production of an array of thiol terminated conjugated diacetylenes, thereby allowing examination and application of these low-dimensional conductive materials.

The influence of nearest-neighbour interactions and assembly dynamics on the transport properties of porphyrin supramolecular assemblies on Au(111).

Here we report on the effect of local molecular organization or "tertiary structure" on the charge transport properties of thiol-tethered tetraphenylporphyrin (ZnTPPF4-SC5SH) nanoscale clusters of ca. 5 nm in lateral dimension embedded within a dodecanethiol (C12) monolayer on Au(111). The structure of the clusters in the mixed monolayers and their resulting transport properties were monitored by Atomic Force Microscopy (AFM), Scanning Tunneling Microscopy (STM) and Spectroscopy (STS). The mixed films were deposited on Au(111) for a period of one to five days, during which the lateral dimensions of the ZnTPPF4-SC5SH islands that were formed after one day reduced by nearly 35% on average by five days, accompanied by a noticeable depletion of the surrounding C12 monolayer. These subtle changes in mixed monolayer morphology were accompanied by drastic differences in conductance. The ZnTPPF4-SC5SH clusters assembled for one day exhibited highly reproducible I-V spectra with simple tunneling behavior. By three days, this evolved into bias-induced switching of conductance, with a ∼100-1000 fold increase. Furthermore, current fluctuations started to become significant, and then dominated transport across the ZnTPPF4-SC5SH clusters assembled over five days. Our data suggests that this evolution can be understood by slow surface diffusion, enabling the ZnTPPF4-SC5SH molecules to overcome initial steric hindrance in the early stages of island formation in the C12 monolayer (at day one), to reach a more energetically-favored, close-packed organization, as noted by the decrease in island size (by day three). However, when desorption of the supporting matrix of C12 became pronounced (by day five), the ZnTPPF4-SC5SH clusters began to lose stabilization, and stochastic switching was then observed to dominate transport in the clusters, illustrating the critical nature of the local organization on these transport properties.

Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper-64.

Nanoparticles labeled with radiometals enable whole-body nuclear imaging and therapy. Though chelating agents are commonly used to radiolabel biomolecules, nanoparticles offer the advantage of attaching a radiometal directly to the nanoparticle itself without the need of such agents. We previously demonstrated that direct radiolabeling of silica nanoparticles with hard, oxophilic ions, such as the positron emitters zirconium-89 and gallium-68, is remarkably efficient. However, softer radiometals, such as the widely employed copper-64, do not stably bind to the silica matrix and quickly dissociate under physiological conditions. Here, we overcome this limitation through the use of silica nanoparticles functionalized with a soft electron-donating thiol group to allow stable attachment of copper-64. This approach significantly improves the stability of copper-64 labeled thiol-functionalized silica nanoparticles relative to native silica nanoparticles, thereby enabling in vivo PET imaging, and may be translated to other softer radiometals with affinity for sulfur. The presented approach expands the application of silica nanoparticles as a platform for facile radiolabeling with both hard and soft radiometal ions.

Fluorinated porphyrinoids as efficient platforms for new photonic materials, sensors, and therapeutics.

Porphyrinoids are robust heterocyclic dyes studied extensively for their applications in medicine and as photonic materials because of their tunable photophysical properties, diverse means of modifying the periphery, and the ability to chelate most transition metals. Commercial applications include their use as phthalocyanine dyes in optical discs, porphyrins in photodynamic therapy, and as oxygen sensors. Most applications of these dyes require exocyclic moieties to improve solubility, target diseases, modulate photophysical properties, or direct the self-organization into architectures with desired photonic properties. The synthesis of the porphyrinoid depends on the desired application, but the de novo synthesis often involves several steps, is time consuming, and results in low isolated yields. Thus, the application of core porphyrinoid platforms that can be rapidly and efficiently modified to evaluate new molecular architectures allows researchers to focus on the design concepts rather than the synthesis methods, and opens porphyrinoid chemistry to a broader scientific community. We have focused on several widely available, commercially viable porphyrinoids as platforms: meso-perfluorophenylporphyrin, perfluorophthalocyanine, and meso-perfluorophenylcorrole. The perfluorophenylporphyrin is readily converted to the chlorin, bacteriochlorin, and isobacteriochlorin. Derivatives of all six of these core platforms can be efficiently and controllably made via mild nucleophilic aromatic substitution reactions using primary S, N, and O nucleophiles bearing a wide variety of functional groups. The remaining fluoro groups enhance the photo and oxidative stability of the dyes and can serve as spectroscopic signatures to characterize the compounds or in imaging applications using (19)F NMR. This review provides an overview of the chemistry of fluorinated porphyrinoids that are being used as a platform to create libraries of photo-active compounds for applications in medicine and materials.

Tuning the Structure and Photophysics of a Fluorous Phthalocyanine Platform.

