Barrier permeation and improved nanomedicine delivery in tumor microenvironments.

Nanomedicines can effectively penetrate tumor sites compared to traditionally used drugs. However, effective drugs that reach the interior of tumors remain limited. Based on studies of the complex tumor microenvironment, we summarized the barriers restricting tumor penetration of nanomedicines in this review. Penetration barriers are mainly caused by tumor blood vessels, stroma, and cell abnormalities. The repair of abnormal tumor blood vessels and tumor stroma and adjusting the physicochemical properties of nanoparticles are considered promising strategies to improve the tumor permeation of nanomedicines. The effects of nanoparticle properties, including size, shape, and surface charge, on tumor penetration were also reviewed. We expect to provide research ideas and a scientific basis for nanomedicines to increase intratumoral permeability and improve anti-tumor effects.

Zebrafish as a model system to study the physiological function of telomeric protein TPP1.

Telomeres are specialized chromatin structures at the end of chromosomes. Telomere dysfunction can lead to chromosomal abnormalities, DNA damage responses, and even cancer. In mammalian cells, a six-protein complex (telosome/shelterin) is assembled on the telomeres through the interactions between various domain structures of the six telomere proteins (POT1, TPP1, TIN2, TRF1, TRF2 and RAP1), and functions in telomere maintenance and protection. Within the telosome, TPP1 interacts directly with POT1 and TIN2 and help to mediate telosome assembly. Mechanisms of telomere regulation have been extensively studied in a variety of model organisms. For example, the physiological roles of telomere-targeted proteins have been assessed in mice through homozygous inactivation. In these cases, early embryonic lethality has prevented further studies of these proteins in embryogenesis and development. As a model system, zebrafish offers unique advantages such as genetic similarities with human, rapid developmental cycles, and ease of manipulation of its embryos. In this report, we detailed the identification of zebrafish homologues of TPP1, POT1, and TIN2, and showed that the domain structures and interactions of these telosome components appeared intact in zebrafish. Importantly, knocking down TPP1 led to multiple abnormalities in zebrafish embryogenesis, including neural death, heart malformation, and caudal defect. And these embryos displayed extensive apoptosis. These results underline the importance of TPP1 in zebrafish embryogenesis, and highlight the feasibility and advantages of investigating the signaling pathways and physiological function of telomere proteins in zebrafish.