Bone-Targeting Nucleic Acid Delivery Polymer Vector for Effective Therapy of Bone Metastasis

Area of Science:

• Biomaterials Science
• Nanotechnology
• Oncology

Background:

• Bone diseases, including metastases, present challenges for targeted nucleic acid therapy delivery due to the unique skeletal microenvironment.
• Current delivery systems like lipid nanoparticles (LNP) and polyethylenimine (PEI) lack efficient bone targeting capabilities.

Purpose of the Study:

• To develop and evaluate a novel polymer-based, bone-targeting, bioreducible nucleic acid delivery vector for skeletal disease therapy.
• To assess the vector's efficacy in targeting bone, delivering therapeutic nucleic acids, and mitigating bone metastasis progression.

Main Methods:

• Synthesized a polymer vector, poly[alendronic acid-co-(N,N'-bis(acryloyl)cystamine-co-4-amino-1-butanol)] (ALN-Pabol), incorporating alendronic acid (ALN) for bone targeting.
• Evaluated hydroxyapatite binding affinity, in vivo skeletal accumulation, and therapeutic efficacy in a murine breast cancer bone metastasis model.
• Assessed the vector's mechanism of action, including polyplex dissociation, miRNA release, osteoclast inhibition, and bone structure restoration via micro-CT.

Main Results:

• ALN-Pabol demonstrated high hydroxyapatite binding (91.1%), significantly exceeding nontargeted and commercial delivery systems.
• In vivo imaging confirmed superior skeletal accumulation of the ALN-Pabol vector.
• The ALN-Pabol/miRNA polyplex reduced bone tumor weight by 79.1% and improved bone architecture, restoring bone volume and trabecular structure.

Conclusions:

• ALN-Pabol is a highly effective bone-targeting delivery vector for nucleic acid therapeutics.
• This vector system shows significant potential for treating bone metastases and offers applications in bone regeneration and cancer therapy.