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Context Chronic non-healing diabetic wound therapy is an important clinical challenge. Manipulating the release of bioactive factors from an adhesive hydrogel is an effective approach to repair chronic wounds. As an endogenous antioxidant, bilirubin (BR) has been shown to promote wound healing. Nonetheless, its application is limited by its low water solubility and oxidative degradation. Objective This study developed a bilirubin-based formulation for diabetic wound healing. Materials and methods Bilirubin was incorporated into β-CD-based inclusion complex (BR/β-CD) which was then loaded into a bioadhesive hydrogel matrix (BR/β-CD/SGP). Scratch wound assays were performed to examine the in vitro pro-healing activity of BR/β-CD/SGP (25 μg/mL of BR). Wounds of diabetic or non-diabetic rats were covered with BR or BR/β-CD/SGP hydrogels (1 mg/mL of BR) and changed every day for a period of 7 or 21 days. Histological assays were conducted to evaluate the in vivo effect of BR/β-CD/SGP. Results Compared to untreated (18.7%) and BR (55.2%) groups, wound closure was more pronounced (65.0%) in BR/β-CD/SGP group. In diabetic rats, the wound length in BR/β-CD/SGP group was smaller throughout the experimental period than untreated groups. Moreover, BR/β-CD/SGP decreased TNF-α levels to 7.7% on day 3, and elevated collagen deposition and VEGF expression to 11.9- and 8.2-fold on day 14. The therapeutic effects of BR/β-CD/SGP were much better than those of the BR group. Similar observations were made in the non-diabetic model. Discussion and conclusion BR/β-CD/SGP promotes wound healing and tissue remodelling in both diabetic and non-diabetic rats, indicating an ideal wound-dressing agent.

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Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB 0,+ ) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.

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