Breaking barriers: nanosystems to overcome solubility and permeability challenges of second-generation tyrosine kinase inhibitors.

Second-generation tyrosine kinase inhibitors (TKIs) - bosutinib, nilotinib, and dasatinib - demonstrate therapeutic efficacy across various chronic malignancies, including chronic myelogenous leukaemia, acute lymphoblastic leukaemia, breast cancer, lung cancer, pancreatic cancer, and hepatocellular cancer. However, in the Biopharmaceutics Classification System, they are classified as class-II and class-IV drugs, exhibiting poor, pH-dependent solubility and low permeability, leading to poor and unpredictable bioavailability and variable plasma concentrations, compromising their clinical efficacy. Even though the oral route is the most widely accepted mode of administration, systematic analysis of the formulation database revealed that the conventional formulations encounter biopharmaceutical barriers limiting the therapeutic performance of drugs. Hence, this review examines nanotechnology-driven solutions that may improve the second-generation TKIs' biopharmaceutical properties for better therapeutic performance by enhancing their pharmacokinetic properties. Various nanosystems, such as solid lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, polymeric nanoparticles, nanocrystals, self-nanoemulsifying drug delivery systems, and nanosuspensions, have been developed to enhance solubility, permeability, and bioavailability. The nanoformulations achieved variable improvements in solubility and bioavailability (1.5- to 38-fold) compared with free drugs, depending on surface characteristics, carrier composition, and drug properties. This was possible through tailored particle size, drug loading, and precise drug release kinetics via various mechanisms. This review consolidates the evidence from peer researchers on positioning nanoformulations as a transformative tool to improve the efficacy of second-generation TKIs. Critical evaluation was performed based on solubility/permeability enhancement potential, safety profile, toxicological burden, long-term stability, scalability, and feasibility for clinical transition.