Ufasomal Nanocarriers for Enhanced Cardiac Delivery of Nifedipine: A Novel Strategy to Mitigate Doxorubicin-Induced Cardiotoxicity in Breast Cancer Therapy

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The cardiotoxicity of doxorubicin significantly restricts its effectiveness, even though it remains a crucial element of breast cancer chemotherapy. Nifedipine (NFP) offers multi-mechanistic therapeutic benefits, including vasodilation, anti-proliferative activities, suppression of cellular apoptosis, and potent anti-inflammatory and antioxidant properties. However, the translation of oral NFP into an effective cardioprotective adjuvant is hindered by its poor solubility, first-pass hepatic metabolism, and poor bioavailability. Hence, this study aimed to develop a nasal NFP-loaded ufasomes (NLU) spray formulation to enhance the permeation, bioavailability, sustained release, and cardiac accumulation of NFP when co-administered with doxorubicin. Various NLU formulations were developed and optimized employing Design-Expert® software. The in vivo cardioprotective efficacy of the nasal NLU was comprehensively evaluated in a doxorubicin-induced cardiotoxicity rat model. The optimal NLU substantially prolonged drug sustainability and amplified mucosal permeability by 69.07% and 6.47-fold, respectively, compared to the free NFP suspension. Furthermore, nasal NLU formulation achieved a remarkable 7.33-fold enhancement in bioavailability and a 5.40-fold increase in cardiac tissue accumulation when contrasted with conventional oral NFP administration. Furthermore, the nasal NLU spray exhibited superior cardioprotective and antioxidant performance over the oral NFP. In conclusion, these findings establish the nasal NLU formulation as a promising therapeutic platform to mitigate doxorubicin-induced cardiotoxicity.