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

TL;DR

Researchers developed a nanoparticle system that targets chemotherapy drugs to the bone marrow, improving treatment for leukemia while reducing side effects.

Contribution

A novel polymeric lipid hybrid nanoparticle platform integrating oleic acid and acetalated dextran for targeted bone marrow drug delivery.

Findings

PLHPs encapsulated diverse payloads and retained over 80% after lyophilization and rehydration.

OA-integrated nanoparticles enhanced drug accumulation in bone marrow of healthy and leukemia-bearing mice.

Vincristine-loaded nanoparticles improved survival and reduced weight loss in a B-cell ALL mouse model.

Abstract

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.

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