Objective To prepare dual-targeted pH-sensitive DOX prodrug-microbubble complex and explore the characterization of complex with ultrasound as well as drug release in vitro . Methods Dual-targeted ligands ,cRGD and folate were conjugated with heparin using carbodiimide method ,and then the dual-targeted pH-sensitive DOX prodrug was synthesized by coupling DOX via a pH-sensitive hydrazone bond . The prodrug was combined with microbubbles to prepare complex by biotin-avidin system . The characterization of complex with/without ultrasound was investigated for size ,morphology and drug loaded capacity .In vitro drug release manner of complex with/without at different pH was analyzed . Results DOX content of the prodrug determined by UV Spectrophotometry was about 18 .9％ . Dynamic laser light scattering analysis( DLS) ,corresponding to transmission electron microscope( TEM ) findings ,revealed its inhomogeneous size distribution [ mean size ( 159 .7 ± 24 .5) nm and ( 1089 .0 ± 174 .9) nm ] . However ,the complex was dispersed into uniform fragment after ultrasound irradiation [ mean size ( 155 .9 ± 29 .8) nm , polymer dispersity index( PDI) 0 .22 ,Zeta potential - ( 20 .6 ± 3 .4) mV ] . The cumulative release rate of DOX from both complex and complex with ultrasound at pH 5 .0 were much faster than that at pH 7 .4 , displaying a pH-triggered release manner . Conclusions Dual-targeted pH-sensitive DOX prodrug-microbubble complex displays excellent drug release activity in acid environment . Uniform fragment and smaller particle size of complex could be achieved via ultrasound irradiation ,promoting DOX accumulation within tumor tissue and facilitating in vivo antitumor ability .

OBJECTIVE To analyze the factors affecting the inclusion of Chinese patent medicines in China’s National reimbursement drug list （NRDL）， and assist these medicines in fully reflecting their actual value in the reimbursement admission process. METHODS From the official website of the China’s National Healthcare Security Administration， the application materials of Chinese patent medicines outside the list that passed the formal review from 2021 to 2023 were obtained， including basic information on the medicines， safety， efficacy， innovation and heritage information， and supplemented with references from the pharmacopeia and the Yaozhi Database. Economic information and enterprise information were obtained through websites such as the Yaozhi Database. Univariate analysis， multivariate Logistic regression analysis and stepwise regression analysis were conducted on the initial application information and admission outcomes of the medicines. Sensitivity analysis was also performed on medicines that applied multiple times in different years as independent samples. RESULTS & CONCLUSIONS There were 27 Chinese patent medicines that passed the formal review from 2021 to 2023， involving 37 applications. The univariate analysis results showed that medicines with descriptions of traditional Chinese medicine （TCM） syndrome types， clear adjustment information for medication plans for specific population groups， short time to market in the indications of the package insert， registered as Class 1 to 6 following or class Ⅰ innovative TCM/class Ⅲ ancient classic prescription compound TCM registered， and those produced by enterprises listed in the “Top 100 Chinese Pharmaceutical Industry Enterprises” list for the current year were more likely to be included in the NRDL （P＜0.05）. The results of the multivariate Logistic regression analysis were not statistically significant， but the stepwise regression results indicated good consistency with the univariate analysis. The results of the sensitivity analysis were consistent with the trend of basic analysis. It is recommended that Chinese patent medicine enterprises further clarify the description of product instructions， expand innovation capabilities， inherit and develop ancient classic prescriptions， and promptly complete clinical trial evidence.

Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS