Search

Photodynamic therapy (PDT) is a treatment in which photoactive compounds delivered to cancerous tissues are excited with light and then transfer the absorbed energy to adjacent tissue oxygen molecules to generate toxic singlet oxygen (1O2). As 1O2 is produced only where light and photosensitizers (PSs) are combined, PDT holds promise as a minimally invasive, highly selective treatment for certain cancers. The practical application of PDT requires easily synthesized, water-soluble PSs that have low dark toxicities, high 1O2 quantum yields, and efficient absorption of 650–850 nm near-infrared (NIR) light, which deeply penetrates tissue. We recently developed a linear tetrapyrrole metal complex, Pd[DMBil1]–PEG750, that meets most of these criteria. This complex is remarkably effective as a PS for PDT against triple-negative breast cancer (TNBC) cells but, critically, it does not absorb NIR light, which is necessary to treat deeper tumors. To enable NIR activation, we synthesized a new derivative, Pd[DMBil1]–PEG5000–SH, which bears a thiol functionality that facilitates conjugation to NIR-absorbing gold nanoshells (NSs). Upon excitation with pulsed 800 nm light, NSs emit two-photon-induced photoluminescence spanning 500–700 nm, which can sensitize the attached PSs to initiate PDT. Additionally, NSs produce heat upon 800 nm irradiation, endowing the NS–PS conjugates with an auxiliary photothermal therapeutic (PTT) capability. Here, we demonstrate that NS–PS conjugates are potent mediators of NIR-activated tandem PDT/PTT against TNBC cells in vitro. We show that Pd[DMBil1]–PEG5000–SH retains the photophysical properties of the parent Pd[DMBil1] complex, and that NS–PS generate 1O2 under pulsed 800 nm irradiation, confirming activation of the PSs by photoluminescence emitted from NSs. TNBC cells readily internalize NS PS conjugates, which generate reactive oxygen species in the cells upon pulsed NIR irradiation to damage DNA and induce apoptosis. Together, these findings demonstrate that exploiting photoluminescent NSs as carriers of efficient Pd[DMBil1] PSs is an effective strategy to enable NIR light-activated tandem PDT/PTT.

Four new molecular Co(II)tetrapyridyl complexes were synthesized and evaluated for their activity as catalysts for proton reduction in aqueous environments. The pyridine groups around the macrocycle were substituted for either one or two pyrazine groups. Single crystal X-ray analysis shows that the pyrazine groups have minimal impact on the Co(II)&ndash, N bond lengths and molecular geometry in general. X-band EPR spectroscopy confirms the Co(II) oxidation state and the electronic environment of the Co(II) center are only very slightly perturbed by the substitution of pyrazine groups around the macrocycle. The substitution of pyrazine groups has a substantial impact on the observed metal- and ligand-centered reduction potentials as well as the overall H2 catalytic activity in a multimolecular system using the [Ru(2,2&prime, bipyridine)3]Cl2 photosensitizer and ascorbic acid as a sacrificial electron donor. The results reveal interesting trends between the H2 catalytic activity for each catalyst and the driving force for electron transfer between either the reduced photosensitizer to catalyst step or the catalyst to proton reduction step. The work presented here showcases how even the difference of a single atom in a molecular catalyst can have an important impact on activity and suggests a pathway to optimize the photocatalytic activity and stability of molecular systems.

[Image: see text] Photodynamic therapy (PDT) represents a minimally invasive and highly localized treatment strategy to ablate tumors with few side effects. In PDT, photosensitizers embedded within tumors are activated by light and undergo intersystem crossing, followed by energy transfer to molecular oxygen, resulting in the production of toxic singlet oxygen ((1)O(2)). Previously, we reported a robust, linear tetrapyrrole palladium(II) complex, Pd[DMBil1], characterized by its facile and modular synthesis, broad absorption profile, and efficient (1)O(2) quantum yield of Φ(Δ) = 0.8 in organic media. However, the insolubility of this porphyrinoid derivative in aqueous solution prevents its use under biologically relevant conditions. In this work, we report the synthesis of Pd[DMBil1]-PEG(750), a water-soluble dimethylbiladiene derivative that is appended with a poly(ethylene) glycol (PEG) functionality. Characterization of this complex shows that this PEGylated biladiene architecture maintains the attractive photophysical properties of the parent complex under biologically relevant conditions. More specifically, the absorption profile of Pd[DMBil1]-PEG(750) closely matches that of Pd[DMBil1] and obeys the Beer–Lambert Law, suggesting that the complex does not aggregate under biologically relevant conditions. Additionally, the emission spectrum of Pd[DMBil1]-PEG(750) retains the fluorescence and phosphorescence features characteristic of Pd[DMBil1]. Importantly, the PEGylated photosensitizer generates (1)O(2) with Φ(Δ) = 0.57, which is well within the range to warrant interrogation as a potential PDT agent for treatment of cancer cells. The Pd[DMBil1]-PEG(750) is biologically compatible, as it is taken up by MDA-MB-231 triple negative breast cancer (TNBC) cells and has an effective dose (ED(50)) of only 0.354 μM when exposed to λ(ex) > 500 nm light for 30 min. Impressively, the lethal dose (LD(50)) of Pd[DMBil1]-PEG(750) without light exposure was measured to be 1.87 mM, leading to a remarkably high phototoxicity index of ~5300, which is vastly superior to existing photosensitizers that form the basis for clinical PDT treatments. Finally, through flow cytometry experiments, we show that PDT with Pd[DMBil1]-PEG(750) induces primarily apoptotic cell death in MDA-MB-231 cells. Overall these results demonstrate that Pd[DMBil1]-PEG(750) is an easily prepared, biologically compatible, and well-tolerated photochemotherapeutic agent that can efficiently drive the photoinduced apoptotic death of TNBC cells.

