Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells.The ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis.When ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes.

Alterations of cardiac functions after chordae tendineae rupture using echocardiogram in dogs.

Chordae tendineae rupture(CTR),mostly occurred posterior,was identified in 16.1%of dogs with mitral valve disease(MVD).We form a hypothesis that selective transect of posterior chordae tendineae(CT)would alter the cardiac functions in dogs.An objective of this study was to observe alterations of cardiac function to make a canine MR model from CTR.1 Materials and methods Nine healthy beagles weighed were used.Dogs had normal heart function from echocardiography.A left thoracotomy was performed through the 6thor 7thintercostal space.A specific hook was inserted into the left ventricle(LV)

Recent trends in molecular aggregates:An exploration of biomedicine

Molecular aggregates are receiving tremendous attention,demonstrating immense potential for biomedical applications in vitro and in vivo.For instance,the molecular aggregates of conventional fluorophores influence the electronic excitation states of the aggregates,causing characteristic photophysical property changes.A fundamental understanding of this classical relationship between molecular aggregate structures and photophysics has allowed for innovative biological applications.The chemical characteristics of drug molecules generally trigger the formation of colloidal aggregates,and this is considered detrimental to the drug discovery process.Furthermore,nano-sized supramolecular aggregates have been used in biomedical imaging and therapy owing to their optimal properties for in vivo utility,including enhanced cell permeability,passive tumor targeting,and convenient surface engineering.Herein,we provide an overview of the recent trends in molecular aggregates for biomedical applications.The changes in photophysical properties of conventional fluorophores and their biological applications are discussed,followed by the effects of conventional drug molecule-aggregates on drug discovery and therapeutics development.Recent trends in the investigation of biologically important analytes with aggregation-induced emission are discussed for conventional and unconventional fluorophores.Lastly,we discuss nano-sized supramolecular aggregates used in imaging and therapeutic purposes,with a focus on in vivo utilization.