Platinum‐Based Azadipyrromethane Complexes for Targeted Cancer Phototherapy: Synthesis, Properties, and Therapeutic Application

Singlet oxygen photo-production by perylene bisimide derivative Langmuir-Schaefer films for photodynamic therapy applications

In this study, we demonstrate a novel H2O2 activatable photosensitizer (compound 7) which contains a diiodo distyryl boron dipyrromethene (BODIPY) core and an arylboronate group that quenches the excited state of the BODIPY dye by photoinduced electron transfer (PET). The BODIPY-based photosensitizer is highly soluble and remains nonaggregated in dimethyl sulfoxide (DMSO) as shown by the intense and sharp Q-band absorption (707 nm). As expected, compound 7 exhibits negligible fluorescence emission and singlet oxygen generation efficiency. However, upon interaction with H2O2, both the fluorescence emission and singlet oxygen production of the photosensitizer can be restored in phosphate buffered saline (PBS) solution and PBS buffer solution containing 20% DMSO as a result of the cleavage of the arylboronate group. Due to the higher concentration of H2O2 in cancer cells, compound 7 even with low concentration is particularly sensitive to human cervical carcinoma (HeLa) cells (IC50 = 0.95 μM) but hardly damage human embryonic lung fibroblast (HELF) cells. The results above suggest that this novel BODIPY derivative is a promising candidate for fluorescence imaging-guided photodynamic cancer therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are emerging modalities for the treatment of tumors and nonmalignant conditions, based on the use of photosensitizers to generate singlet oxygen or heat, respectively, upon light (laser) irradiation. They have potential advantages over conventional treatments, being minimally invasive with precise spatial-temporal selectivity and reduced side effects. However, most clinically employed PDT agents are activated at visible (vis) wavelengths for which the tissue penetration and, hence, effective treatment depth are compromised. In addition, the lipophilicity of near-infrared (NIR) photothermal agents limits their use and efficiency. To achieve combined PDT/PTT effects, both excitation wavelengths need to be tuned into the NIR spectral window of biological tissues. This paper reports the synthesis of neodymium-doped upconversion nanoparticles (NaYF4 :Yb,Er,Nd@NaYF4 :Nd) that convert 800 nm light into vis wavelengths, which can then activate conventional photosensitizers on the nanoparticle surface for PDT. Covalently bonded IR-780 dyes can readily be activated by 800 nm laser irradiation. The PEGylated nanoplatform exhibited a narrow size distribution, good stability and efficient generation of singlet oxygen under laser irradiation. The in vitro photocytotoxicity of this engineered nanoplatform as either a PDT or PTT agent in HeLa cells is demonstrated, while fluorescence microscopy in nanoplatform-incubated cells highlights its potential for bioimaging.

Fullerene derivatives have appealing properties that can potentially be used in materials science and medical applications. In particular, fullerenes are known to produce reactive oxygen species upon their excitation with light. This makes them particularly attractive as photosensitizers for photodynamic therapy (PDT). Photodynamic therapy is a new modality of treatment of cancer as well as some non-cancerous conditions. It involves the combined actions of a drug (photosensitizer) and light to produce a cytotoxic effect. Water-soluble hexa(sulfo- n -butyl)[60]fullerenes (FC 4 S) was reported recently to generate singlet oxygen ( 1 O 2 ) and superoxide radical (O 2 - ·) upon its excitation with light, making it a promising candidate for PDT treatments. Recently, we synthesized new amphiphilic fullerene derivatives, namely, [60]fullerene-diphenylaminofluorene-oligo(ethylene glycol) conjugates, C 60 (>DPAF-PEG600) and C 60 (>DPAF-PEG2000), as potential photosensitizers. In this paper we compare FC 4 S to PEG-based fullerenes in terms of their singlet oxygen photosensitization ability. We measured time-resolved kinetics of singlet oxygen luminescence photosensitized by excitation of fullerenes via a 10 ns pulsed laser at 523 nm. For FC 4 S we observed normal kinetics with a monoexponential decay profile giving a time constant 3.8 us in water. In contrast, for the case of C 60 (>DPAF-PEG600) and C 60 (>DPAF-PEG2000), a non-monoexponential decay profile with a long tail (~ 10 2 μs) in water was observed. We hypothesize that this is due to formation of vesicles by PEG fullerenes in aqueous solution. To investigate photodynamic activity of these fullerene derivatives in vitro , we used HeLa human adenocarcinoma and B16 mouse melanoma cell lines. FC 4 S showed clear photodynamic effects in both cell lines. The total fluence required to kill 50% of the cells at the drug concentration of 20 μM was 36 Jcm -2 for HeLa cells and 72 Jcm -2 for B16 cells. Neither PEG-based fullerene derivatives showed any appreciable photodynamic activity, possibly, due to low efficiency of singlet oxygen generation.

A potential mediator for photodynamic therapy based on silver nanoparticles functionalized with porphyrin

Photodynamic therapy (PDT) combining with near infrared (NIR) imaging is attractive. However, the intrinsic hypoxia in tumor and consumption of oxygen during treatment will decrease PDT. Here an artificial red cell was prepared using polypeptides conjugated hemoglobin as an oxygen carrier. A NIR photosensitizer-brominated 4,4-difluoro-4-bora-3a,a-diaza-s-indacene (BODIPY-Br2) possessing both high fluorescence emission and singlet oxygen generation efficiency was synthesized and also conjugated to polypeptides to achieve NIR imaging-guided PDT. In vitro studies performed on HepG2 cancer cells verified the oxygen carrier, cancer tracing and curing abilities of the as-prepared polymeric nanoparticles. Even under hypoxia condition, it also obviously increases the cell killing rate when exposed light at a low energy (25 mW/cm2, 10 min). Meanwhile, the fluorescence of BODIPY in NPs would light up cells for real-time imaging. These results show the potential of the biocompatible and biodegradable P-Hb-B NPs for enhancement of simultaneous tracing and treating of cancer.