The synthesis, electrochemistry, and photophysical characterization of a 10,10-dimethyl-5,15-bis(pentafluorophenyl)biladiene (DMBil1) linear tetrapyrrole supporting PdII or PtII centers is presented. Both of these nonmacrocyclic tetrapyrrole platforms are robust and easily prepared via modular routes. X-ray diffraction experiments reveal that the Pd[DMBil1] and Pt[DMBil1] complexes adopt similar structures and incorporate a single PdII and PtII center, respectively. Additionally, electrochemical experiments revealed that both Pd[DMBil1] and Pt[DMBil1] can undergo two discrete oxidation and reduction processes. Spectroscopic experiments carried out for Pd[DMBil1] and Pt[DMBil1] provide further understanding of the electronic structure of these systems. Both complexes strongly absorb light in the UV–visible region, especially in the 350–600 nm range. Both Pd[DMBil1] and Pt[DMBil1] are luminescent under a nitrogen atmosphere. Upon photoexcitation of Pd[DMBil1], two emission bands are observed; fluorescence i...

The effect of molecular weight on the rate and extent of melt-infiltration of polystyrene into mesoporous silicon-based photonic crystals is investigated as a function of polymer molecular weight. Polymer viscosity and chain end-to-end (Ree) distance correlate with the rate and extent of infiltration. High molecular weight (Mw) polystyrene (200 or 400 kDa) infiltrates the mesoporous material in two distinct phases: a rapid phase where the larger pores of the template are filled, followed by a slower phase during which the smaller pores fill. Low molecular weight polystyrene (20 and 35 kDa) fills the pores more uniformly, progressing into the film as a single, relatively distinct front of liquid polymer. Scanning electron microscope (SEM) analyses of cross sections of the films are consistent with the optical measurements, showing a lower extent of infiltration for the higher molecular weight polymers. Removal of the porous Si templates by soaking in a chemical etchant generates free-standing films of nano...

Light-activated therapies are ideal for treating cancer because they are non-invasive and highly specific to the area of light application. Photothermal therapy (PTT) and photodynamic therapy (PDT) are two types of light-activated therapies that show great promise for treating solid tumors. In PTT, nanoparticles embedded within tumors emit heat in response to laser light that induces cancer cell death. In PDT, photosensitizers introduced to the diseased tissue transfer the absorbed light energy to nearby ground state molecular oxygen to produce singlet oxygen, which is a potent reactive oxygen species (ROS) that is toxic to cancer cells. Although PTT and PDT have been extensively evaluated as independent therapeutic strategies, they each face limitations that hinder their overall success. To overcome these limitations, we evaluated a dual PTT/PDT strategy for treatment of triple negative breast cancer (TNBC) cells mediated by a powerful combination of silica core/gold shell nanoshells (NSs) and palladium 10,10-dimethyl-5,15-bis(pentafluorophenyl)biladiene-based (Pd[DMBil1]-PEG750) photosensitizers (PSs), which enable PTT and PDT, respectively. We found that dual therapy works synergistically to induce more cell death than either therapy alone. Further, we determined that low doses of light can be applied in this approach to primarily induce apoptotic cell death, which is vastly preferred over necrotic cell death. Together, our results show that dual PTT/PDT using silica core/gold shell NSs and Pd[DMBil1]-PEG750 PSs is a comprehensive therapeutic strategy to non-invasively induce apoptotic cancer cell death.