Molecular and Supramolecular Approach to Highly Photocytotoxic Phthalocyanines with Dual Cell Uptake Pathways and Albumin-Enhanced Tumor Targeting.

Phototherapy for non-invasive cancer treatment has been extensively studied. An urgent challenge in phototherapy application is to fabricate appropriate targeted agents to achieve efficient therapeutic effect. Herein, a molecular and supramolecular approach for targeting phototherapy was reasonably designed and realized through the axial sulfonate modification of silicon(IV) phthalocyanines (Pcs), followed by supramolecular interaction with albumin. This approach can not only improve the photoactivities (e.g., fluorescence emission and reactive oxygen species production) of the Pcs but also enhance their tumor targeting. Most importantly, one of the deigned Pcs (4) can target HepG2 cells through dual cell pathways, leading to an extremely high phototoxicity with an EC50 (i.e., concentration of Pcs to kill 50% of cells under light irradiation) value of 2.0 nM. This finding presents a feasible strategy to realize efficient targeting phototherapy.

A pH-sensitive nanoagent self-assembled from a highly negatively-charged phthalocyanine with excellent biosafety for photothermal therapy.

Photothermal therapy (PTT) is a promising strategy for cancer treatment. However, the development of highly efficient photothermal agents with excellent biosafety, particularly with low liver retention, is very meaningful for clinical applications, but it is also challenging. We herein prepared a pH-sensitive nanoagent (NanoPc3) by the self-assembly of a zinc(ii) phthalocyanine substituted with hexadeca-sulphonates linked by hydrazone bonds for photoacoustic imaging and PTT. Due to the highly negative surface potential (-30.80 mV in water), NanoPc3 could effectively escape the phagocytosis of the reticuloendothelial system and be rapidly cleared from normal tissues, leading to little accumulation in the liver and excellent biosafety. The highly negatively-charged NanoPc3 changed into nearly neutral nanoparticles (NanoPc3H) under slightly acidic conditions, resulting in enhanced cellular uptake and retention time in tumor tissues. Moreover, the tumor of H22 tumor-bearing mice treated with NanoPc3 almost disappeared, suggesting an outstanding photothermal antitumor effect. NanoPc3 also hardly showed skin phototoxicity under irradiation. Its excellent antitumor effect and biosafety make NanoPc3 highly promising in clinical applications. This work will provide a new strategy for the design of tumor-targeted photothermal nanoagents with high biosafety.

Metal-ion exchange, small-molecule sensing, selective dye adsorption, and reversible iodine uptake of three coordination polymers constructed by a new resorcin[4]arene-based tetracarboxylate.

By using a new resorcin[4]arene-based tetracarboxylate, three functional coordination polymers (CPs)--namely, [(CH3)2NH2][Cd2NaL(HCOO)2(HCOOH)(H2O)]·H2O (1), [(CH3)2NH2]2[CdL]·CH3OH·4H2O (2), and [(CH3)2NH2][Zn2Na3L2(H2O)2]·H2O (3)--have been synthesized under solvothermal conditions (H4L = 2,8,14,20-tetra-pentyl-4,10,16,22-tetrakis((4-carboxybenzyl)oxy)-6,12,18,24-tetra-methoxy-resorcin[4]arene and DMF = N,N'-dimethylformamide). The structures of 1-3 have been confirmed by single-crystal X-ray diffraction analyses and further physically characterized. In 1, L and HCOO(-) link Cd(II) and Na(I) ions to yield an unusual three-dimensional (3D) 4-connected heterometallic framework with (4(2)·6(4))(4·8(3)·10·12) topology. In 2, L anions link Cd(II) ions to give a 3D binodal 4-connected framework with (4(2)·6(3)·8)2 topology. In 3, adjacent dodecanuclear heterometallic clusters are joined together by L anions, yielding a two-dimensional (2D) (3,8)-connected (3·4(2))(3(4)·4(6)·5(6)·6(8)·7(3)·8) network. Most strikingly, CPs 1 and 2 display unusual metal-ion exchange characters. CP 2 shows remarkable reversible adsoption of I2 molecules. In addition, CPs 1-3 can selectively adsorb organic dyes and exhibit highly luminescent sensing properties for small molecules.

