Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4.

Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two OA prodrugs (1,3-cyclic propanyl phosphate esters of OA) were designed and synthesized. The hepatoprotective effects of these prodrugs were evaluated against carbon tetrachloride (CCl4) induced liver injury in mice; the levels of alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and aspartate aminotransferase (AST) were significantly increased, and the level of the hepatic malondialdehyde (MDA) was increased. The metabolism, in vitro, of the prodrugs was studied by incubation in rat liver microsome; the plasma pharmacokinetics and the biodistribution in vivo after intravenous (iv) injection to six rats were investigated, respectively. The prodrugs diminished gradually with time; most of the parent drugs were released within 30 min in vitro, and the presumed mechanism of the in vitro metabolism was confirmed. The plasma-concentration data in vivo was analyzed by a compartmental method: both the prodrugs and the corresponding released parent drugs existed at up to 48 h in rats. The t1/2 improved after intravenous administration in rats compared with direct injection of the parent drugs. All analyte concentrations were highest in the liver, and most of the prodrugs were excreted in feces (>47.11%). Therefore, 1,3-cyclic propanyl phosphate esters of OA can serve as a promising lead candidate for drugs.

Novel construction of multifunctional photo-responsive and nucleic acid-triggered doxorubicin-releasing liposomes for cancer therapy.

All-in-one nano theranostics integrating accurate diagnosis and combined therapy is promising for high-efficacy tumor treatment and receiving significant attention. In this study, we develop photo-controlled release liposomes with nucleic acid-triggered fluorescence and photoactivity for tumor imaging and synergistic antitumor therapy. Copper phthalocyanine as a photothermal agent is fused into lipid layers to prepare liposomes encapsulating cationic zinc phthalocyanine ZnPc(TAP)412+ and doxorubicin, followed by the modification of RGD peptide on the surface to obtain the final product RGD-CuPc:ZnPc(TAP)412+:DOX@LiPOs (RCZDL). RCZDL possesses favorable stability, significant photothermal effect, and photo-controlled release function through the characterization of physicochemical properties. It is shown that the fluorescence and ROS generation could be turned on by intracellular nucleic acid after illumination. RCZDL exhibits synergistic cytotoxicity, increased apoptosis, and significantly promoted cell uptake. Subcellular localization analysis indicates that ZnPc(TAP)412+ tends to be distributed in the mitochondria of HepG2 cells treated with RCZDL after exposure to light. The results of experiments in vivo on H22 tumor-bearing mice demonstrate that RCZDL had excellent tumor targeting, a prominent photothermal effect at the tumor sites, and synergistic antitumor efficiency. More importantly, little RCZDL has been found to be accumulated in the liver, and most were quickly metabolized by the liver. The results confirm that the proposed new intelligent liposomes provide a simple and cost-effective way for tumor imaging and combinatorial anticancer therapy.

Recent progress toward developing axial chirality bioactive compounds.

Atropisomers are stereoisomers with axial chirality arising from restricted rotation around a single bond. Lots of representatives of this class of axially chiral compounds exhibit remarkable biological properties for protein targets. This time-dependent chirality shows great potential for drug development. Herein, we comprehensively review axial chirality bioactive compounds, including C-C bonded atropisomers, C-N bonded atropisomers, and N-N bonded atropisomers. Examples of each are provided along with their biological activity. This review highlights the development of various examples of atropisomerism encountered in bioactive compounds, which is beneficial for medicinal chemists to advance atropisomeric drug molecules.

Nanotechnologies for Reactive Oxygen Species"Turn-On" Detection.

Reactive oxygen species (ROS) encompasses a collection of complicated chemical entities characterized by individually specific biological reactivities and physicochemical properties. ROS detection is attracting tremendous attention. The reaction-based nanomaterials for ROS "turn-on" sensing represent novel and efficient tools for ROS detection. These nanomaterials have the advantages of high sensitivity, real-time sensing ability, and almost infinite contrast against background. This review focuses on appraising nanotechnologies with the ROS "turn-on" detection mechanism coupled with the ability for broad biological applications. In this review, we highlighted the weaknesses and advantages in prior sensor studies and raised some guidelines for the development of future nanoprobes.