Synthesis and preclinical evaluation of novel l-cystine-based polyamide nanocapsules loaded with a fixed-dose combination of thymoquinone and doxorubicin for targeted pulmonary anticancer drug delivery

Abstract

Innovative synthetic biodegradable polymers containing amino acid moieties are used as pulmonary anticancer drug delivery systems to efficiently administer drugs in a controlled manner while also altering the physical and chemical characteristics of therapeutic molecules and the way they are delivered to the lungs. In this study, the aim was to prepare a new polyamide based on L-cystine amino acid loaded with a combination of thymoquinone (TQ) and doxorubicin (DOX) nanocapsules (TQ-DOX/Cys-Py/PA NCs) to be delivered directly to the lungs. TQ-DOX/Cys-Py/PA NCs were created using a single-step interfacial polycondensation method. The aerodynamic performance assessment shows that the prepared TQ-DOX/Cys-Py/PA NCs were able to deliver 98.7% and 97.1% of the TQ and DOX nominated dose, respectively. TQ and DOX with emitted doses of 2008.2 and 110.2 μg can reach the lower parts of the respiratory system and have an aerodynamic particle size between 1 and 5 μm, which revealed that the optimum formulation would produce a small particle size (19.89 nm) with high entrapment efficiency (TQ: 85.4%, DOX: 99.49%) and loading efficiency (TQ: 52.2%, DOX: 15.03). The targeted release of TQ and DOX in 0.1 M GSH-containing buffer solution demonstrated a faster onset of action, with 50% released within the first 2 hours. In vivo studies were conducted to demonstrate the efficacy of TQ-DOX/Cys-Py/PA NCs in enabling targeted drug delivery to the lungs for the treatment of lung cancer. The results demonstrate exceptional lung targeting and sustained lung retention for at least 24 hours. Furthermore, the toxicity of the TQ-DOX/Cys-Py/PA NCs was assessed by quantifying the protein carbonyl content. The results showed that the TQ-DOX/Cys-Py/PA NCs exhibited reduced toxicity to the heart, liver, and kidney compared to free DOX and DOX/Cys-Py/PA NCs.