Evasion of apoptosis is a hallmark of cancer, attributed in part to overexpression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). In a variety of cancer types, including lymphoma, Bcl-2 is overexpressed. Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy. Therefore, the development of co-delivery systems for Bcl-2 targeting agents, such as small interfering RNA (siRNA), and chemotherapeutics, such as doxorubicin (DOX), holds promise for enabling combination cancer therapies. Lipid nanoparticles (LNPs) are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery. Inspired by ongoing clinical trials of albumin-hitchhiking doxorubicin prodrugs, here we developed a DOX-siRNA co-delivery strategy via conjugation of doxorubicin to the surface of siRNA-loaded LNPs. Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts' lymphoma (Raji) cells, leading to effective inhibition of tumor growth in a mouse model of lymphoma. Based on these results, our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies.

ObjectiveTo investigate the effectiveness and safety of insulin glargine in the treatment of patients with type 2 diabetes mellitus (T2DM),and verify the new remedy called one central and three steps for T2DM.MethodsUsed multicenter,random,open and self-control study.Two hundred and three cases with T2DM treated with insulin glargine were divided into four groups according to different therapy:30 cases with one needle method,106 cases with one needle and one pill method,48 cases with one long-acting and several short-acting method,and 19 cases with one long-acting,one pill and several short-acting method.The changes of blood glucose,glycosylated hemoglobin (HbA1c),weight and so on before and after treatment were observed.ResultsThe levels of fasting plasma glucose(FPG),2 h postprandial plasma glucose (2hPPG) and HbA1c decreased significantly after treatment than those before treatment[(5.78 ±0.76)mmol/L,(8.37 ±:1.37) mmol/L,(6.81 ±0.38)％ vs. (11.73 ±4.49) mmol/L,(16.73 ±4.96) mmol/L,(9.43 ± 2.31 )％,P ＜ 0.01 ].The weight and body mass index had no obvious changes before and after treatment( P ＞ 0.05 ).There was significant difference in the level of FPG,2hPPG and HbA1c before and after treatment in four groups respectively(P＜0.01 ).There was only 1 case who occurred hypoglycemia during the treatment.ConclusionThe therapy,one central and three steps,is not only effective and safe,but also convenient and cheap for T2DM.

Compared with the 39 cases with T2DM treated by SU+metformin,the 43 T2DM patients treated by SU+metformin+rosiglitazone for 12 weeks had the improved glycemic and lipid profile controls,increased insulin sensitivity,and decreased CRP level(all P