Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer.

Nano-targeted delivery systems have been widely used for breast tumor drug delivery. Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells. However, targeted ligands have a significant impact on the safety and effectiveness of active delivery systems, limiting the clinical transformation of nanoparticles. Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor. In the present study, molecular docking was used to select tanshinone IIA (Tan IIA) among phytoestrogens as a target ligand to be used in nanodelivery systems with some modifications. Modified Tan IIA (Tan-NH2) showed a good biosafety profile and demonstrated tumor-targeting, anti-tumor and anti-tumor metastasis effects. Moreover, the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN. Tan-Dox-MSN had a uniform particle size, good dispersibility and high drug loading capacity. Validation experiments in vivo and in vitro showed that it also had a better targeting ability, anti-tumor effect and lower toxicity in normal organs. These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.

The Flavonoid Components of Scutellaria baicalensis: Biopharmaceutical Properties and their Improvement using Nanoformulation Techniques.

Scutellaria baicalensis georgi, known as "Huangqin" in its dried root form, is a herb widely used in traditional Chinese medicine for "clearing away heat, removing dampness, purging fire and detoxification". Baicalin, baicalein, wogonin, and wogonoside are the main flavonoid compounds found in Scutellaria baicalensis. Scutellaria baicalensis flavonoid components have the potential to prevent and treat a host of diseases. The components of S. baicalensis have limited clinical application due to their low water solubility, poor permeability, and microbial transformation in vivo. Nanopharmaceutical techniques can improve their biopharmaceutical properties, enhance their absorption in vivo, and improve their bioavailability. However, due to the limited number of clinical trials, doubts remain about their toxicity and improvements in human absorption as a result of nanoformulations. This review summarizes the latest and most comprehensive information regarding the absorption, distribution, metabolism, and excretion of the Scutellaria baicalensis components in vivo. We examined the main advantages of nanodrug delivery systems and collected detailed information on the nanosystem delivery of the Scutellaria baicalensis components, including nanosuspensions and various lipid-based nanosystems. Lipid-based systems including liposomes, solid lipid nanoparticles, nanoemulsions, and self-micro emulsifying drug delivery systems are introduced in detail. In addition, we make recommendations for related and future research directions. Future research should further examine the absorption mechanisms and metabolic pathways of nanoformulations of the components of Scutellaria baicalensis in vivo, and accurately track the in vivo behavior of these drug delivery systems to discover the specific reasons for the enhanced bioavailability of nanoformulations of the scutellaria baicalensis components. The development of targeted oral administration of intact nanoparticles of Scutellaria baicalensis components is an exciting prospect.

Synthesis of tetrasubstituted allenes via a 1,4-palladium migration/carbene insertion/ß-H elimination sequence.

A palladium-catalyzed synthesis of tetrasubstituted allenes from aryl bromides and aryl diazoacetates is developed. This transformation proceeded via an aryl to alkenyl 1,4-palladium migration/carbene insertion/ß-H elimination sequence under mild reaction conditions.

Baicalin-berberine complex nanocrystals orally promote the co-absorption of two components.

Baicalin (BA)-berberine (BBR) have been proposed as the couple in the prevention and treatment of numerous diseases due to their multiple functional attributes. However, with regard to certain factors involving unsatisfactory aqueous solubility and low bioavailability associated with its clinical application, there is need for continuous researches by scientist. In this study, after successfully preparing BA-BBR complex, BA-BBR complex nanocrystals were obtained through high-pressure homogenization and evaluated (in vitro and in vivo). The particle size, distribution, morphology, and crystalline properties for the optimal BA-BBR complex nanocrystals were characterized by the use of scanning electron microscope, dynamic light scattering, powder X-ray diffraction, and differential scanning calorimetry. The particle size and poly-dispersity index of BA-BBR complex nanocrystals were 318.40 ± 3.32 nm and 0.26 ± 0.03, respectively. In addition, evaluation of the in vitro dissolution extent indicated that BA and BBR in BA-BBR complex nanocrystals were 3.30- and 2.35-fold than BA-BBR complex. Subsequently, single-pass intestinal perfusion combined with microdialysis test and oral pharmacokinetics in SD rats was employed to evaluate the in vivo absorption improvement of BA-BBR complex nanocrystals. The pharmacokinetics results exhibited that the area under curve of BA and BBR in the BA-BBR complex nanocrystals group were 622.65 ± 456.95 h·ng/ml and 167.28 ± 78.87 h·ng/ml, respectively, which were separately 7.49- and 2.64-fold than the complex coarse suspension. In conclusion, the above results indicate that the developed and optimized BA-BBR complex nanocrystals could improve the dissolution rate and extent and oral bioavailability, as well as facilitate the co-absorption of the drug prescriptions BA and BBR.

Nuclear Targeted Peptide Combined With Gambogic Acid for Synergistic Treatment of Breast Cancer.

As a natural compound, gambogic acid (GA) emerged a shining multi-target antitumor activity in a variety of tumors. Whereas its poor solubility and non-specific effect to tumor blocked the clinical application of this drug. Herein, we reported a simple and effective strategy to construct liposome modified with nuclear targeted peptide CB5005N (VQRKRQKLMPC) via polyethylene glycol (PEG) linker to decrease the inherent limitations of GA and promote its anti-tumor activity. In this study, liposomes were prepared by thin film hydration method. The characterization of formulations contained particle size, Zeta potential, morphology and encapsulation efficiency. Further, in vitro cytotoxicity and uptake tests were investigated by 4T1 and MDA-MB-231 cells, and nuclear targeting capability was performed on MDA-MB-231 cells. In addition, the in vivo antitumor effect and biological distribution of formulations were tested in BALB/c female mice. The GA-loaded liposome modified by CB5005N showed small size, good uniformity, better targeting, higher anti-tumor efficiency, better tumor inhibition rate and lower toxicity to normal tissues than other groups. In vitro and in vivo research proved that CB5005N-GA-liposome exhibited excellent anti-tumor activity and significantly reduced toxicities. As a result, CB5005N-GA-liposome nano drug delivery system enhanced the tumor targeting and antitumor effects of GA, which provided a basis for its clinical application.

Cloning and Characterization of the Acetylcholinesterase1 Gene of Tetranychus cinnabarinus (Acari: Tetranychidae).

The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is a major agriculture pest. It can be found worldwide, has an extensive host plant range, and has shown resistance to pesticides. Organophosphate and carbamate insecticides account for more than one-third of all insecticide sales. Insecticide resistance and the toxicity of organophosphate and carbamate insecticides to mammals have become a growing concern. Acetylcholinesterase (AChE) is the major targeted enzyme of organophosphate and carbamate insecticides. In this study, we fully cloned, sequenced and characterized the ace1 gene of T. cinnabarinus, and identified the differences between T. cinnabarinus AChE1, Tetranychus urticae Koch AChE1, and human AChE1. Resistance-associated target-site mutations were displayed by comparing the AChE amino acid sequences and their AChE three-dimensional (3D) structures of the insecticide-susceptible strains of T. cinnabarinus and T. urticae to that of a T. urticae-resistant strain. We identified variation in the active-site gorge and the sites interacting with gorge residues by comparing AChE1 3D structures of T. cinnabarinus, T. urticae, and humans, though their 3D structures were similar. Furthermore, the expression profile of T. cinnabarinus AChE, at the different developmental stages, was determined by quantitative real-time polymerase chain reaction; the transcript levels of AChE were higher in the larvae stage than in other stages. The changes in AChE expression between different developmental stages may be related to their growth habits and metabolism characteristics. This study may offer new insights into the problems of insecticide resistance and insecticide toxicity of nontarget species.