RESUMEN
This study aimed to develop gastro-retentive sustained-release ambroxol (ABX) nanosuspensions utilizing ambroxol-kappa-carrageenan (ABX-CRGK) complexation formulations. The complex was characterized by differential scanning calorimetry, powder x-ray diffractometer, and scanning electron microscopy. The prepared co-precipitate complex was used for the development of the sustained-release formulation to overcome the high metabolic and poor solubility problems associated with ABX. Furthermore, the co-precipitate complex was formulated as a suspension in an aqueous floating gel-forming vehicle of sodium alginate with chitosan, which might be beneficial for targeting the stomach as a good absorption site for ABX. The suspension exhibited rapid floating gel behaviour for more than 8 h, thus confirming the gastro-retentive effects. Particle size analysis revealed that the optimum nanosuspension (ABX-NS) had a mean particle size of 332.3 nm. Afterward, the ABX released by the nanoparticles would be distributed to the pulmonary tissue as previously described. Based on extensive pulmonary distribution, the developed nanosuspension-released ABX nanoparticles showed significant cytotoxic enhancement compared to free ABX in A549 lung cancer cells. However, a significant loss of mitochondrial membrane potential (MMP) also occurred. The level of caspase-3 was the highest in the ABX-NS-released particle-treated samples, with a value of 416.6 ± 9.11 pg/mL. Meanwhile, the levels of nuclear factor kappa beta, interleukins 6 and 1 beta, and tumour necrosis alpha (NF-kB, IL-6, IL-1ß, and TNF-α, respectively) were lower for ABX-NS compared to free ABX (p < 0.05). In caspase-3, Bax, and p53, levels significantly increased in the presence of ABX-NS compared to free ABX. Overall, ABX-NS produced an enhancement of the anticancer effects of ABX on the A549 cells, and the developed sustained-release gel was successful in providing a gastro-retentive effect.
RESUMEN
Naringenin (NAR), a flavonoid mainly found in citrus and grapefruits, has proven anti-cancer activities. However, the poor water solubility and low bioavailability of NAR limits its use as a therapeutic agent. The aim of this study was to develop and optimize stable naringenin nanoemulsions (NAR-NE) using a Box-Behnken experimental design to obtain a formulation with a higher efficiency. Anticancer activity of optimized NAR-NE was evaluated in A549 lung cancer cells using cell viability, flow-cytometric assays, and enzyme-linked immunosorbent assay. The stabilized nanoemulsion, which showed a spherical surface morphology, had a globule size of 85.6 ± 2.1 nm, a polydispersity index of 0.263 ± 0.02, a zeta potential of -9.6 ± 1.2 mV, and a drug content of 97.34 ± 1.3%. The NAR release from the nanoemulsion showed an initial burst release followed by a stable and controlled release for a longer period of 24 h. The nanoemulsion exhibited excellent thermodynamic and physical stability against phase separation and storage. The NAR-NE showed concentration-dependent cytotoxicity in A549 lung cancer cells, which was greater than that of free NAR. The percentage of apoptotic cells and cell cycle arrest at the G2/M and pre-G1 phases induced by NAR-NE were significantly higher than those produced by free NAR (p < 0.05). NAR-NEs were more effective than the NAR solution in reducing Bcl2 expression, while increasing pro-apoptotic Bax and caspase-3 activity. Therefore, stabilized NAR-NE could be a suitable drug delivery system to enhance the effects of NAR in the treatment of lung cancer.
