Synthesis of Bacteria-mimetic Gold Nanoparticles for Phagocytosis by Immune Cells.

Cell-based carrier exhibits inherent advantages as the next generation of drug delivery system, namely high biocompatibility and physiological function. Current cell-based carriers are constructed via direct payload internalization or conjugation between cell and payload. However, the cells involved in these strategies must be firstly extracted from the body and the cell-based carrier must be prepared in vitro. Herein, we synthesize bacteria-mimetic gold nanoparticles (GNPs) for the construction of cell-based carrier in mice. Both ß-cyclodextrin (ß-CD)-modified GNPs and adamantane (ADA)-modified GNPs are coated by E. coli outer membrane vesicles (OMVs). The E. coli OMVs induce the phagocytosis of GNPs by circulating immune cells, leading to intracellular degradation of OMVs and subsequent supramolecular self-assembly of GNPs driven by ß-CD-ADA host-guest interactions. In vivo construction of cell-based carrier based on bacteria-mimetic GNPs avoids the immunogenicity induced by allogeneic cells and restriction by the number of separated cells. Due to the inflammatory tropism, endogenous immune cells carry the intracellular GNP aggregates to the tumor tissues in vivo. Graphical overview Collect the outer membrane vesicles (OMVs) of E. coli by gradient centrifugation (a) and coat on gold nanoparticles (GNP) surface (b) to prepare OMV-coated cyclodextrin (CD)-GNPs and OMV-coated adamantane (ADA)-GNPs (c) via ultrasonic method.

Supramolecular Dual Polypeptides Induced Tubulin Aggregation for Synergistic Cancer Theranostics.

The advent of macrocycle-based supramolecular chemistry can offer powerful strategies for regulating vital bioactivities in living systems and bring about emerging technology in biomedical science. Herein, we construct a supra-biomacromolecular nanosystem involving microtubules, cell-permeable porphyrins, and antimitotic peptide-decorated permethyl-ß-cyclodextrins for promoting cell apoptosis in a cooperative manner. Through specific polypeptide-tubulin recognition, cyclodextrin moieties are capable of anchoring to the tubulin surface and providing abundant hydrophobic microenvironments to accommodate the photosensitive porphyrins. Consequently, spherical tubulin aggregates are formed, and reactive oxygen species can be efficiently generated via the host-guest complexation. The combined usage of complexation-promoted photodynamic efficacy and tubulin aggregation gives more serious cell apoptosis under light irradiation in vitro and in vivo. To be envisioned, this supramolecularly enhanced photodynamic performance together with controlled aggregation of natural biomacromolecules may be developed as an innovative approach to improve the therapeutic potency against many diseases.

Cyclodextrin-Activated Porphyrin Photosensitization for Boosting Self-Cleavable Drug Release.

Supramolecular prodrugs that combine the merits of stimuli-responsiveness and targeting ability in a controllable manner have shown appealing prospects in disease diagnostics and therapeutics. Herein, we report that a new theranostic agent with the host-guest-binding-activated photosensitization has been fabricated by a binary supramolecular assembly consisting of the permethyl-ß-cyclodextrin-grafted hyaluronic acid and a combretastatin A-4-appended porphyrin derivative. Illuminated by a red-light source, the production efficiency of singlet oxygen (1O2) pronouncedly increases by ∼60-fold once the porphyrin core is encapsulated by cyclodextrins. Consequently, the cell-selective fluorescence emission is dramatically enhanced, the microtubule-targeted drug is rapidly and completely released, and the 1O2-involved combinational treatment is simultaneously achieved both in vitro and in vivo. To be envisaged, this complexation-boosted light-activatable photosensitizing prodrug delivery system with improved photophysical performance and remarkable phototheranostic outcomes will make a significant contribution to the creation of more advanced stimulus-based biomaterials.

Dual-responsive drug release and fluorescence imaging based on disulfide-pillar[4]arene aggregate in cancer cells.

The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported the pH- and glutathione dual-responsive supramolecular assemblies fabricated by the disulfide-containing pillar[4]arene and tetraphenylethylene derivatives possessing different alkyl chains in length. Morphological characterization experiments showed the binary supramolecular assemblies formed well-defined nanoparticles, which could facilitate their endocytosis in cells. More remarkably, due to the compact nanostructures and the existence of acidifiable carboxyl group and bioreducible disulfide linkage in pillar[4]arene, the obtained nanoaggregates presented high drug-loading efficiency and sustained drug release behaviors, as well as the targeted fluorescence imaging ability in cancer cells. Thus, it can be envisioned that such microenvironment-adaptable supramolecular nanoassemblies featuring dual stimuli-responsiveness and fluorescence-imaging abilities may be developed as more appealing nanosystems for the therapy of refractory disease.

Sequestration of pyridinium herbicides in plants by carboxylated pillararenes possessing different alkyl chains.

We report that the sequestration of pyridinium-containing herbicides can be achieved on plant foliage through the strong supramolecular complexation with water-soluble pillararenes. The host-guest interaction appears to exert a protective effect on the plant growth, thus holding great promise in agricultural application.

[Protective effect of Yimucao (Herba leonuri) injection against cerebral ischemia: an experimental study in mice and rats].

