Oleic Acid Integrated Acetalated Dextran Nanoparticles for Enhanced Chemotherapeutic Delivery to the Bone Marrow

Bone marrow targeted delivery of chemotherapeutics remains critical in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL). Current drug delivery platforms to treat ALL do not specialize in enhancing drug accumulation in the bone marrow, often leading to suboptimal therapeutic responses and off-target side effects. Here, we developed a polymeric lipid hybrid nanoparticle (PLHP) platform through integration of a pH-responsive acetalated dextran (Ac-Dex) polymer and oleic acid (OA), an endogenous bone marrow-rich fatty acid, for enhanced accumulation of therapeutic payloads to bone marrow. PLHPs formulated using the flash nanoprecipitation were monodisperse with sizes below 200 nm and allowed encapsulation of diverse payloads. Of note, lyophilized PHLPs retained greater than 80% of encapsulated payloads following rehydration. Confocal imaging confirmed precise intracellular release of hydrophilic and hydrophobic payloads in B-cell ALL cell lines. In healthy BALB/c mice and B-cell ALL bearing NSG mice, we demonstrate that incorporation of OA into the Ac-Dex nanoparticles enhances payload accumulation in the femur and tibia compared to non-OA containing nanoparticles. In the B-cell ALL disease model, vincristine encapsulated into Ac-Dex OA nanoparticles significantly improved the survival of mice while preserving locomotor function, and mitigated terminal weight loss as compared to the systemically administered free drug and blank nanoparticles. Together, these findings show the promising translational potential of oleic acid integrated Ac-Dex nanoparticles for clinical use in bone marrow-derived diseases.