ngjae You

Singlet Oxygen Generation by Novel NIR BODIPY Dyes

Five novel near-infrared BODIPY dyes were prepared for improved singlet oxygen generation using thiophene and bromine. Theoretical, optical, photostable, and singlet oxygen generation characteristics of these dyes were assessed. Predicted excitation energies by TDDFT calculations were in good agreement (ΔE ≈ 0.06 eV) with experimental data. All five dyes showed both excitation and emission in the NIR range. In particular, two dyes having sulfur and bromine atoms showed efficient singlet oxygen generation with high photostability.

Visible Light Controlled Release of Anticancer Drug through Double Activation of Prodrug.

We designed and synthesized a novel double activatable prodrug system (drug-linker-deactivated photosensitizer), containing a photocleavable aminoacrylate-linker and a deactivated photosensitizer, to achieve the spatiotemporally controlled release of parent drugs using visible light. Three prodrugs of CA-4, SN-38, and coumarin were prepared to demonstrate the activation of deactivated photosensitizer by cellular esterase and the release of parent drugs by visible light (540 nm) via photounclick chemistry. Among these prodrugs, nontoxic coumarin prodrug was used to quantify the release of parent drug in live cells. About 99% coumarin was released from the coumarin prodrug after 24 h of incubation with MCF-7 cells followed by irradiation with low intensity visible light (8 mW/cm(2)) for 30 min. Less toxic prodrugs of CA-4 and SN-38 killed cancer cells as effectively as free drugs after the double activation.

Click and photo-unclick chemistry of aminoacrylate for visible light-triggered drug release

Click and Photo-unclick Chemistry of aminoacrylates is proposed for a new photo-labile linker. Adducts are built in 2 steps with good yields and cleaved rapidly by tissue penetrable visible light (690 nm) with a photosensitizer. Facile synthesis, release of mother drug, and stability and cleavage in medium are demonstrated.

Dual Functioning Thieno-Pyrrole Fused BODIPY Dyes for NIR Optical Imaging and Photodynamic Therapy: Singlet Oxygen Generation without Heavy Halogen Atom Assistance.

We discovered a rare phenomenon wherein a thieno-pyrrole fused BODIPY dye (SBDPiR690) generates singlet oxygen without heavy halogen atom substituents. SBDPiR690 generates both singlet oxygen and fluorescence. To our knowledge, this is the first example of such a finding. To establish a structure-photophysical property relationship, we prepared SBDPiR analogs with electron-withdrawing groups at the para-position of the phenyl groups. The electron-withdrawing groups increased the HOMO-LUMO energy gap and singlet oxygen generation. Among the analogs, SBDPiR688, a CF3 analog, had an excellent dual functionality of brightness (82290u2009m(-1) u2009cm(-1) ) and phototoxic power (99170u2009m(-1) u2009cm(-1) ) comparable to those of Pc 4, due to a high extinction coefficient (211u2009000u2009m(-1) u2009cm(-1) ) and balanced decay (Φflu =0.39 and ΦΔ =0.47). The dual functionality of the lead compound SBDPiR690 was successfully applied to preclinical optical imaging and for PDT to effectively control a subcutaneous tumor.

Evaluation of delocalized lipophilic cationic dyes as delivery vehicles for photosensitizers to mitochondria

Mitochondria are attractive targets in photodynamic therapy. Two conjugates: TPP-Rh (a porphyrin-rhodamine B conjugate) and TPP-AO (a porphyrin-acridine orange conjugate), each possessing a single delocalized lipophilic cation, were designed and synthesized as photosensitizers. Their ability to target the mitochondria for photodynamic therapy was evaluated. The conjugates were synthesized by conjugating a monohydroxy porphyrin (TPP-OH) to rhodamine B (Rh B) and acridine orange base (AO), respectively, via a saturated hydrocarbon linker. To evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro photodynamic activities were studied in comparison to those of TPP-OH. Although fluorescence energy transfer (FRET) was observed in the conjugates, they were capable of generating singlet oxygen at rates comparable to TPP-OH. Biologically, exciting results were observed with TPP-Rh, which showed a much higher phototoxicity [IC(50), 3.95 microM: irradiation of 400-850 nm light (3 mW cm(-2)) for 1 h] than either TPP-OH or Rh B (both, IC(50), >20 microM) without significant dark toxicity at 20 microM. This improved photodynamic activity might be due to a greater cellular uptake and preferential localization in mitochondria. The cellular uptake of TPP-Rh was 8 and 14 times greater than TPP-OH and Rh B, respectively. In addition, fluorescence imaging studies suggest that TPP-Rh localized more in mitochondria than TPP-OH. On the other hand, TPP-AO showed some dark toxicity at 10 microM and stained both mitochondria and nucleus. Our study suggests that conjugation of photosensitizers to Rh might provide two benefits, higher cellular uptake and mitochondrial localization, which are two important subjects in photodynamic therapy.

