Erlotinib-Modified BODIPY Photosensitizers for Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is an innovative, non-invasive and highly selective therapeutic modality for tumours and non-malignant diseases. BODIPY based molecules can function as new generation photosensitizers (PSs) in various PDT applications. Despite numerous conjugated PS systems are available, BODIPYs containing erlotinib lagged behind other photosensitizer units. In this study, smart photosensitizers containing BODIPY, erlotinib and hydrophilic units were prepared for the first time, their physicochemical properties and PDT effects were investigated. Compared with non-halogenated compound, halogenated derivatives possessed much lower fluorescence profile as well as the good ROS generation ability under red light. In vitro PDT studies were performed on both healthy (PNT1a) and prostate cancerous cells (PC3) to determine the selectivity of the compounds on cancerous cells and their effects under light. The halogenated conjugates, exposed to low dose of light illumination exhibited potent activity on cancer cell viability and the calculated IC₅₀ values proved the high phototoxicity of the photosensitizers. It was also determined that the PSs have very low dark toxicity and that the light illumination and ROS formation are required for the initiation of the cell death mechanism. As a result, erlotinib modified BODIPYs could serve as promising agents in anticancer photodynamic therapy.     

Self-Assembled BODIPY Derivative with A-D-A Structure as Organic Nanoparticles for Photodynamic/Photothermal Cancer Therapy

Organic nanomaterials have attracted considerable attention in the area of photodynamic and photothermal therapy, owing to their outstanding biocompatibility, potential biodegradability, well-defined chemical structure, and easy functionalization. However, it is still a challenge to develop a single organic molecule that obtains both photothermal and photodynamic effects. In this contribution, we synthesized a new boron-dipyrromethene (BODIPY)-based derivative (DPBDP) with an acceptor–donor–acceptor (A-D-A) structure by coupling 3,6-di(2-thienyl)-2,5-dihydropyrrolo [3,4-c] pyrrole-1,4-dione (DPP) and BODIPY. To enhance the hydrophilicity of the BODIPY derivative, the polyethylene glycol (PEG) chains were introduced to the meso- position of BODIPY core. The amphiphilic DPBDP was then self-assembled into related nanoparticles (DPBDP NPs) with improved hydrophilicity and enhanced absorbance in the NIR region. DPBDP NPs could simultaneously generate the singlet oxygen (¹O₂) and heat under the irradiation of a single laser (690 nm). The ¹O₂ quantum yield and photothermal conversion efficiency (PCE) of DPBDP NPs were calculated to be 14.2% and 26.1%, respectively. The biocompatibility and phototherapeutic effect of DPBDP NPs were evaluated through cell counting kit-8 (CCK-8) assay. Under irradiation of 690 nm laser (1.0 W/cm²), the half maximal inhibitory concentration (IC₅₀) of DPBDP NPs was calculated to be 16.47 µg/mL. Thus, the as-prepared DPBDP NPs could be acted as excellent candidates for synergistic photodynamic/photothermal therapy.     

Photodynamic Therapy (PDT) with Chemotherapy for Advanced Lung Cancer with Airway Stenosis

Intractable advanced lung cancer can be treated palliatively with photodynamic therapy (PDT) combined with chemotherapy to remove central and peripheral (lobar or segmental bronchi) bronchial stenosis and obstruction. We present data for 12 (eight men, four women) consecutive patients with 13 advanced non-small cell lung carcinomas in whom curative operations were contraindicated, who underwent PDT combined with chemotherapy for local control of the intraluminal lesions. The mean age was 73.3 years (range, 58–80 years), and the stages of cancer were IIA–IV. The median stenosis rates before treatment, one week post-treatment, and one month post-treatment were 60% (range, 30%–100%), 15% (range, 15%–99%), and 15% (range 15%–60%), respectively. The mean and median survival times were 9.3 and 5.9 months, respectively. The overall 1-year survival rate was 30.0%. No PDT-related morbidity or mortality occurred. In this single-institution study, all patients experienced improved symptoms and quality of life at one week after treatment; furthermore, an objective response was evidenced by the substantial increase in the openings of the bronchial lumen and prevention of obstructive pneumonia. Therefore, PDT with chemotherapy was useful and safe for the treatment of bronchial obstruction.     

Photo-Responsive Supramolecular Micelles for Controlled Drug Release and Improved Chemotherapy

Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1–2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.     

Fabrication of Cross‐Linked Anion Exchange Membranes Using a Pillar[5]arene Bearing Multiple Alkyl Bromide Head Groups as Cross‐Linker

A pillararene‐based macrocycle with up to 10 flexible chains bearing alkyl bromide head groups is synthesized and investigated for the first time as a multiarm cross‐linker for tertiary‐amine functionalized polyethersulfone. Different from any previously reported cross‐linker, this has a unique pillar‐shaped structure and abundant reactive sites to form multifunctional clusters in the conductive domain. This advantage enables cross‐linking to occur smoothly at the membrane‐casting stage and endows the cross‐linked membranes with improved performance. The cross‐linked anion exchange membranes are found to possess high conductivities and excellent alkaline stability. With a controllable swelling ratio of 19.5%, the maximum conductivity of a membrane can reach 155 mS cm^–1 at 80 °C. Due to its local high‐density cross‐linked structure, a delay in degradation kinetics under alkaline condition can be observed, and the loss of conductivity is <10% after 400 h of alkaline stability test at 80 °C.     

