Doxorubicin is one of the most effective chemotherapeutic agents; however, it has various side effects, such as cardiotoxicity. Therefore, novel methods are needed to reduce its adverse effects. Quercetin is a natural flavonoid with many biological activities. Liposomes are lipid-based carriers widely used in medicine for drug delivery. In this study, liposomal doxorubicin with favorable characteristics was designed and synthesized by the thin-film method, and its physicochemical properties were investigated by different laboratory techniques. Then, the impact of the carrier, empty liposomes, free doxorubicin, liposomal doxorubicin, and quercetin were analyzed in animal models. To evaluate the interventions, measurements of cardiac enzymes, oxidative stress and antioxidant markers, and protein expression were performed, as well as histopathological studies. Additionally, cytotoxicity assay and cellular uptake were carried out on H9c2 cells. The mean size of the designed liposomes was 98.8 nm, and the encapsulation efficiency (EE%) was about 85%. The designed liposomes were anionic and pH-sensitive and had a controlled release pattern with excellent stability. Co-administration of liposomal doxorubicin with free quercetin to rats led to decreased weight loss, creatine kinase (CK-MB), lactate dehydrogenase (LDH), and malondialdehyde (MDA), while it increased the activity of glutathione peroxidase, catalase, and superoxide dismutase enzymes in their left ventricles. Additionally, it changed the expression of NOX1, Rac1, Rac1-GTP, SIRT3, and Bcl-2 proteins, and caused tissue injury and cell cytotoxicity. Our data showed that interventions can increase antioxidant capacity, reduce oxidative stress and apoptosis in heart tissue, and lead to fewer complications. Overall, the use of liposomal doxorubicin alone or the co-administration of free doxorubicin with free quercetin showed promising results.

Hydrogel scaffold has been widely applied as drug delivery systems for treating skin injuries. However, the poor drug loading and rapid drug release of hydrogel restricted their application. In the current study, we present a nanoliposome containing sulforaphane (SF) as a nano-drug delivery system that is encapsulated within the scaffold hydrogel system to overcome these limitations and improve wound healing. The hydrogel substrate consisting of 10% polyvinyl alcohol (PVA)/5% polyethylene glycol 400 (PEG400) was prepared by the freeze–thaw method, and the nanoliposomal system was manufactured by the thin film hydration method at different molar ratios of cholesterol: SPC: DPPC: DSPE-PEG2000. The nanoliposome and hydrogel system was characterized by physicochemical analyses. The findings achieved from the optimization of the sulforaphane-loaded nanoliposome (SFNL) displayed an increase in the molar ratio of SPC, leading to a higher entrapment efficiency and a gradual release profile. Narrow size distribution, optimal electrical charge, and the lack of molecular interactions between SF and nanoliposome components in the FTIR analysis make SFNL a suitable drug delivery system for the wound healing process. The obtained SFNL-encapsulated freeze–thawed hydrogel system has sufficient and specific swelling ability at different pH values and increased mechanical strength and elongation. Additionally, the release pattern of SFNL at different pH values showed that the release of SF from liposomes depends on the pH value of the environment and accelerates in line with decreasing pH values. Encapsulation of nanoliposomal SF in the hydrogel structure provides a sustained release pattern of SF compared to its free form and increased as the pH environments continued to raise. The cytotoxicity and cell uptake of SFNL-loaded hydrogels against human skin fibroblasts (HFF cell line) were investigated. The in vitro analyses displayed that the toxicity properties of SF and SFNL were dose-dependent, and SFNL exhibited lower toxicity compared to free SF. Furthermore, the proper cell compatibility of the prepared hydrogel against the HFF cell line was confirmed by the MTT assay. These findings imply that the hydrogel scaffold loaded with SFNL may have wound-healing potential.

Doxorubicin (DOX) is an effective anticancer drug used for the treatment of osteosarcoma. Liposomal nanocarriers for doxorubicin administration are now regarded as one of the most promising approaches to overcome multiple drug resistance and adverse side effects. The use of hydrogel as a 3D scaffold to mimic the cellular environment and provide comparable biological conditions for deeper investigations of cellular processes has attracted considerable attention. This study aimed to evaluate the impact of liposomal doxorubicin on the osteosarcoma cell line in the presence of alginate hydrogel as a three-dimensional scaffold. Different liposomal formulations based on cholesterol, phospholipids, and surfactants containing doxorubicin were developed using the thin-layer hydration approach to improve therapeutic efficacy. The final selected formulation was superficially modified using DSPE-mPEG2000. A three-dimensional hydrogel culture model with appropriate structure and porosity was synthesized using sodium alginate and calcium chloride as crosslinks for hydrogel. Then, the physical properties of liposomal formulations, such as mechanical and porosity, were characterized. The toxicity of the synthesized hydrogel was also assessed. Afterward, the cytotoxicity of nanoliposomes was analyzed on the Saos-2 and HFF cell lines in the presence of a three-dimensional alginate scaffold using the MTT assay. The results indicated that the encapsulation efficiency, the amount of doxorubicin released within 8 h, the mean size of vesicles, and the surface charge were 82.2%, 33.0%, 86.8 nm, and −4.2 mv, respectively. As a result, the hydrogel scaffolds showed sufficient mechanical resistance and suitable porosity. The MTT assay demonstrated that the synthesized scaffold had no cytotoxicity against cells, while nanoliposomal DOX exhibited marked toxicity against the Saos-2 cell line in the 3D culture medium of alginate hydrogel compared to the free drug in the 2D culture medium. Our research showed that the 3D culture model physically resembles the cellular matrix, and nanoliposomal DOX with proper size could easily penetrate into cells and cause higher cytotoxicity compared to the 2D cell culture.