Bisphosphonate-Functionalized PLGA Nanocarriers for Doxorubicin Delivery to Primary Bone Tumors and Bone Metastases: From Mineral Affinity to Translational Evidence

Poly(lactic-co-glycolic acid) (PLGA), doxorubicin, and bisphosphonates combine a biodegradable drug reservoir, a cytotoxic payload, and a mineral-binding ligand with potential antiresorptive activity. Their integration into a single nanocarrier, however, requires evidence of lesion-specific drug delivery and an improved therapeutic index. This structured critical narrative review evaluates the development and translational potential of bisphosphonate-functionalized PLGA nanocarriers for doxorubicin delivery to primary bone tumors and bone metastases. PubMed/MEDLINE, Scopus, and Web of Science were searched to identify formulation, mechanistic, preclinical, and clinically relevant evidence. The analysis distinguishes hydroxyapatite binding from lesion localization, nanoparticle uptake from intracellular availability of pharmacologically active doxorubicin, and skeletal protection from direct antitumor activity. Preclinical studies support the feasibility of alendronate- and zoledronate-modified carriers, but substantial differences in ligand chemistry, payload, architecture, disease models, and outcome measures prevent generalization of therapeutic superiority. Clinical evidence with bisphosphonates, including the negative OS2006 osteosarcoma trial, further cautions against extrapolating preclinical skeletal activity to clinical antitumor benefit. A staged translational framework is proposed linking product identity, biological stability, mineral interaction, drug-resolved biodistribution, intracellular exposure, comparative efficacy, safety, and reproducible manufacture. Future development should prioritize clearly defined disease settings and demonstration of a measurable exposure advantage over established therapeutic comparators.