Synthesis and in vitro Anticancer Activity of Zinc(II) Phthalocyanines Conjugated with Coumarin Derivatives for Dual Photodynamic and Chemotherapy

The combination of photodynamic therapy and chemotherapy is a promising strategy to overcome growing problems in contemporary medicine, such as low therapeutic efficacy and drug resistance. Four zinc(II) phthalocyanine–coumarin conjugates were synthesized and characterized. In these complexes, zinc(II) phthalocyanine was used as the photosensitizing unit, and a coumarin derivative was selected as the cytostatic moiety; the two components were linked via a tri(ethylene glycol) chain. These conjugates exhibit high photocytotoxicity against HepG2 human hepatocarcinoma cells, with low IC₅₀ values in the range of 0.014–0.044 μM . The high photodynamic activities of these conjugates are in accordance with their low aggregation tendency and high cellular uptake. One of these conjugates exhibits high photocytotoxicity and significantly higher chemocytotoxicity. The results clearly show that the two antitumor components in these conjugates work in a cooperative fashion. As shown by confocal microscopy, the conjugates can localize in the mitochondria and lysosomes, and one of the conjugates can also localize in the cell nuclei.     

All-in-one functional supramolecular nanoparticles based on pillar[5]arene for controlled generation,storage and release of singlet oxygen

The storage and controlled release of singlet oxygen (¹O₂) have attracted increasing attention due to the wide application and microsecond lifetime of ¹O₂ in water. Herein we provide an integrated nanoplatform consisting of a diphenylanthracene derivative, a water-soluble pillar[5]arene and a photosensitizer tetrakis(4-hydroxyphenyl)porphyrin (TPP), that may provide the controlled generation, storage and release of singlet oxygen. We design a new diphenylanthracene derivative with two trimethylammonium bromide groups on both ends that can be well recognized by the pillar[5]arene. The formed nanocarriers can be used to load TPP through their supramolecular self-assembly. The resulting nanoparticles show good water-solubility and uniform spherical morphology. After laser irradiation (660 nm), the nanoparticles exhibit excellent ability for the generation and storage of ¹O₂. When the irradiated nanoparticles are heated above 80 °C, ¹O₂ can be released from the system. Therefore, in this paper we pioneer the use of noncovalent interaction to integrate the diphenylanthracene derivatives and photosensitizers into one functional system, which provides a new strategy for the controlled generation, storage and release of singlet oxygen. We believe this groundbreaking strategy will have a great potential in providing necessary amounts of ¹O₂ for the photodynamic therapy of tumors in dark.     

An Amphiphilic BODIPY‐Porphyrin Conjugate: Intense Two‐Photon Absorption and Rapid Cellular Uptake for Two‐Photon‐Induced Imaging and Photodynamic Therapy

The new amphiphilic BODPY‐porphyrin conjugate BZnPP and its precursor BZnPH were synthesised, and their linear and two‐photon photophysical properties, together with their cellular uptake and photo‐cytotoxicity, were studied. This amphiphilic conjugate consists of a hydrophobic BODIPY moiety and a hydrophilic tetra(ethylene glycol) chain bridging a cationic triphenylphosphonium group to an amphiphilic porphyrin ZnP through acetylide linkers at its meso positions. A large two‐photon absorption cross‐section (σ=1725 GM) and a high singlet oxygen quantum yield (0.52) were recorded. Intense linear‐ and two‐photon‐induced red emissions were also observed for both BZnPP and BZnPH. Further in vitro studies showed that BZnPP exhibited very efficient cellular uptake and strong photocytotoxic but weak dark cytotoxic properties towards human breast carcinoma MCF‐7 cells. In summary, the two‐photon‐induced emission and the potent photo‐cytotoxicity of BZnPP make it an efficacious dual‐purpose tumour‐imaging and photodynamic therapeutic agent in the tissue‐transparent spectral windows.     

