Search

Fabrication of supramolecular prodrug of SN38 based on endogenous albumin and SN38 prodrug modified with semaglutide side chain, and their enhanced drug distribution in tumor and tumor growth inhibition. [Display omitted] • SI-Gly-SN38 prodrug which could be noncovalently bound to albumin was successfully synthesized. • The prodrug showed enhanced stability and significantly increased toxicity to tumor cells. • The prodrug of SI-Gly-SN38 showed prolonged circulation half-time in vivo. • Compared with Irinotecan, SI-Gly-SN38 prodrug showed improved distribution in tumor in vivo and essentially increased tumor growth inhibition activity. To improve the biodistribution of the drug in the tumor, a supramolecular prodrug of SN38 was fabricated in situ between endogenous albumin and SN38 prodrug modified with semaglutide side chain. Firstly, SN38 was conjugated with semaglutide side chain and octadecanedioic acid via glycine linkers to obtain SI-Gly-SN38 and OA-Gly-SN38 prodrugs, respectively. Both SI-Gly-SN38 and OA-Gly-SN38 exhibited excellent stability in PBS for over 24 h. Due to the strong binding affinity of the semaglutide side chain with albumin, the plasma half-life of SI-Gly-SN38 was 2.7 times higher than that of OA-Gly-SN38. Furthermore, with addition of HSA, the fluorescence intensity of SI-Gly-SN38 was 4 times higher than that of OA-Gly-SN38, confirming its strong binding capability with HSA. MTT assay showed that the cytotoxicity of SI-Gly-SN38 and OA-Gly-SN38 was higher than that of Irinotecan. Even incubated with HSA, the SI-Gly-SN38 and OA-Gly-SN38 still maintained high cytotoxicity, indicating minimal influence of HSA on their cytotoxicity. In vivo pharmacokinetic studies demonstrated that the circulation half-life of SI-Gly-SN38 was twice that of OA-Gly-SN38. SI-Gly-SN38 exhibited significantly reduced accumulation in the lungs, being only 0.23 times that of OA-Gly-SN38. The release of free SN38 in the lungs from SI-Gly-SN38 was only 0.4 times that from OA-Gly-SN38 and Irinotecan. The SI-Gly-SN38 showed the highest accumulation in tumors. The tumor inhibition rate of SI-Gly-SN38 was 6.42% higher than that of OA-Gly-SN38, and 8.67% higher than that of Irinotecan, respectively. These results indicate that the supramolecular prodrug delivery system can be constructed between SI-Gly-SN38 and endogenous albumin, which improves drug biodistribution in vivo , enhances tumor accumulation, and plays a crucial role in tumor growth inhibition. [ABSTRACT FROM AUTHOR]

Graphical abstract In vitro hydrolysis, co-prodrug 1a could release PTX and SAHA more efficiently and was further prepared to nanomicelles with mPEG2000-PLA1750. 1a nanomicelles had a comparable or even better cytotoxicity than PTX especially in the drug-resistant MCF-7/ADR cells. Highlights • Design of PTX and SAHA co-prodrugs are based on the synergistic antitumor effect. • In this study, we successfully bound PTX and SAHA to form co-prodrugs 1a and 1b. • 1a was further prepared to nanomicelles with mPEG 2000 -PLA 1750 as the carrier. • PTX-SAHA co-prodrug nanomicelles are promising for treatment of drug-fast cancer. Abstract Paclitaxel (PTX) is the first-line treatment drug for breast cancer. However, drug resistance after a course of treatment and low selectivity restricted its clinical utility sometimes. In this study, we successfully bound PTX and vorinostat (SAHA) to form co-prodrugs based on the synergistic anticancer effects. The PTX-SAHA co-prodrugs were conjugated by glycine (1a) and succinic acid (1b) respectively and the former has shown better activity in cytotoxicity, cell cycle arrest and western-blot experiments. Therefore, 1a was further prepared to nanomicelles with mPEG 2000 -PLA 1750 as the carrier by using thin film method. PTX-SAHA co-prodrug nanomicelles were spherical with a particle size of 20–100 nm. In vitro drug release test showed 1a nanomicelles had sustained release effect, which could reduce the resistance of PTX. In vitro cytotoxicity was evaluated by SRB assay in HCT-116 cells, MCF-7 cells and drug-resistant MCF-7/ADR cells. The results showed 1a nanomicelles had comparable or even better cytotoxicity than PTX especially in the MCF-7/ADR cells. All the results suggested that PTX-SAHA co-prodrug nanomicelles were promising treatment for PTX resistance cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel difluoromethyl-containing indole scaffold as 5-HT 6 R antagonists. • The PK properties improved by utilizing CF 2 H replacing of methyl. • Compound 6p showed good cognition-enhancing property in vivo. • Compound 6p and donepezil produces synergistic effects on increasing the acetylcholine levels. Serotonin type 6 receptor (5-HT 6 R) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1 H -indole derivatives as potent 5-HT 6 R antagonists. Structure-activity relationship study led to the discovery of five compounds (6a , 6m , 6n , 6p and 6q) with potent binding affinity at 5-HT 6 R. In in vivo pharmacokinetic studies in rats, 6p showed 30-folds higher AUC (267 ng·h/mL) and better bioavailability (34.39 %) than those of 6a (9.37 ng·h/mL and 5.95 %, respectively) by using difluoromethyl group replacing a methyl group. Besides, 6p showed good brain penetration with C b /C p ratio ∼6. Based on the pharmacological characteristics and favorable pharmacokinetic properties, 6p was further chosen to evaluate cognition-enhancing property in the preliminary in vivo models. It is identified that 6p not only prevented scopolamine-induced learning deficits in the novel object recognition test but also rescued the recognition barrier caused by scopolamine. Finally, the combination of 6p and donepezil produces synergistic effects on increasing the acetylcholine levels in the intracerebral hippocampus. In light of these findings, we propose 6p as a potential 5-HT 6 R antagonist for treatment of AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel difluoromethyl-containing indole scaffold as 5-HT 6 R antagonists. • Compound C14 showed10 folds higher 5-HT 6 R affinity than idalopirdin in vitro. • Compound C14 exhibited good in vitro metabolic properties. • Compound C14 showed good cognition-enhancing property in vivo. Herein, a series of novel 1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)- 1 H -indole derivatives were designed and synthesized via hybridization strategy of idalopirdine and SB-271046. The optimal compound C14 (K i = 0.085 nM), with difluoromethyl on C3 position on indole scaffold, increased the affinity for the 5-HT 6 R up to 10-folds than idalopirdine (K i = 0.83 nM). Additionally, C14 had good pharmacokinetic properties and in vitro metabolic properties. Finally, C14 could efficiently reverse the scopolamine induced emotional memory deficits in novel object recognition assay in rats. Thus, we propose C14 might be considered as a new cognition-enhancing agent and the further studies are now underway in our laboratory. [ABSTRACT FROM AUTHOR]