Background: Itraconazole (ITZ) is an antiangiogenic agent recognized as a potent suppressor of endothelial cell growth that suppresses angiogenesis. Nevertheless, its exploitation is significantly restricted by its low bioavailability and systematic side effects. The objective of this study was to utilize glycerosomes (GLY), glycerol-developed vesicles, as innovative nanovesicles for successful ITZ pulmonary drug delivery. Methods: The glycerosomes were functionalized with hyaluronic acid (HA-GLY) to potentiate the anticancer efficacy of ITZ and extend its local bio-fate. ITZ-HA-GLY were fabricated using soybean phosphatidylcholine, tween 80, HA, and sonication time via a thin-film hydration approach according to a 24 full factorial design. The impact of formulation parameters on ITZ-HA-GLY physicochemical properties, as well as the optimal formulation option, was evaluated using Design-Expert^®. Sulphorhodamine-B (SRB) colorimetric cytotoxicity assay of the optimized ITZ-HA-GLY versus ITZ suspension was explored in the human A549 cell line. The in vivo pharmacokinetics and bio-distribution examined subsequent to intratracheal administrations of ITZ suspension, and ITZ-HA-GLY were scrutinized in rats. Results: The optimized ITZ-HA-GLY unveiled vesicles of size 210.23 ± 6.43 nm, zeta potential of 41.06 ± 2.62 mV, and entrapment efficiency of 73.65 ± 1.76%. Additionally, ITZ-HA-GLY manifested a far lower IC50 of 13.03 ± 0.2 µg/mL on the A549 cell line than that of ITZ suspension (28.14 ± 1.6 µg/mL). Additionally, the biodistribution analysis revealed a higher concentration of ITZ-HA-GLY within the lung tissues by 3.64-fold as compared to ITZ suspension. Furthermore, the mean resistance time of ITZ-HA-GLY declined more slowly with 14 h as compared to ITZ suspension, confirming the accumulation of ITZ inside the lungs and their promising usage as a target for the treatment of lung disease. Conclusions: These data indicate that the improved ITZ-HA-GLY demonstrates significant promise and represents an exciting prospect in intratracheal delivery systems for lung cancer treatment, meriting further investigation.

Isoxsuprine (ISX) is a blood flow-improving beta-adrenergic agonist that provides cardiotoxicity protection. However, the limited effectiveness of ISX can be attributed to a short half-life and low bioavailability. The focus of this study was to create ISX-loaded transbilosomes (ILT), improving sustainability, permeability, bioavailability, safety, and ISX therapeutic efficacy as a safe option for managing cardiotoxicity. Different ILT formulations were developed using design expert software. Additionally, a rat model of cardiotoxicity was used to conduct an in vivo study to assess its bioavailability, safety, and efficacy. An optimized ILT formulation was identified, consisting of 275 mg phospholipid, 20 mg cholesterol, 25 mg Span 60, and 20 mg sodium deoxycholate. This formulation achieved a release rate of 29.22%, a permeation rate of 95.66%, and resulted in a 3.55-fold increase in bioavailability. Compared to the disease group, the optimized ILT significantly reduced mortality and levels of troponin-1, LDH, CK-MB, and MDA by 23.89%, 99.03%, 94.77%, 96.77%, and 96.57%, respectively. Furthermore, it enhanced the GSH, SOD, and CAT by 3.69-fold, 3.54-fold, and 3.57-fold, respectively. These findings suggest that nasal ILT could be an innovative avenue to consider for treating cardiotoxicity.