pH-triggered liposomal delivery of alendronate enables acid-responsive drug release and improves osteoblast viability

Bisphosphonates, such as sodium alendronate (ALN), are primary treatments for osteoporosis and osteosarcoma; however, their long-term use is limited by causing severe side effects. A pH-sensitive liposomal formulation was developed to enhance ALN delivery, enabling controlled drug release specifically in acidic biological microenvironments and niches. Release efficiency of pH-sensitive liposomes was evaluated and compared with that of standard and PEGylated liposomes. Molecular dynamics simulations demonstrated the stability and structural behavior of liposome formulations under physiological conditions, both with and without ALN. Membrane properties were consistent with experimental data. Liposomes were synthesized by the lipid bilayer rehydration method and characterized in vitro for vesicle size, zeta potential, lipid quantification, encapsulation efficiency, and release kinetics. Morphology was assessed by AFM and SEM. pH-sensitive liposomes released only 12% of ALN over 8 h under neutral pH conditions, while acidic conditions triggered a complete (100%) release. In hFOB 1.19 osteoblasts, pH-sensitive liposomes increased cell viability by 60% compared to free ALN in solution. To the best of current knowledge, no previously reported liposomal formulation has demonstrated complete (100%) ALN release under acidic conditions. The resulting pH-sensitive liposomes, with a mean diameter of 126 nm, exhibit physicochemical characteristics compatible with intravenous administration. The computational and experimental methodology presented here may be useful for the design and optimization of formulations for ALN and other bisphosphonates. Further in vitro and in vivo validations are needed to assess their performance and potential applications.