Improving the bioavailability and therapeutic efficacy of valsartan for the control of cardiotoxicity-associated breast cancer

Cardiotoxicity remains the most severe side effect of breast cancer (BC) treatments. Valsartan, an angiotensin II receptor blocker, has antioxidant properties that can mitigate cardiotoxicity-associated BC (CABC). However, valsartan's limited solubility and low bioavailability result in reduced effectiveness. Therefore, this study developed an <i>in-situ</i> nasal pH-responsive valsartan-loaded novasome (ISVLN) to enhance valsartan's sustainability, bioavailability, targeting and efficacy when used alongside chemotherapy to prevent CABC. Various VLN formulations were created and optimised using the Box-Behnken design. The optimal formulation was mixed with chitosan and glyceryl monooleate to develop ISVLN, which was further assessed <i>in vivo</i> using a DMBA-induced breast cancer (DIBC) rat model to evaluate its bioavailability and efficacy. The optimal VLN formulation comprises oleic acid (26 mg), Span 60 (65 mg) and cholesterol (52 mg). The ISVLN formulation improved valsartan's sustainability, permeability and bioavailability compared to free valsartan by 66.40%, 7.46-fold and 4.57-fold, respectively. The ISVLN formulation enhanced valsartan's targeting in both the tumour and heart by 2.30-fold and 1.96-fold, respectively. Compared with the DIBC-positive group, the ISVLN group reduced the tumour volume and mortality rate by 86.20% and 23.53%, respectively. Furthermore, the ISVLN group reduced the LDH and CK-MB levels by 96.11% and 95.97%, respectively. Histopathological analysis confirmed the efficacy of the ISVLN formulation. These findings suggest that a nasal ISVLN could serve as an adjuvant therapy to prevent CABC.