Background/Objectives: Non-small cell lung cancer (NSCLC) constitutes over 84% of all lung cancer cases and is a leading cause of cancer-related mortality globally. Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is effective in ALK-positive NSCLC; however, its clinical potential is hampered by poor aqueous solubility and limited oral bioavailability. This study aimed to develop Alectinib-loaded chitosan–alginate nanoparticles (ACANPs) to enhance its solubility, oral bioavailability, and therapeutic efficacy. Methods: ACANPs were synthesized using a novel combined solid/oil/water (s/o/w) emulsification technique with ionotropic gelation. Characterization was performed using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic light scattering (DLS), and zeta potential measurements. A validated high-performance liquid chromatography (HPLC) method quantified the Alectinib. In vitro drug release studies compared free Alectinib with ACANPs. Cytotoxicity against NSCLC cell lines (A549 and H460) was assessed using MTT assays. Pharmacokinetic parameters were evaluated in rats using LC–MS/MS. Results: ACANPs showed a high encapsulation efficiency (~97%), an average particle size of 161 nm, and a positive zeta potential of +21 mV. In vitro release studies revealed a threefold increase in drug release from ACANPs over 48 h compared to free Alectinib. Cytotoxicity assays demonstrated significantly reduced IC₅₀ values for ACANPs. Pharmacokinetic analyses showed an enhanced maximum plasma concentration (C_max) and area under the curve (AUC), indicating a 78% increase in oral bioavailability. Conclusions: ACANPs substantially improved the solubility, cytotoxic efficacy, and oral bioavailability of Alectinib, suggesting their potential as a promising nanocarrier system for enhancing NSCLC treatment outcomes.

Background/Objectives: Alectinib, a second-generation tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer (NSCLC), exhibits suboptimal oral bioavailability, primarily attributable to its inherently low aqueous solubility and limited dissolution kinetics. This study aimed to enhance Alectinib’s solubility and therapeutic efficacy by formulating a G4-NH2-PAMAM dendrimer complex. Methods: The complex was prepared using the organic solvent evaporation method and characterized by DSC, FTIR, dynamic light scattering (DLS), and zeta potential measurements. A validated high-performance liquid chromatography (HPLC) method quantified the Alectinib. In vitro drug release studies compared free Alectinib with the G4-NH2-PAMAM dendrimer complex. Cytotoxicity against NSCLC cell line A549 was assessed using MTT assays, clonogenic assay, and scratch-wound assay. Xenograft effect was investigated in the H460 lung cell line. Pharmacokinetic parameters were evaluated in rats using LC–MS/MS. Results: Alectinib exhibited an encapsulation efficiency of 59 ± 5%. In vitro release studies demonstrated sustained drug release at pH 6.8 and faster degradation at pH 2.5. Anticancer activity in vitro showed comparable efficacy to free Alectinib, with 98% migration inhibition. In vivo tumor suppression studies revealed near-complete tumor regression (~100%) after 17 days of treatment, compared to 75% with free Alectinib. Pharmacokinetic analysis indicated enhanced absorption (shorter Tmax), prolonged systemic circulation (longer half-life), and higher bioavailability (increased AUC) for the dendrimer-complexed drug. Conclusions: These findings suggest that the G4-NH2-PAMAM dendrimer system significantly improves Alectinib’s pharmacokinetics and therapeutic potential, making it a promising approach for NSCLC treatment.