Recent advances in c-Met-based dual inhibitors in the treatment of cancers.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

Oral delivery of decanoic acid conjugated plant protein shell incorporating hybrid nanosystem leverage intestinal absorption of polyphenols.

Polyphenols are potent antioxidants, but their poor oral bioavailability owing to intrinsic insolubility and low permeability significantly hampers their effectiveness for clinical translation. Herein, upper intestinal absorptive polymer-lipid hybrid nanoparticles (PLN) was designed by exploiting the lipidic core for drug encapsulation and the decanoic acid conjugated rapeseed protein as the biopolymeric shell for gastrointestinal stability, retention and permeability. Polyphenol ellagic acid loaded core-shell PLN (EA-PLN(C/S)) was characterized of favorable physicochemical properties in simulated gastric- and intestinal fluids, including high drug loading capacity, slow drug release and prolonged stability. In Caco-2 monolayers, the cellular transport of EA-PLN(C/S) involved dual-paracellular and endocytosis pathways. Compared to drug in suspension or lipidic core nanoparticles, orally administered EA-PLN(C/S) was retained longer and more permeable via the duodenum and jejunum of upper intestine, resulting in up to 5.3-fold and 1.4-fold enhancement in the extent of drug absorption and colonic accumulation, respectively. In an acute colitis murine model, EA-PLN(C/S) at 6 mg/kg low dose markedly reduced colonic lipid peroxidation in contrast to no antioxidant effect in other EA formulations. This work suggests that integration of engineered plant protein biopolymer with lipid nanoparticles created unique oral drug delivery systems enabling intestinal site-specific absorption for effective antioxidant therapeutics.

Microsurgical Skills of Establishing Permanent Jugular Vein Cannulation in Rats for Serial Blood Sampling of Orally Administered Drug.

Blood sampling in small laboratory animals is necessary for pharmaceutical lead optimization but can cause great harm and stress to experimental animals, which could potentially affect results. The jugular vein cannulation (JVC) in rats is a widely used model for repeated blood collection but requires adequate training of surgery skills and animal care. This article details the microsurgical procedures for establishing and maintaining a permanent JVC rat model with specific focus on the placement and sealing of the jugular cannula. The importance of monitoring physiological (e.g., body weight, food, and water intake) and hematological parameters, was highlighted with results presented for 6 days post-surgery during the rat's recovery. The drug-plasma concentration-time profile of orally administered natural phenol ellagic acid was determined in the JVC rat model.

The physiological and pathological roles and applications of sialyl Lewis x, a common carbohydrate ligand of the three selectins.

In the past decades, the roles of carbohydrates in living organisms and their potential use in many fields have been extensively investigated. Sialyl Lewis x (sLex), a member of body carbohydrate, is an inherent blood-type tetrasaccharide on the surface of different cells, the lymphocyte, neutrophil, some T cells, multiple tumor cells and so on. SLex is a common ligand of the three selectins, L-selectin, E-selectin and P-selectin, and plays important roles in multiple physiological phenomenas by interacting with selectins. Under normal physiological conditions, sLex can affect the immune process and fertilization process. Lower expression of sLex could cause leukocyte adhesion defects (LAD) II. Overexpression of sLex on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and some blood disease including Hodgkin disease, some B cell chronic lymphocytic leukemias, acute lymphoblastic leukemias, and most acute nonlymphocytic leukemias. This paper mainly reviews the physiological functions and pathological effects of sLex and its applications in disease diagnosis, drug delivery, gene transfer and medical molecular imaging. We aim to help researchers and other readers quickly grasp the physiological and pathological roles and its medical applications of sLex, and give some suggestions for research directions.