Design and synthesis of N-2,6-difluorophenyl-5-methoxyl-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide as acetohydroxyacid synthase inhibitor.

Triazolopyrimidine-2-sulfonamide belongs to a herbicide group called acetohydroxyacid synthase inhibitors. With the aim to discover new triazolopyrimidine sulfonanilide compounds with high herbicidal activity and faster degradation rate in soil, the methyl group of Flumetsulam (FS) was modified into a methoxy group to produce a new herbicidal compound, N-2,6-difluorophenyl-5-methoxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (experimental code: Y6610). The enzymatic kinetic results indicated that compound Y6610 and FS have k(i) values of 3.31x10(-6) M and 3.60x10(-7) M against Arabidopsis thaliana AHAS, respectively. The 10-fold lower enzyme-inhibiting activity of Y6610 was explained rationally by further computational simulations and binding free energy calculations. In addition, compound Y6610 was found to display the same level in vivo post-emergent herbicidal activity as FS against some broad-leaf weeds and good safety to rice, maize, and wheat at the dosages of 75-300 gai/ha. Further determination of the half-lives in soil revealed that the half-life in soil of Y6610 is 3.9 days shorter than that of FS. The experimental results herein showed that compound Y6610 could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study.

[Effects of paeoniflorin on pathological changes in global brain ischemia model rats].

OBJECTIVE: To explore the effects of paeoniflorin on blood brain barrier and pathological changes in brain ischemia. METHOD: Mice were divided into sham operation group, model group, positive control group-Deng zhanhua tablet group and three different dose (high, middle, low-dose) groups of paeoniflorin. The neurological symptoms of rats were observed. The SOD of ischemic brain tissue, MDA BBB and EAA contents were determined. The ultrastructure on the brain cells was inspected by transmission electron microscope. RESULT: Paeoniflorin had the protetive effects on 4VO model of total cerebral ischemia. Paeoniflorin could obviously increase SOD content, reduce MDA content in rat brain-tissue and alleviate oxidative stress damage by cerebral ischemia on rat brain. Paeoniflorin could improve pathological changes of cell nuclear, perikaryon, mitochondria and myelin sheath, which was the morphologic basis of the protective effect on ischemia. Paeoniflorin could alleviate the incrense of EAA content caused by and hypoxia and inhibit the excitatory neural toxicity by EAA. CONCLUSION: Paeoniflorin has the protection effect on the brain edema after cerebral ischemia, the oxidative stress damage on brain tissue, the ultrastructure lesions of cells and the BBB. The protective mechanism may be related to inhibiting intracellular calcium overload, anti-free radical and reducing EAA content.

[Effects of paeoniflorin on cerebral energy metabolism, nitric oxide and nitric oxide synthase after cerebral ischemia in mongoliagerbils].

OBJECTIVE: To explore the effects of paeoniflorin on antagonising the delayed neuronal death (DND) induced by cerebral ischemia,and the relation between DND, cerebral tissue energy metabolism, nitric oxide (NO) and nitric oxide synthase (NOS). METHOD: Incomplete cerebral ischemia induced was induced by ligating bilateral arteries carotis communis for 20 min followed by reperfusion 48 h in rats. The indexes including Na(+)-K(+)-ATPase activity, lactic acid content, Ca(2+)-ATPase, Mg(2+)-ATPase activity, NO content and NOS activity were determined in fore brain cortex at 48 h after reperfusion. RESULT: Na(+)-K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase activity were lowered (P < 0.01), NO level was decreased (P < 0.01), NOS activity dropped (P < 0.01) in cerebral tissue at 48h after reperfusion, but lactic acid level had no change. Paeoniflorin could prevent reduction of Na(+)-K(+)-ATPase activity (P < 0.05, P < 0.01), increase NO level (P < 0.01), enhance NOS activity (P < 0.01) at 48h after reperfusion. CONCLUSION: DND induced by ischemia may be concerned with energy metabolism disorder and decrease of NO formation. Paeoniflorin may play the role of antagonising cerebral ischemia by adjusting cerebral energy metabolism and nitric oxide formation.