An NIR-II-Emissive Photosensitizer for Hypoxia-Tolerant Photodynamic Theranostics.

As a common feature in a majority of malignant tumors, hypoxia has become the Achilles' heel of photodynamic therapy (PDT). The development of type-I photosensitizers that show hypoxia-tolerant PDT efficiency provides a straightforward way to address this issue. However, type-I PDT materials have rarely been discovered. Herein, a π-conjugated molecule with A-D-A configuration, COi6-4Cl, is reported. The H2 O-dispersible nanoparticle of COi6-4Cl can be activated by an 880 nm laser, and displays hypoxia-tolerant type I/II combined PDT capability, and more notably, a high NIR-II fluorescence with a quantum yield over 5%. Moreover, COi6-4Cl shows a negligible photothermal conversion effect. The non-radiative decay of COi6-4Cl is suppressed in the dispersed and aggregated state due to the restricted molecular vibrations and distinct intermolecular steric hindrance induced by its four bulky side chains. These features make COi6-4Cl a distinguished single-NIR-wavelength-activated phototheranostic material, which performs well in NIR-II fluorescence-guided PDT treatment and shows an enhanced in vivo anti-tumor efficiency over the clinically approved Chlorin e6, by the equal stresses on hypoxia-tolerant anti-tumor therapy and deep-penetration imaging. Therefore, the great potential of COi6-4Cl in precise PDT cancer therapy against hypoxia challenges is demonstrated.

Influence of pH on property and lipolysis behavior of cinnamaldehyde conjugated chitosan-stabilized emulsions.

In the present study, we prepared cinnamaldehyde (CA) conjugated chitosan-stabilized emulsions (CSCAEs), and the influence of pH on their properties and lipolysis behavior was investigated. Compared to the emulsions stabilized by chitosan itself (CSEs), CSCAEs had better stability against pH during storage. As pH increased from 2.5 to 6.25, the viscosity and modulus of CSCAEs increased. However, when pH shifted from 6.25 to 6.5, emulsion showed lower viscosity and modulus. Confocal laser scanning microscopy results demonstrated that oil droplets still kept intact and individually distributed, and chitosan homogenously covered on the oil droplets at low pH conditions (pH 2.5, 4.0). At higher pH conditions (pH 5.0, 5.5), a few chitosan aggregates on the oil droplets were observed. At pH 6.0 and 6.25, the compact gel network structure was formed. At pH 6.5, some void was found among the chitosan gel network. In vitro simulated digestion experiments presented that pH had no significant effect on the lipolysis process of emulsions. When the oil content varied from 10% to 50%, emulsions still kept good stability against pHs, but the lipolysis extent after digestion decreased. This knowledge provides a strategy for improving stability of chitosan-stabilized emulsion against harsh pH conditions.

One-Step Dynamic Imine Chemistry for Preparation of Chitosan-Stabilized Emulsions Using a Natural Aldehyde: Acid Trigger Mechanism and Regulation and Gastric Delivery.

Chitosan is a polysaccharide widely used as a structuring agent in foods and other materials because of its positive charge (amino groups). At present, however, it is difficult to form and stabilize emulsions using chitosan due to its high hydrophilicity. In this study, oil-in-water emulsions were prepared using a one-pot green-chemistry method. The chitosan and aldehyde molecules were in situ interfacially conjugated during homogenization, which promoted the adsorption of chitosan onto the oil droplet surfaces where they created a protective coating. The universality of this method was verified by using chitosan with different molecular weights and four kinds of natural aldehydes [cinnamaldehyde (CA), citral (CT), citronella (CN), and vanillin (VL)]. Chitosan with higher molecular weight facilitated the formation of emulsions. By harnessing the dynamic covalent nature of imine bonds, chitosan emulsions with an imine link display dynamic behavior with acid-catalyzed hydrolysis. The aldehyde structure could control the pH point of trigger for breakdown of emulsions, which was 1.0, 3.0, 4.0, and 4.0 for CA emulsion, CT emulsion, CN emulsion, and VL emulsion, respectively. At pH 6.5, aldehyde helped to decrease the interfacial tension of chitosan to about 10 mN/m, while this value would increase if the pH decreased by adding acid during the measurement. Chemical kinetics studies indicated that the hydrophobicity and conjugation effect of the aldehyde together determined the trigger points and properties of the emulsion. Finally, we used the optimized emulsions to encapsulate and control the release of curcumin. The gastric release behavior of the curcumin depended on aldehyde structure: VL > CN > CT ≈ CA. Hence, a tailor-made trigger release emulsion system can be achieved by rational selection and design of aldehyde structure to control hydrophobicity and conjugation effect of aldehydes.

Tailoring of structured hydroxypropyl methylcellulose-stabilized emulsions for encapsulation of nobiletin: modification of the oil and aqueous phases.

