Harnessing immunotherapy to enhance the systemic anti-tumor effects of thermosensitive liposomes.

Chemotherapy plays an important role in debulking tumors in advance of surgery and/or radiotherapy, tackling residual disease, and treating metastatic disease. In recent years many promising advanced drug delivery strategies have emerged that offer more targeted delivery approaches to chemotherapy treatment. For example, thermosensitive liposome-mediated drug delivery in combination with localized mild hyperthermia can increase local drug concentrations resulting in a reduction in systemic toxicity and an improvement in local disease control. However, the majority of solid tumor-associated deaths are due to metastatic spread. A therapeutic approach focused on a localized target area harbors the risk of overlooking and undertreating potential metastatic spread. Previous studies reported systemic, albeit limited, anti-tumor effects following treatment with thermosensitive liposomal chemotherapy and localized mild hyperthermia. This work explores the systemic treatment capabilities of a thermosensitive liposome formulation of the vinca alkaloid vinorelbine in combination with mild hyperthermia in an immunocompetent murine model of rhabdomyosarcoma. This treatment approach was found to be highly effective at heated, primary tumor sites. However, it demonstrated limited anti-tumor effects in secondary, distant tumors. As a result, the addition of immune checkpoint inhibition therapy was pursued to further enhance the systemic anti-tumor effect of this treatment approach. Once combined with immune checkpoint inhibition therapy, a significant improvement in systemic treatment capability was achieved. We believe this is one of the first studies to demonstrate that a triple combination of thermosensitive liposomes, localized mild hyperthermia, and immune checkpoint inhibition therapy can enhance the systemic treatment capabilities of thermosensitive liposomes.

Effects of melittin on laying performance and intestinal barrier function of quails.

To study the effects of melittin on egg-laying performance and intestinal barrier of quails, 240 quails (aged 70 d) were randomly divided into 4 groups with 6 replicates (10 quails per replicate). They were fed with basal diet (group B), basal diet + 0.08 g/kg melittin (group BA1), basal diet + 0.12 g/kg melittin (group BA2) and basal diet + 0.16 g/kg melittin (group BA3). The experiment lasted for 21 days. The eggs were collected every day. At the end of the experiment, duodenal, jejunal, and ileal tissues were collected, and the cecal contents were sampled. Intestinal antioxidant index, barrier function, and intestinal flora were analyzed. The results showed that the addition of melittin significantly increased the laying rate and average egg weight. Addition of melittin significantly increased the antioxidant function, mechanical barrier, immune barrier, and the villus height to crypt depth ratio of small intestine. Addition of melittin had no significant effect on the α and ß diversity of cecal flora, but significantly increased the abundance of Bacteroidales at family level and genus level. Bioinformatics analysis of cecal content showed significant increase in COG functional category of cytoskeleton, and significant decrease in RNA processing and modification in group BA2. KEGG functional analysis showed significant decrease in steroid biosynthesis, caffeine metabolism, and cytochrome P450 pathways in group BA2. In conclusion, addition of 0.12 g/kg melittin to feed improved the laying performance and the intestinal antioxidant capacity and barrier function of quails but had no significant effect on the composition and structure of cecal microbial community. This study provides experimental data and theoretical basis for the application of melittin as a new quail feed additive.

Triggered release from thermosensitive liposomes improves tumor targeting of vinorelbine.

Triggered drug delivery strategies have been shown to enhance drug accumulation at target diseased sites in comparison to administration of free drug. In particular, many studies have demonstrated improved targetability of chemotherapeutics when delivered via thermosensitive liposomes. However, most studies continue to focus on encapsulating doxorubicin while many other drugs would benefit from this targeted and localized delivery approach. The proposed study explores the therapeutic potential of a thermosensitive liposome formulation of the commonly used chemotherapy drug vinorelbine in combination with mild hyperthermia (39-43 °C) in a murine model of rhabdomyosarcoma. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, is largely treated using conventional chemotherapy which is associated with significant adverse long-term sequelae. In this study, mild hyperthermia was pursued as a non-invasive, non-toxic means to improve the efficacy and safety profiles of vinorelbine. Thorough assessment of the pharmacokinetics, biodistribution, efficacy and toxicity of vinorelbine administered in the thermosensitive liposome formulation was compared to administration in a traditional, non-thermosensitive liposome formulation. This study shows the potential of an advanced formulation technology in combination with mild hyperthermia as a means to target an untargeted therapeutic agent and result in a significant improvement in its therapeutic index.