Mitigating doxorubicin-induced toxicity in breast cancer treatment with <i>in situ</i> pH-sensitive carvedilol-loaded transbilosomes: <i>in vitro</i> and <i>in vivo</i> characterization

Doxorubicin (DRC) is widely used as a breast cancer treatment. However, its use is limited due to cardio, hepatic, and renal toxicities. Carvedilol (CVL) has emerged as a potential protective agent against DRC-induced toxicity (DIT). Despite this, CVL has a short half-life, resulting in poor efficacy. Therefore, this study aimed to develop a nasal <i>in situ</i> pH-sensitive CVL-transbilosome (IPCT) formulation to enhance the sustainability, targeting, and effectiveness of CVL when administered alongside DRC (DRC-IPCT) to prevent DIT. Various CVL-transbilosomes (CT) were developed using design expert software to identify the optimal formulation. The selected optimal CT formulation was subsequently combined with chitosan and glyceryl monooleate to develop the IPCT formulation. The effectiveness of the DRC-IPCT formulation was evaluated <i>in vivo</i> using a breast cancer model induced by 12-Dimethylbenz(a)anthracene. The IPCT formulation enhanced the sustainability and permeability of CVL by 78.24% and 8.58-fold, respectively, compared to free CVL. The DRC-IPCT formulation reduced tumour volume and the levels of lactate dehydrogenase, creatine kinase, and malondialdehyde by 96.89%, 86.02%, 95.26%, and 68.28%, respectively. Furthermore, DRC-IPCT increased the levels of glutathione, superoxide dismutase, and catalase by 2.03-fold, 1.52-fold, and 1.94-fold, respectively. These findings indicate that the DRC-IPCT formulation is a promising therapy to prevent DIT-associated breast cancer.