Targeting ligands displayed on liposome surface had been used to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after IV injection. In this study, we incorporated an EGFR targeting peptide GE11 on liposome surfaces in addition to PEG at different densities and evaluated their targeting properties and antitumor effects. We found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. The inclusion of GE11-PEG-DSPE and PEG-DSPE at 2% and 4% mol ratios in the liposome formulation mediated a rapid accumulation of liposomes within 1 h after IV injection in the tumor tissues surrounding neovascular structures. This is in addition to the EPR effect that was most prominently described for surface PEG modified liposomes. Therefore, despite the fact that the distribution of liposomes into interior tumor tissues was still limited by diffusion, GE11 targeted doxorubicin loaded liposomes showed significantly better antitumor activity in tumor bearing mice as a result of the fast active-targeting efficiency. We anticipate these understandings can benefit further optimization of targeted drug delivery systems for improving efficacy in vivo.
Abstract The trans‐cleavage property of CRISPR‐Cas12a system makes it an excellent tool for disease diagnosis. Nevertheless, most methods based on CRISPR‐Cas system still require pre‐amplification of the target to achieve the desired detection sensitivity. Here we generate Framework‐Hotspot reporters (FHRs) with different local densities to investigate their effect on trans‐cleavage activity of Cas12a. We find that the cleavage efficiency increases and the cleavage rate accelerates with increasing reporter density. We further construct a modular sensing platform with CRISPR‐Cas12a‐based target recognition and FHR‐based signal transduction. Encouragingly, this modular platform enables sensitive (100 fM) and rapid (<15 min) detection of pathogen nucleic acids without pre‐amplification, as well as detection of tumor protein markers in clinical samples. The design provides a facile strategy for enhanced trans cleavage of Cas12a, which accelerates and broadens its applications in biosensing.
The key problem of cryoablation is that only freezing is often unable to kill the capillaries at tumor edges, leading to a high rate of recurrence. Here, we found that Fe3O4 nanoparticles were highly useful to improve the freezing capability of cryosurgery due to their ability to alter intracellular ice formation (IIF) and growth in tumor cells. The killing efficiency of cryoablation for MCF-7 breast cancer cells can be expected to be enhanced as the Fe3O4 nanoparticles concentration increased, it was mainly because that more IIF was induced by the participation of Fe3O4 nanoparticles during freezing, recrystallization and thawing. Furthermore, our results also showed that recrystallization contributed to the formation of extracellular embryonic crystals, which was capable of enhancing the efficiency of killing MCF-7 cells. This research is to develop an understanding of the mechanism of the cryoablation enhancing the killing efficiency in the presence of the Fe3O4 nanoparticles, and to promote their further application in tumor therapy.
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