Competition and regulation between triplet phosphorescence and singlet oxygen generation efficiency

Brominated BODIPYs as potential photosensitizers for photodynamic therapy using a low irradiance excitation

Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species. We recently reported the rational design of a Hf-porphyrin nanoscale metal-organic framework, DBP-UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP-UiO efficiently generates singlet oxygen owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile singlet oxygen diffusion through porous DBP-UiO nanoplates. Consequently, DBP-UiO displayed greatly enhanced PDT efficacy both in vitro and in vivo, leading to complete tumor eradication in half of the mice receiving a single DBP-UiO dose and a single light exposure. The photophysical properties of DBP-UiO are however not optimum with the lowest energy absorption at 634 nm and a relatively small extinction coefficient of 2200 M-1·cm-1. We recently designed a chlorin-based NMOF, DBC-UiO, with much improved photophysical properties and PDT efficacy in two colon cancer mouse models. Reduction of the DBP ligands in DBP-UiO to the DBC ligands in DBC-UiO led to a 13 nm red-shift and an 11-fold extinction coefficient increase of the lowest energy Q-band. While inheriting the crystallinity, stability, porosity, and nanoplate morphology of DBP-UiO, DBC-UiO sensitizes more efficient singlet oxygen generation and exhibits much enhanced photodynamic therapy (PDT) efficacy on two colon cancer mouse models as a result of its improved photophysical properties. Both apoptosis and immunogenic cell death contributed to cancer cell-killing in DBC-UiO induced PDT. Our work has thus demonstrated that NMOFs represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic.

Herein, novel silicon (IV) phthalocyanines peripherally substituted by triethylene glycol groups and bearing axial hydroxyl groups were synthesized and fully characterized by using different analyses techniques. The photophysical and photochemical properties of octa (2a) and tetra (2b) derivatives were investigated in DMF and DMSO. The effect of octa or tetra substitution on fluorescence quantum yield, singlet oxygen generation and photodegradation were examined, and the differences were evaluated regarding their potential efficiency in photodynamic therapy (PDT). Their pH-responses were investigated to determine the influence of protonation of azomethine nitrogen atoms on singlet oxygen generation efficiencies. Dramatic optical changes were observed by protonation of azomethine bridges of 2a and 2b. They exhibited signal decrease from pH4.0 to 1.0 for 2a (pKa=2.6) and pH3.0 to 1.0 for 2b (pKa=1.8). Besides, the compounds exhibited no aggregation tendency, moderate fluorescence quantum yield, solubility in common organic solvents, high singlet oxygen quantum yield and high photostability in DMF and in DMSO, these favorable properties making them good candidates as photosensitizer for PDT.

Perylene Diimide-Based Multicomponent Metallacages as Photosensitizers for Visible Light-Driven Photocatalytic Oxidation Reaction

Insights into the binding mechanism of BODIPY-based photosensitizers to human serum albumin: A combined experimental and computational study

Genetic deviation associated with photodynamic therapy in HeLa cell

Potential of Ruthenium as a photosensitizer in radiation-activated Photodynamic Therapy (radioPDT)

In this dissertation, development of new materials to the field of photonics, more specifically solar energy conversion and cancer therapy was studied. In particular, a series of group of uniform materials based on organic salts (GUMBOS) were developed for use as improved photosensitizers in dye-sensitized solar cells (DSSCs) and photodynamic therapy (PDT). GUMBOS are solid phase organic salts that are similar to ionic liquids, but with melting points ranging from 25 to 250 °C. Properties of GUMBOS can easily be tuned by changing the cation or anion used to form these materials. Thus, new materials can easily be produced with properties that are beneficial for applications in DSSCs or PDT. In this dissertation, porphyrin-based GUMBOS as well as nanomaterials derived from these GUMBOS (nanoGUMBOS) were synthesized and characterized as photosensitizers in DSSCs. These GUMBOS and nanoGUMBOS displayed interesting properties such as increased molar absorptivity and broadened absorption spectra, which are important characteristics for photosensitizers used in DSSCs. NanoGUMBOS-based photosensitizers were applied in DSSCs after precise optimization of the DSSCs structure with regard to the semiconductor (working electrode) and electrolyte. In another application, GUMBOS were developed as energy relay dyes (ERDs) in DSSCs due to the tunable properties of GUMBOS such as solubility, molar absorptivity, and fluorescence quantum yield. GUMBOS-based ERDs were applied in DSSCs, and increases in solar conversion efficiencies of up to 14.6% were observed. Interestingly, the magnitude of increase in solar conversion efficiency was found to depend on the counterion used in synthesis of GUMBOS-based ERDs. Finally, porphyrin- and phthalocyanine-based nanoGUMBOS were studied for application as photosensitizers in PDT. By using a facile, ion exchange reaction to form GUMBOS, a bulky cation was introduced to prevent aggregation of porphyrin and phthalocyanine dyes. Overall increases in singlet oxygen production were observed with GUMBOS in comparison to the parent compounds. Singlet oxygen quantum yields of porphyrin and phthalocyanine GUMBOS were 0.57 ± 0.05 and 0.55 ± 0.01 in comparison to yields from the parent dyes, which were 0.50 ± 0.02 and 0.46 ±0.04, respectively. As a whole, these studies demonstrate substantial advantages of GUMBOS-based materials in the field of photonics.