Liposomes for systematic delivery of vancomycin hydrochloride to decrease nephrotoxicity:Characterization and evaluation

Vancomycin hydrochloride(VANH),the first glycopeptide antibiotic,is a water-soluble drug for the treatment of acute osteomyelitis.Liposomal formulations of VANH have already been manipulated and characterized,which was a mean of increasing their therapeutic index,reducing their toxicity and altering drug biodistribution.One of the challenges for preparing VANH-Lips is their low encapsulation efficiency(EE).In the present study,we aim to improve the liposomal formulation of VANH for higher EE,longer systemic circulation,reduced nephrotoxicity and enhanced antimicrobial activities.Vancomycin hydrochloride-loaded liposomes(VANH-Lips)were formulated by the method of modified reverse phase evaporation.Based on the optimization of formulation with orthogonal experimental design,the average drug encapsulation efficiency and the mean particle size of VANH-Lips were found to be 40.78±2.56%and 188.4±2.77 nm.In vitro drug release of VANH-Lips possessed a sustained release characteristic and their release behavior was in accordance with the Weibull equation.After intravenous injection to mice,the mean residence time(MRT)of VANH-Lips group was significantly prolonged in vivo and the AUC value was improved as well compared with the vancomycin hydrochloride solution(VANH-Sol)group.Furthermore,the biodistribution results in mice showed that VANH-Lips decreased the accumulation of VANH in kidney after intravenous injection.In conclusion,VANH-Lips may be a potential delivery system for VANH to decrease nephrotoxicity in the treatment of osteomyelitis.

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Metastasis is the leading cause of cancer-related death.The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis.Surgery is a common intervention for most primary solid tumors.However,surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells(ECs).Currently,there are no effective interventions to prevent distant metastasis.Here,we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models.HECTD3 depletion downregulates expression of adhesion molecules,such as VCAM-1,ICAM-1 and E-selectin,in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo.We demonstrate that HECTD3 promotes stabilization,nuclear localization and kinase activity of IKKa by ubiquitinating IKKa with K27-and K63-linked polyubiquitin chains at K296,increasing phosphorylation of histone H3 to promote NF-kB target gene transcription.Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization,while conditional knockin promotes that.IKKa kinase inhibitors prevented LPS-induced pulmonary metastasis.These findings reveal the promotional role of the HECTD3-IKKa axis in tumor hematogenous metastasis and providea potential strategy for tumormetastasis prevention.