Jian-Dong Huang

A pH-Responsive Layered Double Hydroxide (LDH)–Phthalocyanine Nanohybrid for Efficient Photodynamic Therapy

A pH-responsive nanohybrid (LDH-ZnPcPS4 ), in which a highly hydrophilic zinc(II) phthalocyanine tetra-α-substituted with 4-sulfonatophenoxy groups (ZnPcPS4 ) is incorporated with a cationic layered double hydroxide (LDH) based on electrostatic interaction, has been specially designed and prepared through a facile co-precipitation approach. ZnPcPS4 is an excellent singlet-oxygen generator with strong absorption at the near-infrared region (692 nm) in cellular culture media, whereas the photoactivities of ZnPcPS4 were remarkably inhibited after incorporation with the LDH. The nanohybrid is essentially stable in aqueous media at pH 7.4; nevertheless, in slightly acidic media of pH 6.5 or 5.0, ZnPcPS4 can be efficiently released from the LDH matrix, thus leading to restoration of the photoactivities. The nanohybrid shows a high photocytotoxicity against HepG2 cells as a result of much more efficient cellular uptake and preferential accumulation in lysosomes, whereby the acidic environment leads to the release of ZnPcPS4 . The IC50 value of LDH-ZnPcPS4 is as low as 0.053 μM, which is 24-fold lower than that of ZnPcPS4 . This work provides a facile approach for the fabrication of photosensitizers with high photocytotoxicity, potential tumor selectivity, and rapid clearance character.

A Tumor-pH-Responsive Supramolecular Photosensitizer for Activatable Photodynamic Therapy with Minimal In Vivo Skin Phototoxicity

A major challenge in photodynamic therapy (PDT) is the development of new tumor-targeting photosensitizers. The tumor-specific activation is considered to be an effective strategy for designing these photosensitizers. Herein, we describe a novel tumor-pH-responsive supramolecular photosensitizer, LDH-ZnPcS8, which is not photoactive under neutral conditions but is precisely and efficiently activated in a slightly acidic environment (pH 6.5). LDH-ZnPcS8 is prepared by using a simple coprecipitation method based on the electrostatic interaction between negatively charged octasulfonate-modified zinc(II) phthalocyanine (ZnPcS8) and cationic hydroxide layers of layered double hydroxide (LDH). The in vitro photodynamic activities of LDH-ZnPcS8 in cancer cells are dramatically enhanced relative to those of ZnPcS8 alone. The results of in vivo fluorescence imaging demonstrate that the nanohybrid is activated in tumor tissues, where it displays an excellent PDT effect resulting in 95.3% tumor growth inhibition. Furthermore, the minimal skin phototoxicity of LDH-ZnPcS8 highlights its high potential as a novel photosensitizer for activatable PDT.

Highly positive-charged zinc(II) phthalocyanine as non-aggregated and efficient antifungal photosensitizer.

A new tetra-α-substituted zinc(II) phthalocyanine containing dodeca-amino groups (compound 4) and its quaternized analogue (compound 5) have been prepared and evaluated for their photoactivities against Candida albicans. Compared with the dodeca-amino phthalocyanine 4, the dodeca-cationic phthalocyanine 5 exhibits a higher photodynamic inactivation against C. albicans with an IC90 value down to 1.46 μM, which can be attributed to its non-aggregated nature in aqueous environments and more efficient cellular uptake. More interestingly, 5 shows a higher photodynamic inactivation on C. albicans due to its stronger affinity to C. albicans cells than mammalian cells. These results suggest that the highly positive-charged phthalocyanine 5 is a potential non-aggregated antifungal photosensitizer, which shows some selectivity toward the fungus.

Preparation and sonodynamic activities of water-soluble tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine and its bovine serum albumin conjugate.

Sonodynamic therapy (SDT) is a new approach for cancer treatment, involving the synergistic effect of ultrasound and certain chemical compounds termed as sonosensitizers. A water-soluble phthalocyanine, namely tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine (ZnPcC4), has been prepared and characterized. The interactions between ZnPcC4 and bovine serum albumin (BSA) were also investigated by absorption and fluorescence spectroscopy. It was found that there were strong interactions between ZnPcC4 and BSA with a binding constant of 6.83×10(7)M(-1). A non-covalent BSA conjugate of ZnPcC4 (ZnPcC4-BSA) was prepared. Both ZnPcC4 and ZnPcC4-BSA exhibited efficient sonodynamic activities against HepG2 human hepatocarcinoma cells. Compared with ZnPcC4, conjugate ZnPcC4-BSA showed a higher sonodynamic activity with an IC50 value of 7.5μM. Upon illumination with ultrasound, ZnPcC4-BSA can induce an increase of intracellular reactive oxygen species (ROS) level, resulting in cellular apoptosis. The results suggest that the albumin conjugates of zinc(II) phthalocyanines functionalized with carboxyls can serve as promising sonosensitizers for sonodynamic therapy.

