A Yeast Cell Wall Derived Hybrid Hydrogel with Photothermal and Immune Combined Modality Therapy for Enhanced Anti-Melanoma Efficacy.

Introduction: The effect of traditional treatment for melanoma is quite limited, especially for its recurrence. As the major components of yeast cell wall, chitin and ß-glucan exhibit good immune activation effect and are promising candidates for adjuvant. Therefore, melanoma cell membrane (CM) and indocyanine green (ICG) was loaded in a chitin and ß-glucan hybrid hydrogel to achieve an enhanced anti-melanoma therapy. Methods: The novel hybrid hydrogel was prepared, and its physicochemical properties were examined. Its effect towards melanoma prevention and treatment was evaluated via a melanoma-bearing mice model. Results: The CM-ICG-hybrid hydrogel was successfully prepared with excellent injectability, self-healing, drug loading, rheological, in vitro and in vivo photothermal stability, and retention properties. It also exhibited good cellular and in vivo safety profiles. In the primary melanoma mice model, it quickly ablated the in-situ melanoma, effectively inhibited the tumor growth, increased the survival rate of melanoma-bearing mice, and increased the level of IFN-γ and TNF-α. In the distal secondary melanoma model, it efficiently prevented the reoccurrence of melanoma and activated the memory T cells. In both models, a synergistic effect of photothermal therapy and immune therapy was found. The hydrogel effectively recruited CD3+ CD4+ T cells and CD3+ CD8+ T cells, inhibited the proliferation of melanoma cells, and induced the apoptosis of melanoma cells. Conclusion: The hybrid hydrogel was successfully prepared, and it showed excellent efficacy towards melanoma prevention and treatment due to its efficient tumor ablation and immune activation capability.

A hybrid hydrogel composed of chitin and ß-glucan for the effective management of wound healing and scarring.

Non-functional scars commonly form after cutaneous injuries. At present, most clinical treatments for scar eradication typically have long treatment courses, low curative effects, and are expensive. In this research, three hydrogels, namely chitin hydrogel, ß-glucan hydrogel, and hybrid hydrogel composed of chitin and ß-glucan, were successfully prepared, and they exhibited good shear thinning property and bioadhesiveness. In a full-thickness skin defect mouse model, the three hydrogels were found to effectively promote wound closure and inhibit scar formation. Through the immunohistochemistry staining and immunofluorescence staining of the wound tissues, the hydrogels could significantly promote the formation of collagen III, the regeneration of hair follicles, and the expression of keratin K14 and K15. They could also regulate the production of VEGF and immune factors such as IL-10 and IL-12, and inhibit the expression of the fibroblast regulatory factor En-1 in the wound site, which correlated well with their improved wound healing promoting effect and anti-scarring effect. Among all the hydrogels, the hybrid hydrogel was the best to promote wound healing and inhibit scarring. This study, for the first time, proved the excellent therapeutic effect of chitin and ß-glucan hydrogels in the management of wound healing and skin regeneration without scar formation, which will lay a solid foundation for the development of skin regeneration medication and future clinical transformation.

L-Se-methylselenocysteine loaded mucoadhesive thermogel for effective treatment of Vulvar candidiasis.

Vulvar candidiasis (VVC) is a vaginitis caused by vaginal mucosa infection of Candida, which greatly impairs women's health. Although there are more and more thiazoles on the market, new classes of antifungal drugs are still missing, it is still challenging to treat azole-resistant candidal vaginitis. We found that L-Se-methylselenocysteine (L-SeMC) could effectively inhibit the growth of Candida albicans, reduce the density and length of the mycelia. To extend the retention time of L-SeMC in the vaginal tract and enhance its therapeutic effect for VVC, a mucoadhesive thermogel (NAC-HA thermogel) was successfully synthesized and prepared. The gelation window was around 29-56 °C for L-SeMC loaded mucoadhesive thermogel (L-SeMC@NAC-HA thermogel), which exhibited a sustained release profile in the in vitro release study and an extended retention time in the vaginal tract. Besides, L-SeMC@NAC-HA thermogel exhibited a good safety profile in the in vivo safety study. The in vivo anti-VVC effect was examined in a rat VVC model and L-SeMC@NAC-HA thermogel significantly reduced the number of Candida albicans in the vaginal secreta, mitigated the vaginal damage and reduced the secretion of proinflammatory factors (TNF-α, IL-1α and IL-ß). Therefore, it is a promising therapy for the clinical treatment of VVC in the near future.

Dasatinib loaded nanostructured lipid carriers for effective treatment of corneal neovascularization.

Corneal neovascularization (CNV) is one of the most important causes of visual impairment worldwide. Dasatinib, a poorly water-soluble tyrosine kinase inhibitor with dual Src family kinase and platelet derived growth factor receptor inhibiting capability, has great potential in the treatment of CNV. In this study, dasatinib was successfully encapsulated into a nanostructured lipid carrier (Dasa-NLC) and the size was approximately 78 nm with a small polydispersity index. The NLC increased the solubility of dasatinib by more than 1220 times, sustained the drug release, reduced the ocular toxicity and facilitated its penetration into the cornea. Dasa-NLC significantly inhibited the proliferation, migration and tube formation of HUVEC cells, the three most important angiogenesis-related cellular changes of the CNV. Next, the in vivo anti-CNV effect of Dasa-NLC was evaluated using an alkaline burned mice CNV model, in which the development of the CNV and pathological changes of the cornea were significantly inhibited. The immunohistochemistry analysis indicated that Dasa-NLC could inhibit both the expression and activation of Src family kinase, a key component in the angiogenesis cascade. Therefore, Dasa-NLC showed considerable promise in the treatment of CNV.

Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris.

BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.