Synthesis of Various Calix[4]arene Derivatives with Mercaptoalkyl Chains and Their Application in Removing Cr(VI) from Aqueous Solution

Four different mercaptoalkyl-substituted calixarene derivatives (5,11,17,23-tetra-tert-butyl-25,27-bis(3-mercaptopropoxyl)-26,28-dihydroxycalix[4]arene, 25,27-bis(3-mercaptopropoxyl)-26,28-dihydroxycalix[4]arene, 25,27-bis(5-mercaptopentanoxyl)-26,28-dihydroxycalix[4]arene and 5,17-di-tert-butyl-11,23-di-carboxyl-26,28-bis(3-mercaptopropoxyl)-25,27-di-hydroxycalix[4]arene) were synthesized. Their structures were characterized by Fourier transform infrared spectroscopy (FTIR), ¹H and ¹³C NMR spectroscopy, and elemental analysis techniques. Moreover, their extraction capabilities at different parameters such as pH, shaking speed, and shaking time were examined toward dichromate ions. Results implied that all mercaptoalkyl-substituted calixarene derivatives showed an extraction capability toward dichromate anion while the carboxyl-functionalized calixarene-marcapto-alkyl derivative exhibited the highest extraction capability.     

Supramolecular Amphiphiles Based on Pillar[5]arene and Meroterpenoids: Synthesis,Self-Association and Interaction with Floxuridine

In recent years, meroterpenoids have found wide biomedical application due to their synthetic availability, low toxicity, and biocompatibility. However, these compounds are not used in targeted drug delivery systems due to their high affinity for cell membranes, both healthy and in cancer cells. Using the approach of creating supramolecular amphiphiles, we have developed self-assembling systems based on water-soluble pillar[5]arene and synthetic meroterpenoids containing geraniol, myrtenol, farnesol, and phytol fragments. The resulting systems can be used as universal drug delivery systems. It was shown by turbidimetry that the obtained pillar[5]arene/synthetic meroterpenoid systems do not interact with the model cell membrane at pH = 7.4, but the associates are destroyed at pH = 4.1. In this case, the synthetic meroterpenoid is incorporated into the lipid bilayer of the model membrane. The characteristics of supramolecular self-assembly, association constants and stoichiometry of the most stable pillar[5]arene/synthetic meroterpenoid complexes were established by UV-vis spectroscopy and dynamic light scattering (DLS). It was shown that supramolecular amphiphiles based on pillar[5]arene/synthetic meroterpenoid systems form monodisperse associates in a wide range of concentrations. The inclusion of the antitumor drug 5-fluoro-2′-deoxyuridine (floxuridine) into the structure of the supramolecular associate was demonstrated by DLS, 19F, 2D DOSY NMR spectroscopy.     

Modulation of Biodistribution,Pharmacokinetics, and Photosensitivity with the Delivery Vehicle of a Bacteriochlorin Photosensitizer for Photodynamic Therapy

Intravenous (i.v.) formulations with various amounts of organic solvents [PEG₄₀₀, propylene glycol (PG), cremophor EL (CrEL)] were used to deliver a fluorinated sulfonamide bacteriochlorin to mice, rats, and minipigs. Biodistribution studies in mice showed that a low‐content CrEL formulation combines high bioavailability with high tumor‐to‐muscle and tumor‐to‐skin ratios. This formulation was also the most successful in the photodynamic therapy of mice with subcutaneously implanted CT26 murine colon adenocarcinoma tumors. Pharmacokinetic studies in mice and minipigs revealed that with the same low CrEL formulation, the half‐life of the photosensitizer in the central compartment was longer in minipigs. Differences in biodistribution with the various formulations, and in pharmacokinetics between the two animal species with the same formulation, are attributed to the interaction of the formulations with low‐density lipoproteins (LDLs). Skin photosensitivity studies in rats showed that 30 min exposure of the skin to a solar simulator 7 days after i.v. administration of the fluorinated sulfonamide bacteriochlorin at 1 mg kg^?1 did not elicit significant skin reactions.     

Dual-Targeted Supramolecular Vesicles Based on the Complex of Galactose Capped Pillar[5]Arene and Triphenylphosphonium Derivative for Drug Delivery

In this study, a dual targeted supramolecular glycol-vesicle based on the host-guest complexation of galactose capped pillar[5]arene ( GALWP5 ) and triphenylphosphonium derivative ( D-TPP ) have been constructed ( GALWP5⊃D-TPP ), which showed dual target potential (cell and mitochondria targeting) resulting from its galactose units and TPP units, respectively. The dual targeted glycol-vesicle displays ignorable cytotoxicity and good mitochondria targeting. Our work presents a good example of rational design for an effective cell and subcellular organelles dual targeted delivery system.     

Fast NMR Methods for Measuring in the Direct and/or Competition Mode the Dissociation Constants of Chemical Fragments Interacting with a Receptor

Ligand-based NMR screening represents a powerful method in fragment-based drug discovery for the identification of chemical matter interacting with the receptor of interest. The large dynamic range of these methods allows the detection of weakly binding ligands. However, the methodology has not been extensively used for quantifying the strength of these interactions. This knowledge is important for ranking fragments according to their binding strength and for prioritizing structure-based and medicinal chemistry activities. Rapid NMR methods for measuring the dissociation constant in direct and competition modes are presented here. The theory underpinning these methods are presented, along with their application to the measurement of the binding affinities of several ligands of the heat shock protein 90.