Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing in vivo trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (−21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective coburst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.

ObjectiveFetuin-A is a glycoprotein produced by hepatocytes and has been associated with insulin resistance and bone growth in postnatal life. Gestational diabetes mellitus (GDM) is a condition characterized by insulin resistance. It is unclear whether GDM may affect cord blood fetuin-A levels and whether fetuin-A is associated with fetal growth.Research design and methodsIn a nested case–control study of 153 matched pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we evaluated cord blood fetuin-A in association with GDM and fetal growth.ResultsComparing the newborns of GDM versus euglycemic mothers, cord blood fetuin-A concentrations were similar (mean±SD: 783.6±320.0 vs 754.8±281.9 µg/mL, p=0.53), while insulin-like growth factor (IGF)-I (76.6±27.8 ng/mL vs 68.1±25.1 ng/mL, p=0.008) and IGF-II (195.3±32.5 ng/mL vs 187.5±30.8 ng/mL, p=0.042) concentrations were higher. Cord blood fetuin-A was not correlated with insulin, IGF-I or IGF-II. Cord blood fetuin-A was negatively correlated with birth weight (r=−0.19, p=0.025) and birth length (r=−0.24, p=0.005) z scores in GDM pregnancies, while there were no significant correlations in euglycemic pregnancies (tests for interaction: p=0.014 for birth length, p=0.013 for birth length). Adjusting for maternal and neonatal characteristics, the differential associations remained.ConclusionsGDM was not associated with cord blood fetuin-A levels. Fetuin-A was negatively associated with fetal growth in GDM but not in euglycemic pregnancies. This novel observation suggests a GDM-conditional negative correlation of fetuin-A with fetal growth.

Fetal excessive exposure to glucocorticoids may program cardiometabolic risk. Placental 11 b-hydroxysteroid dehydrogenase 2 (11b-HSD2) serves as a barrier to prevent fetal overexposure to maternal glucocorticoids. It has not been explored whether placental 11b-HSD2 levels are associated with cardiometabolic health in postnatal life. RESEARCH DESIGN AND METHODS In a prospective birth cohort study of 246 mother-infant pairs, we measured placental 11b-HSD2 expression and maternal (32-35 weeks of gestation) and cord plasma cortisol concentrations. The primary outcomes were HOMA of insulin resistance (IR) and blood pressure (BP) in infants at age 1 year. Other outcomes included fasting insulin, HOMA b-cell function, carotid intima-media thickness, weight z score, and skinfold thickness (triceps and subscapular) at age 1 year. RESULTS Placental 11b-HSD2 expression was negatively correlated with HOMA-IR (r = 20.17, P = 0.021) and fasting insulin (r = 20.18, P = 0.017) and marginally negatively correlated with systolic BP (r = 20.16, P = 0.057) but was not correlated with HOMA of b-cell function, diastolic BP, carotid intima-media thickness, and skinfold thickness (all P > 0.1) in infants at age 1 year. Cord plasma cortisol was negatively correlated to skinfold thickness (r = 20.20, P = 0007) but was not correlated with other outcomes at age 1 year. Maternal plasma cortisol was positively correlated with maximal carotid intima-media thickness (r = 0.20, P = 0.03) but was not correlated with other outcomes. Adjusting for maternal and infant characteristics, the associations were similar. CONCLUSIONS The study is the first to show that higher placental 11b-HSD2 expression is associated with lower IR in infancy. Independent cohort studies are required to confirm this novel finding. Epidemiological and experimental studies (1-3) have shown that the vulnerability to cardiometabolic diseases such as type 2 diabetes in adulthood may originate from an adverse intrauterine environment. Exposures to excessive glucocorticoids (e.g., cortisol) may be involved in such fetal programming of cardiometabolic risk (4,5). Circulating cortisol levels are elevated in pregnancy, rise progressively over advancing gestation, and peak in the third trimester of pregnancy (6). The proper elevation of cortisol concentrations is critical for the development of fetal organs and