OBJECTIVE: To investigate the protective effect and mechanism of Yimucao (Herba leonuri) injection against experimental cerebral ischemia. METHODS: Mouse models of cerebral ischemia induced by bilateral carotid artery occlusion or potassium cyanide and rat models of middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injury were established to evaluate the protective effect of Yimucao injection by measuring the changes in cerebral malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD) and lactate dehydrogenase (LDH) after the injections. RESULTS: Yimucao injection significantly lowered the cerebral index of mice with cerebral ischemia, prolonged the survival time of mice poisoned with potassium cyanide, resulting also in significantly decreased MDA content and increased activities of SOD and LDH in the brain tissue of rats after a 10-min cerebral ischemia followed by 30 min of reperfusion. CONCLUSION: Yimucao injection provides protective effect against experimental cerebral ischemia.

Growth inhibition and apoptosis-induced effect on human cancer cells of toosendanin, a triterpenoid derivative from chinese traditional medicine.

Toosendanin, a triterpenoid derivative isolated from the barks of Melia toosendan Sieb et Zucc, has been used as an anthelmintic vermifuge against ascaris for more than fifty years in China. In the present study, we investigated the growth inhibition and apoptosis-induced effect of toosendanin on human cancer cells. The result showed that toosendanin significantly suppressed the proliferation of tested human cancer cell lines. The IC(50) values were less than 1.7 x 10(-7) M and U937 was the most sensitive cell line with a IC(50) of 5.4 x 10(-9) M. Flow cytometric analysis revealed that treatment of U937 cells with toosendanin resulted in a dose- and time-dependent accumulation of cells in the S phase with a concomitant decrease in cells processing to G(0)/G(1) phase. The growth inhibition of U937 cells after exposure to toosendanin was subsequently associated with the induction of apoptosis, as evidence by the typical condensed and fragmented nuclei, DNA fragmentation, and exposure of phosphatidylserine on the outer leaflet of plasma membrane. All these results indicated that toosendanin could serve as a potential candidate for anticancer drug.

Involvement of cytochrome c release and caspase activation in toosendanin-induced PC12 cell apoptosis.

Our previous study showed that toosendanin, a triterpenoid derivative isolated from a Chinese traditional medicine, could induce apoptosis in PC12 cells. In this study we confirmed the apoptosis-inducing effect of toosendanin in PC12 cells with new evidences in morphology and biochemistry: the shrinkage of cytosol, the condensation and fragmentation of nuclei and the formation of DNA ladder. It was also demonstrated that toosendanin decreased the PC12 cell viability in a time- and concentration-dependent manner. To elucidate the pathway linked with the toosendanin-induced apoptosis, the cytochrome c in the cytosol and the cleavage of poly(ADP-ribose) polymerase (PARP) were examined. The obtained results showed that toosendanin caused the release of cytochrome c from mitochondria into the cytosol and then led to the activation of caspase, indicating that the cytochrome c release and caspase activation were involved in the toosendanin-induced apoptosis process. These results suggested the possibility that toosendanin could serve as a candidate for anti-cancer drug.

Antagonism of botulinum toxin type A-induced cleavage of SNAP-25 in rat cerebral synaptosome by toosendanin.

Toosendanin (TSN), a triterpenoid derivative extracted from Chinese traditional medicine, has been demonstrated to be an effective cure for experimental botulism. This study is designed to explore its antibotulismic mechanism by Western blotting. The results showed that TSN incubation did not change the electrophoresis pattern and the amounts of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin and synaptobrevin/vesicle-associated membrane protein in rat cerebral synaptosomes, but made the synaptosomes completely resistant to botulinum neurotoxin A (BoNT/A)-mediated cleavage of SNAP-25. After binding of BoNT/A to synaptosomes, TSN still partially antagonized the toxin-mediated cleavage of SNAP-25. However, TSN-incubated synaptosomal membrane fraction did not resist the cleavage of SNAP-25 by the light chain of BoNT/A. It is suggested that the antibotulismic effect of TSN results from blocking the toxin's approach to its enzymatic substrate.

Toosendanin induces outgrowth of neuronal processes and apoptosis in PC12 cells.

In the present study, the effects of toosendanin on cell differentiation and apoptosis were investigated in PC12 cells. The results showed that after 24-48 h of culture in a medium containing toosendanin (approximately 1-10x10(-7) M), cell differentiation and outgrowth of neuronal processes were promoted. Combined treatment with toosendanin and a calcium channel blocker, nifedipine or omega-conotoxin GVIA, resulted in a significant inhibition of the toosendanin-induced effects. Pretreatment of PC12 cells with BAPTA-AM also inhibited the toosendanin-induced effects; however, these effects were not inhibited by pertussis toxin and H-7 in the medium. Toosendanin also induced cell apoptosis. Based on the DNA content determined by flow cytometric analysis, the number of apoptotic cells significantly increased when the incubation time in the toosendanin-containing medium was lasted up to 72 h. Toosendanin at a higher concentration (> or =1 x 10(-6) M) caused cell death while it had no effect on cell division at concentrations lower than 1 x 10(-7) M.