Synthesis and in vitro biological evaluation of lipophilic cation conjugated photosensitizers for targeting mitochondria

Mitochondria-specific photosensitizers were designed by taking advantage of the preferential localization of delocalized lipophilic cations (DLCs) in mitochondria. Three DLC-porphyrin conjugates: CMP-Rh (a core modified porphyrin-rhodamine B cation), CMP-tPP (a core modified porphyrin-mono-triphenyl phosphonium cation), CMP-(tPP)(2) (a core modified porphyrin-di-tPP cation) were prepared. The conjugates were synthesized by conjugating a monohydroxy core modified porphyrin (CMP-OH) to rhodamine B (Rh B), or either one or two tPPs, respectively, via a saturated hydrocarbon linker. Their ability for delivering photosensitizers to mitochondria was evaluated using dual staining fluorescence microscopy. In addition, to evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro biological activities were studied in comparison to those of CMP-OH. Fluorescence imaging study suggested that CMP-Rh specifically localized in mitochondria. On the other hand, CMP-tPP and CMP-(tPP)(2) showed less significant mitochondrial localization. All conjugates were capable of generating singlet oxygen at rates comparable to CMP-OH. Interestingly, all cationic conjugates showed dramatic increase in cellular uptake and phototoxicity compared to CMP-OH. This improved photodynamic activity might be primarily due to an enhanced cellular uptake. Our study suggests that Rh B cationic group is better at least for CMP than tPP as a mitochondrial targeting vector.

Thieno-pyrrole-fused BODIPY intermediate as a platform to multifunctional NIR agents.

We report the synthesis, photophysical and electrochemical properties, and in vivo fluorescence imaging of a series of new thieno-pyrrole-fused near-infrared (NIR) BODIPY agents by using a versatile intermediate as a building block. The versatile thieno-pyrrole-fused BODIPY intermediate was rationally designed to bear bromo-substituents and absorb in the mid-red region (635 nm) to act as an organic electrophile for the development of NIR multifunctional agents. The use of subsequent palladium-catalyzed and nucleophilic substitution reactions afforded highly conjugated NIR BODIPYs. The novel BODIPYs exhibit long-wavelength absorptions in the NIR region (650-840 nm). The agents produce sharp fluorescence bands, and most of them display respectable quantum yields of fluorescence (0.05-0.87) useful for biomedical imaging, as demonstrated by in vivo imaging with SBDPiR740. Interestingly, a number of agents in the series that are non-halogenated were reactive to O2 at the triplet photo-excited state coupled with a favorable redox potential and decent fluorescence, and hence could be potential candidates for use as photosensitizers in fluorescence-guided photodynamic therapy. Furthermore, the synthetic approach allows further functionalization of the highly conjugated NIR BODIPYs to tune the excited states (PET, ICT) and to conjugate targeting moieties for enhanced biological applications.

Structural effects of core-modified porphyrins in dye-sensitized solar cells

A series of core-modified porphyrins with different meso aryl groups (R1), anchoring groups (R2), and core atoms (X) were studied as light-harvesting sensitizers for dye-sensitized solar cells (DSSCs). DSSCs were fabricated using these porphyrins as well as TiO2 nanoparticles with a particle diameter of around 25 nm. A dense layer of TiO2 was deposited as an interfacial layer on fluorine-doped tin dioxide (FTO) substrates. A TiO2 nanocrystalline film was then deposited on the dense layer by spin coating. The comparison of DSSC performance from different core-modified porphyrins was studied. The UV-vis absorption spectroscopy of porphyrin films attached on TiO2 and porphyrin solutions were also measured. The results indicated that both anchoring and meso aryl groups impacted on cell performance. The cell efficiency was correlated to the absorption of porphyrin films attached on TiO2 at the Soret band.

Core-modified porphyrins. Part 6: Effects of lipophilicity and core structures on physicochemical and biological properties in vitro

Thiaporphyrins 2-8 were prepared as analogues of 5,20-diphenyl-10,15-bis[4-(carboxymethyleneoxy)-phenyl]-21,23- dithiaporphyrin (1) to examine the effect of structural modifications: substituent changes in meso aryl groups of dithiaporphyrins with one water-solubilizing group (2-5), dihydroxylation of a pyrrole double bond and reduction to dihydroxychlorins (6 and 7), and the removal of two meso aryl groups to give unsubstituted meso positions (8). The impact of these structural modifications was measured in both physicochemical (UV spectra, generation of singlet oxygen, lipophilicity, and aggregate formation) and biological properties (dark toxicity and phototoxicity, cellular uptake, and subcellular localization). Mono-functionalized porphyrins had much higher lipophilicity than di-functionalized porphyrin 1 and, consequently, formed more aggregates in aqueous media. The formation of aggregates might lower the efficiency of lipophilic porphyrins as photosensitizers. Interestingly, dihydroxylation of a core pyrrole group in the dithiaporphyrin core did not affect either the absorption spectrum or the efficiency for generating singlet oxygen. The phototoxicity of dihydroxydithiachlorins mainly depended on their intracellular uptake. The potent phototoxicity of 6, IC(50)=0.18muM, was attributed to the extraordinarily high uptake. The intracellular uptake of 6 was about 7.6 times higher than 1. In contrast, thiaporphyrin 8 with only two meso aryl groups was less effective as a photosensitizer, perhaps due to poorer uptake and a lower quantum yield for the generation of singlet oxygen.

Synthesis and Singlet Oxygen Reactivity of 1,2‐Diaryloxyethenes and Selected Sulfur and Nitrogen Analogs

1,2‐Diaryloxyethene has recently been proposed as a linker in singlet oxygen‐mediated drug release. Even though 1,2‐diaryloxyethenes look very simple, their synthesis was not an easy task. Previous methods are limited to symmetric molecules, lengthy step and low yield. We report on a facile synthetic method not only for 1,2‐diaryloxyethenes but also their sulfur and nitrogen analogs in yields ranging from 40 to 90% with more than 90% purity at the vinylation reaction.