Hydroxypropyl methylcellulose (HPMC)-stabilized emulsions were produced and their structure was further modified by altering the oil (glycerol monolaurate, GML) and aqueous (whey protein concentrate, WPC) phases. Then, the encapsulation and release of nobiletin were evaluated. HPMC (3%) could efficiently stabilize the oil droplets with a particle size around 370 nm. When HPMC was the emulsifier, the stabilization time of nobiletin in the emulsion was prolonged, but its encapsulation amount was still maintained around 4.5 mg g-1. Nobiletin crystals were found to adsorb on the interface of oil droplets. The addition of GML and WPC changed the microstructure of HPMC-stabilized emulsions. Both of them enhanced the encapsulation efficiency and storage stability of nobiletin. Nobiletin crystals became softer and shorter. After modification, nobiletin was stable for one week at a level of 7.5 mg g-1. The bioaccessibility of nobiletin was modulated in the presence of GML and WPC. The results demonstrate that the structure of emulsion-based delivery systems affects the encapsulation and delivery of hydrophobic components.

In Situ Interfacial Conjugation of Chitosan with Cinnamaldehyde during Homogenization Improves the Formation and Stability of Chitosan-Stabilized Emulsions.

The emulsifying properties of a natural cationic polysaccharide (chitosan) were improved by in situ conjugation with a natural essential oil (cinnamaldehyde, CA) during homogenization. In the absence of CA, chitosan-coated medium-chain triglyceride droplets were highly susceptible to creaming and coalescence at pH values ranging from 1 to 6.5. However, incorporation of relatively low levels of CA in the oil phase greatly improved the formation and stability of oil-in-water emulsions. These effects were attributed to two main factors: (i) covalent binding of lipophilic CA moieties to hydrophilic chitosan chains leading to conjugates with a good surface activity and (ii) interfacial cross-linking of adsorbed chitosan layers by CA leading to the formation of a rigid polymeric coating around the lipid droplets, which improved their stability against coalescence. The encapsulation technique developed in this study may be useful for applications in a range of commercial products; regulatory and flavor issues associated with chitosan and CA would have to be addressed.

Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways.

We evaluated the vasorelaxation effects of formononetin, an isoflavone/phytoestrogen found abundantly in Astragalus mongholicus Bunge, on rat isolated aorta and the underlying mechanisms involved. Cumulative administration of formononetin, genistein, daidzein and biochanin A relaxed phenylephrine-preconstricted aorta. Formononetin and biochanin A caused a similar magnitude of relaxation whereas daidzein was least potent. Mechanical removal of endothelium, L-NAME (100 microM) and methylene blue (10 microM) suppressed formononetin-induced relaxation. Formononetin increased endothelial nitric oxide (NO) synthase (eNOS), but not inducible NO synthase, activity with an up-regulation of eNOS mRNA and p-eNOS(Ser1177) protein expression. In endothelium-denuded preparations, formononetin-induced vasorelaxation was significantly reduced by glibenclamide (3 microM) and iberiotoxin (100 nM), and a combination of glibenclamide (3 microM) plus iberiotoxin (100 nM) abolished the relaxation. In contrast, formononetin-elicited endothelium-independent relaxation was not altered by ICI 182,780 (10 microM, an estrogen receptor (ER alpha/ER beta) antagonist) or mifepristone (10 microM, a progesterone receptor antagonist). In single aortic smooth muscle cells, formononetin caused opening of iberiotoxin-sensitive Ca(2+)-activated K(+) (BK(Ca)) channels and glibenclamide-sensitive adenosine triphosphate (ATP)-dependent K(+) (K(ATP)) channels. Thus, our results suggest that formononetin caused vascular relaxation via endothelium/NO-dependent mechanism and endothelium-independent mechanism which involves the activation of BK(Ca) and K(ATP) channels.

[Isolation of Mycoplasma penetrans and detection of the levels of serum IL-6 and TNF-alpha in the blood of patients with autoimmune disease].

AIM: To investigate the isolation of Mycoplasma penetrans from the blood of autoimmune disease patients and to evaluate the levels of serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients with autoimmune disease (AID). METHODS: M. penetrans was isolated and cultured from the blood specimens of 44 patients with AID. Among them 16 patients were control group I, who were the objects. 28 patients were in control group II as contrast. The serum ASO or RF level of the patients in control group I was higher than that in control group II. The positive specimens were confirmed by nPCR and the levels of IL-6 and TNF-alpha were measured by RIA in the blood samples. RESULTS: M. penetrans was detected in the blood of 17 patients and the positive detection rate was 38.6% (17/44) in AID group. There was significant difference between the detection rate from group I (12.5%, 2/16, P<0.01) and that in group II (0%, 0/28, P<0.01). The serum level of IL-6 in the AID with M. penetrans infection patients in group I (3.30+/-1.49) microg/L was significantly different from that in the AID without M. penetrans infection patients in group I (2.43+/-0.95) microg/L and that in group II(1.14+/-0.32) microg/L, P<0.01. The serum level of TNF-alpha in the AID with M. penetrans infection patients in group I (293.3+/-179.9) ng/L was significantly different from that in the AID without M. penetrans infection patients in group I (173.9+/-73.9) ng/L and that in group II(108.8+/-33.8) ng/L, P<0.01. CONCLUSION: M. penetrans occurs with high frequency in the blood of autoimmune disease patients. The evident increase of serum levels of IL-6 and TNF-alpha in AID with M. penetrans infection than the control groups.