Synthesis of Paclitaxel Derivatives for Remote Loading into Liposomes and Improved Therapeutic Effect.

A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)2 and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of 4d, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.1 w/w), was the most stable. Furthermore, the liposomes of compound 4d (8 mg/kg, 4 times) and higher dose of compound 4d (24 mg/kg, 4 times) showed better therapeutic effect than paclitaxel (8 mg/kg, 4 times) in the 4T1 tumor model in vivo, and the rates of tumor inhibition were 74.3%, 81.9% and 58.5%, respectively. This study provided a reasonable design strategy for the insoluble drugs to improve their drug loading into liposomes and anti-tumor effect in vivo.

GHR is involved in gastric cell growth and apoptosis via PI3K/AKT signalling.

Growth hormone receptor (GHR), the cognate receptor of growth hormone (GH), is a membrane bound receptor that belongs to the class I cytokine receptor superfamily. GH binding GHR induces cell differentiation and maturation, initiates the anabolism inside the cells and promotes cell proliferation. Recently, GHR has been reported to be associated with various types of cancer. However, the underlying mechanism of GHR in gastric cancer has not been defined. Our results showed that silence of GHR inhibited the growth of SGC-7901 and MGC-803 cells, and tumour development in mouse xenograft model. Flow cytometry showed that GHR knockout significantly stimulated gastric cancer cell apoptosis and caused G1 cell cycle arrest, which was also verified by Western blot that GHR deficiency induced the protein level of cleaved-PARP, a valuable marker of apoptosis. In addition, GHR deficiency inhibited the activation of PI3K/AKT signalling pathway. On the basis of the results, that GHR regulates gastric cancer cell growth and apoptosis through controlling G1 cell cycle progression via mediating PI3K/AKT signalling pathway. These findings provide a novel understanding for the role of GHR in gastric cancer.