A nuclear delivery strategy for curative treatment of COPD using 1α,25-dihydroxyvitamin D3 and lipid nanoparticles

Chronic obstructive pulmonary disease (COPD) presents with obstructive ventilation disorders. Because no drugs can regenerate destroyed alveoli, there is an urgent need for new treatments that repair alveolar damage. We previously reported revealed that 1α,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) showed emphysema-improving effects in COPD model mice. However, because 1,25(OH)₂D₃ carries a risk of serious adverse effects such as hypercalcemia, strategies to reduce the risk are needed to allow further dose reduction. To solve this problem and achieve efficient intracellular drug delivery, we focused on SS-cleavable proton-activated lipid-like material O-Phentyl-P4C2 (COATSOME^ⓇSS-OP; hereafter "SS-OP") and helper lipid as the components of lipid nanoparticles. In this study, we investigated intracellular drug delivery, emphysema-improving effect, and reduction of adverse effect risk by 1,25(OH)₂D₃-encapsulated SS-OP lipid nanoparticle (SLPs) prepared using either of two helper lipids: 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Only 1,25(OH)₂D₃-encapsulated SLPs prepared using DOPE achieved efficient drug delivery, increased nuclear translocation relative to Free 1,25(OH)₂D₃, and successfully induced lung cell differentiation and improvement of the respiratory function at a lower dose. Moreover, the use of DOPE-based 1,25(OH)₂D₃-encapsulated SLPs, reduced elevated serum Ca²⁺ levels, and these formulations are expected to be a therapeutic candidate for COPD.