Discovery of two aminoglycoside antibiotics as inhibitors targeting the menin-mixed lineage leukaemia interface

Menin functions as an oncogenic cofactor of mixed lineage leukaemia (MLL) fusion proteins in leukaemogenesis. The menin-MLL interface is a potential therapeutic target in acute leukaemia cases. In this study, approximately 900 clinical compounds were evaluated and ranked using pharmacophore-based virtual screening, the top 29 hits were further evaluated by biochemical analysis to discover the inhibitors that target the menin-MLL interface. Two aminoglycoside antibiotics, neomycin and tobramycin, were identified as menin-MLL inhibitors with binding affinities of 18.8 and 59.9 μM, respectively. The results of thermal shift assay validated the direct interactions between the two antibiotics and menin. The results of isothermal titration calorimetry showed that the equilibrium dissociation constant between menin and neomycin was approximately 15.6 μM. We also predicted the binding modes of inhibitors at the menin-MLL interface through molecular docking analysis. The results indicated that neomycin and tobramycin competitively occupy the binding site of MLL. This study has shed light on the development of powerful probes and new therapies for MLL-mediated leukaemogenesis.

Synthesis and photobiological properties of novel silicon(IV) phthalocyanines axially modified by paracetamol and 4-hydroxyphenylacetamide

Two novel axial-disubstituted silicon(IV) phthalocyanines (compounds 1 and 2) have been prepared by introducing paracetamol (a common antipyretic analgesic) or its isomer 4-hydroxyphenylacetamide at the axial positions of silicon(IV) phthalocyanine, respectively. Their photophysical and biological properties have been examined. Both compounds are highly soluble and exhibit very similar absorption spectra in N, N-dimethylformamide, which is typical for non-aggregated phthalocyanines. Both compounds are photocytotoxic against HT29 human colon adenocarcinoma cells. Compound 2 shows a very high in vitro photodynamic activity, with the IC50 value down to 15 nM. In contrast, compound 1 exhibits a much lower in vitro photodynamic activity toward HT29 cells, which can be attributed to its higher aggregating trend in the biological medium and lower singlet oxygen quantum yield.

Silicon(IV) phthalocyanines substituted axially with different nucleoside moieties. Effects of nucleoside type on the photosensitizing efficiencies and in vitro photodynamic activities.

A series of new silicon(IV) phthalocyanines (SiPcs) di-substituted axially with different nucleoside moieties have been synthesized and evaluated for their singlet oxygen quantum yields (ΦΔ) and in vitro photodynamic activities. The adenosine-substituted SiPc shows a lower photosensitizing efficiency (ΦΔ=0.35) than the uridine- and cytidine-substituted analogs (ΦΔ=0.42-0.44), while the guanosine-substituted SiPc exhibits a weakest singlet oxygen generation efficiency with a ΦΔ value down to 0.03. On the other hand, replacing axial adenosines with chloro-modified adenosines and purines can result in the increase of photogenerating singlet oxygen efficiencies of SiPcs. The formed SiPcs 1 and 2, which contain monochloro-modified adenosines and dichloro-modified purines respectively, appear as efficient photosensitizers with ΦΔ of 0.42-0.44. Both compounds 1 and 2 present high photocytotoxicities against HepG2 and BGC823 cancer cells with IC50 values ranging from 9nM to 33nM. The photocytotoxicities of these two compounds are remarkably higher than the well-known anticancer photosensitizer, chlorin e6 (IC50=752nM against HepG2 cells) in the same condition. As revealed by confocal microscopy, for both cell lines, compound 1 can essentially bind to mitochondria, while compound 2 is just partially localized in mitochondria. In addition, the two compounds induce cell death of HepG2 cells likely through apoptosis.

Synthesis, characterization and properties of some metallophthalocyanine complexes substituted by N -piperidineethanol

The preparation of eight metallophthalocyanine complexes substituted by N-piperidineethanol was achieved by tetramerization of 3-[2-(piperidin-1-yl)ethoxyl] phthalonitrile and 4-[2-(piperidin-1-yl)ethoxyl]phthalonitrile in the presence of a metal salt with n-pentanol as solvent and DBU as catalyst, respectively. These complexes were characterized by IR, elemental analysis, 1H NMR and mass spectra. Some properties such as UV/visible absorption spectra, rate of singlet oxygen yields, fluorescence spectra and quantum yields were examined and discussed.

Progress in the development of nanosensitizers for X-ray-induced photodynamic therapy

In recent years, photodynamic therapy has been applied in cancer treatment because of its high selectivity and marginal invasion properties. However, the excitation light used has limited ability to penetrate tissue, which creates a stumbling block for its future development. To overcome this, X-rays have been introduced to transmit energy to deeper tissues. Given that a large number of X-ray-induced sensitizers have been designed to facilitate X-ray excitation and generate reactive oxygen species (ROS), this has led to the concept of X-ray-induced photodynamic therapy (X-PDT). After 10 years of development, this treatment now shows good therapeutic effects as well as shortcomings. Going forward, it will be important to improve tumor targeting and a standard deep-seated tumor model should be established.

Phthalocyanine‐Assembled Nanodots as Photosensitizers for Highly Efficient Type I Photoreactions in Photodynamic Therapy

Owing to their unique, nanoscale related optical properties, nanostructures assembled from molecular photosensitizers (PSs) have interesting applications in phototheranostics. However, most nanostructured PS assemblies are super-quenched, thus, preventing their use in photodynamic therapy (PDT). Although some of these materials undergo stimuli-responsive disassembly, which leads to partial recovery of PDT activity, their therapeutic potentials are unsatisfactory owing to a limited ability to promote generation reactive oxygen species (ROS), especially via type I photoreactions (i.e., not by 1 O2 generation). Herein we demonstrate that a new, nanostructured phthalocyanine assembly, NanoPcA, has the ability to promote highly efficient ROS generation via the type I mechanism. The results of antibacterial studies demonstrate that NanoPcA has potential PDT applications.