CAGE ionic liquid-mediated co-solubilization of lapatinib and resveratrol enhances cytotoxicity in lung cancer cells with uniform aerosolization for pulmonary delivery.

Abstract

Choline and geranic acid-based ionic liquids (CAGE-IL) have emerged as powerful delivery vehicles for many challenging drug molecules via different routes of administration. However, their potential for aerosol delivery remains unreported. In this study, CAGE-IL is investigated for its ability to solubilise a combination of lapatinib ditosylate (LPT) and resveratrol (RSV) and act as a potential vehicle for localised delivery in lung cancer therapy. The results showed that CAGE-IL had much higher solubility for LPT (114.6 ± 3.5 mg/mL vs. 0.02 mg/mL) and RSV (58.1 ± 6.8 mg/mL vs. 0.03 mg/mL) than their respective aqueous solubilities, as determined using a validated HPLC method developed for the simultaneous estimation of the molecules. An octanol/water partition coefficient of 2.34 for LPT from LPT-CAGE-IL and 2.18 for RSV from RSV-CAGE-IL was obtained. Upon evaluation in A549, a lung adenocarcinoma cell line, the IC₅₀ value of LPT+RSV-co-loaded CAGE-IL was significantly lower (1.2 times, p˂0.006) than LPT solution (5.3 times, p˂0.0001) or RSV solution (2.7 times, p˂0.001). Importantly, we performed the first nebulization efficiency characterisation for CAGE-IL, obtaining 48 ± 1% for LPT and 49 ± 1% for RSV, with drug output rates of 15 mg/min for LPT and 7 mg/min for RSV and D₅₀ of 2.74 µm. The MMAD, FPF, and GSD were 2.00 ± 0.2 µm, 74 ± 5%, and 2.48 ± 0.2 for RSV, and 2.10 ± 0.3 µm, 70 ± 7%, and 2.87 ± 0.2 for LPT showing the suitability of the prepared formulation for pulmonary use. Overall, achieving high solubility of both drugs in a single medium, along with near-identical recovery, signified uniform co-aerosolisation without phase separation during nebulization, indicating CAGE-IL as a possible vehicle for inhalation delivery, and enhance the therapeutic efficacy for localised lung cancer treatment.