The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications.The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.

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Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF 4 @NaYb 0.92 F 4 :Er 0.08 @NaYF 4 )zirconium/iron porphyrin metal−organic framework core−shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core−shell UMOF NPs are realized by using a unique "solventassisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a nearinfrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

The dense fibrotic stroma in pancreatic ductal adenocarcinoma (PDA) resists drug diffusion into the tumor and leads to an unsatisfactory prognosis. To address this problem, we demonstrate a dendrimer–camptothecin (CPT) conjugate that actively penetrates deep into PDA tumors through γ-glutamyl transpeptidase (GGT)-triggered cell endocytosis and transcytosis. The dendrimer–drug conjugate was synthesized by covalent attachment of CPT to polyamidoamine (PAMAM) dendrimers through a reactive oxygen species (ROS)-sensitive linker followed with surface modification with glutathione. Once the conjugate was delivered to the PDA tumor periphery, the overexpressed GGT on the vascular endothelial cell or tumor cell triggers the γ-glutamyl transfer reactions of glutathione to produce primary amines. The positively charged conjugate was rapidly internalized via caveolae-mediated endocytosis and followed by vesicle-mediated transcytosis, augmenting its deep penetration within the tumor parenchyma and releasing active CPT throughout the tumor after cleavage by intracellular ROS. The dendrimer–drug conjugate exhibited high antitumor activity in multiple mice tumor models, including patient-derived PDA xenograft and orthotopic PDA cell xenograft, compared to the standard first-line chemotherapeutic drug (gemcitabine) for advanced pancreatic cancer. This study demonstrates the high efficiency of an active tumor-penetrating dendrimer–drug conjugate via transcytotic transport with ROS-responsive drug release for PDA therapy.

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