Phthalocyanines are an important class of industrial dyes with potential commercial applications ranging from photovoltaics to biomedical imaging and therapeutics. We previously demonstrated the versatility of the commercially available zinc(II) hexadecafluorophthalocyanine (ZnF16Pc) as a platform for rapidly developing functional materials for these applications and more. Because this core-platform approach to dye development is increasingly common, it is important to understand the photophysical and structural consequences of the substitution chemistry involved. We present a fundamental study of a series of ZnF16Pc derivatives in which the aromatic fluorine atoms are progressively substituted with thioalkanes. Clear spectroscopic trends are observed as the substituents change from electron-withdrawing to electron-releasing groups. Additionally, there is evidence for significant structural distortion of the normally planar heterocycle, with important ramifications for the photophysics. These results are also correlated to DFT calculations, which show that the orbital energies and symmetries are both important factors for explaining the excited-state dynamics.

Silica nanoparticles as substrates for chelator-free labeling of oxophilic radioisotopes.

Chelator-free nanoparticles for intrinsic radiolabeling are highly desirable for whole-body imaging and therapeutic applications. Several reports have successfully demonstrated the principle of intrinsic radiolabeling. However, the work done to date has suffered from much of the same specificity issues as conventional molecular chelators, insofar as there is no singular nanoparticle substrate that has proven effective in binding a wide library of radiosotopes. Here we present amorphous silica nanoparticles as general substrates for chelator-free radiolabeling and demonstrate their ability to bind six medically relevant isotopes of various oxidation states with high radiochemical yield. We provide strong evidence that the stability of the binding correlates with the hardness of the radioisotope, corroborating the proposed operating principle. Intrinsically labeled silica nanoparticles prepared by this approach demonstrate excellent in vivo stability and efficacy in lymph node imaging.

Synthesis and cell phototoxicity of a triply bridged fused diporphyrin appended with six thioglucose units.

A triply bridged fused diporphyrin appended with six thioglucose units is reported. This new, chemically and photochemically stable amphiphilic compound is taken up by breast cancer cells and causes cell death upon light exposure. Photophysical studies reveal absorption bands in the near IR region, and photosensitized formation of singlet oxygen in high quantum yields.

Self-organization of Zr(IV) porphyrinoids on graphene oxide surfaces by axial metal coordination.

The protruding oxophilic central metal ion of Zr(IV) porphyrinoids facilitates axial coordination to the oxygen bearing functional groups on graphene oxide (GO) surfaces to result in new supramolecular photonic materials with high dye loading especially on edges and large defects. The reaction proceeds at room temperature with GO dispersed in tetrahydrofuran and GO films on glass. Since the Zr(IV) serves as a conduit, the photophysical properties of the dye sensitized GO derive from both the axially bound chromophores and the GO substrate. Self-organization of metalloporphyrinoids on GO mediated by axial coordination of group (IV) metal ions allows for direct sensitization of graphene and graphenic materials without requiring covalent chemistries with poorly conducting linkers.

Adaptive organic nanoparticles of a teflon-coated iron (III) porphyrin catalytically activate dioxygen for cyclohexene oxidation.

Self-organized organic nanoparticles (ONP) are adaptive to the environmental reaction conditions. ONP of fluorous alkyl iron(III) porphyrin catalytically oxidize cyclohexene to the allylic oxidation products. In contrast, the solvated metalloporphyrin yields both allylic oxidation and epoxidation products. The ONP system facilitates a greener reaction because about 89% reaction medium is water, molecular oxygen is used in place of synthetic oxidants, and the ambient reaction conditions used require less energy. The enhanced catalytic activity of these ONP is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the TON should diminish by self-oxidative degradation. The fluorous alkyl chain stabilizes the ONP toward self-oxidative degradation.

Synthesis and photophysics of an octathioglycosylated zinc(II) phthalocyanine.

A water soluble zinc(II) phthalocyanine symmetrically appended with eight thioglucose units was synthesized from commercially available hexadecafluorophthalocyaninatozinc(II) by controlled nucleophilic substitution of the peripheral fluoro groups. The photophysical properties and cancer cell uptake studies of this nonhydrolyzable thioglycosylated phthalocyanine are reported. The new compound has amphiphilic character, is chemically stable, and can potentially be used as a photosensitizer in photodynamic therapy.

Lithography of Polymer Nanostructures on Glass for Teaching Polymer Chemistry and Physics.

As nanolithography becomes increasingly important in technology and daily life, a variety of inexpensive and creative methods toward communicating the concepts underpinning these processes in the classroom are necessary. An experiment is described that uses simple CD-Rs, C-clamps, an oven, and a freezer to provide concrete examples and insights into the chemistry and principles of nanolithography. The experiment also has flexibility, making it suitable for a range of classroom levels from high school to more advanced labs in college. Because CD-Rs are composed of grooves of polycarbonate, the experiment provides a basis for discussions and exploration into the chemistry and physics of polymers on the nanoscale.

Phthalocyanine blends improve bulk heterojunction solar cells.

A core phthalocyanine platform allows engineering of the solubility properties the band gap, shifting the maximum absorption toward the red. A simple method for increasing the efficiency of heterojunction solar cells uses a self-organized blend of phthalocyanine chromophores fabricated by solution processing.