Dual-Layered, pH-Responsive PLGA-Based Nanocarriers for Enhanced Niclosamide Delivery and Anticancer Activity

The clinical translation of niclosamide as an anticancer drug remains as a significant challenge mainly due to its poor aqueous solubility. To address this, a dual layered nanocarrier system, PLGA@Na-CMC-CaCO3 was developed in which the presence of PLGA enhanced the encapsulation of niclosamide, Na-CMC improved the bioavailability, and CaCO3 nanoparticles helped in pH-responsive drug release. The fabricated nanocarrier exhibited a uniform size with low polydispersity index when analyzed using DLS. The stepwise incorporation of all the elements along with the drug was confirmed using FTIR and XRD, and the thermal stability of the nanocarrier was assessed using TGA. The PLGA@Na-CMC-CaCO3 nanocarrier system demonstrated a high niclosamide encapsulation efficiency of ∼95.67%. Further a pH-dependent drug release profile was observed, with increased drug release under acidic pH mimicking the tumor microenvironment. The release kinetics followed the first-order and Higuchi models, confirming diffusion-dependent drug release. In vitro biological studies on MDA-MB-231 cells using the alamar blue assay demonstrated negligible cytotoxicity of PLGA@Na-CMC-CaCO3 nanocarriers alone, indicating their biocompatibility. In contrast, niclosamide-loaded PLGA@Na-CMC-CaCO3 nanocarriers showed enhanced dose-dependent cytotoxicity compared to niclosamide alone. The presence of apoptosis in niclosamide-loaded PLGA@Na-CMC-CaCO3 nanocarriers was confirmed by the JC-1 assay, which clearly demonstrated a dose-dependent decrease in mitochondrial membrane potential in the drug encapsulated nanocarrier system. Overall, this PLGA@Na-CMC-CaCO3 nanocarrier system has the potential to effectively address the key limitations of niclosamide delivery for improved cancer therapy.