A self-assembling prodrug nanosystem to enhance metabolic stability and anticancer activity of gemcitabine

Self-assembly is a powerful approach in molecular engineering for biomedical applications,in particu-lar for creating self-assembling prodrugs.Here,we report a self-assembling prodrug of the anticancer drug gemcitabine(Gem)based on amphiphilic dendrimer approach.The prodrug reported in this study demonstrates high drug loading(40%)and robust ability to self-assemble into small nanomicelles,which increase the metabolic stability of Gem and enable entry into cells via endocytosis,hence bypassing transport-mediated uptake.In addition,this prodrug nanosystem exhibited an effective pH-and enzyme-responsive release of Gem,resulting in enhanced anticancer activity and reduced toxicity.Harboring ad-vantageous features of both prodrug-and nanotechnology-based drug delivery,this self-assembling Gem prodrug nanosystem constitutes a promising anticancer candidate.This study also offers new perspectives of the amphiphilic dendrimer nanoplatforms for the development of self-assembling prodrugs.

HBXIP blocks myosin-ⅡA assembly by phosphorylating and interacting with NMHC-ⅡA in breast cancer metastasis

Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton.As a key component of actomyosin filaments,non-muscle myosin-ⅡA disassembly contributes to tumor cell spreading and migration.However,its regulatory mechanism in tumor migration and invasion is poorly understood.Here,we found that oncoprotein hepatitis B X-interacting protein(HBXIP) blocked the myosin-ⅡA assemble state promoting breast cancer cell migration.Mechanistically,mass spectrometry analysis,co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain(ACD) of non-muscle heavy chain myosin-ⅡA(NMHC-ⅡA).The interaction was enhanced by NMHC-ⅡA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβⅡ.Moreover,HBXIP induced the transcription of PRKCB,encoding PKCβⅡ,by coactivating Sp1,and triggered PKCβⅡ kinase activity.Interestingly,RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate(BZF) suppressed breast cancer metastasis via inhibiting PKCβⅡ-mediated NMHC-ⅡA phosphorylation in vitro and in vivo.We reveal a novel mechanism by which HBXIP promotes myosin-ⅡA disassembly via interacting and phosphorylating NMHC-ⅡA,and BZF can serve as an effective anti-metastatic drug in breast cancer.

Two human monoclonal SARS-CoV-2 antibodies that maintain neutralizing potency against the SARS-CoV-2 Omicron BA.1 and BA.2 variants

The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continues to sweep the globe with devastating consequences on human lives and world economy.As an RNA virus,SARS-CoV-2 has a relatively high mutation rate and is rapidly evolving.Thus,new SARS-CoV-2 variants continued to emerge,5 of which were designated by the World Health Organization(WHO)as variants of concern(VOCs),Alpha(B.1.1.7).

A dynamically evolving war between autophagy and pathogenic microorganisms

Autophagy is an intracellular degradation process that maintains cellular homeostasis.It is essential for protecting organisms from environmental stress.Autophagy can help the host to eliminate invading pathogens,including bacteria,viruses,fungi,and parasites.However,pathogens have evolved multiple strategies to interfere with autophagic signaling pathways or inhibit the fusion of autophagosomes with lysosomes to form autolysosomes.Moreover,host cell matrix degradation by different types of autophagy can be used for the proliferation and reproduction of pathogens.Thus,determining the roles and mechanisms of autophagy during pathogen infections will promote understanding of the mechanisms of pathogen-host interactions and provide new strategies for the treatment of infectious diseases.