Advancing Targeted Drug Delivery via Optimization of Drug-Loaded Polymeric Nanoparticles and Red Blood Cell-Mediated Approaches

Bronchopulmonary Dysplasia (BPD) represents a complex pathophysiological challenge in neonatal care, predominantly affecting preterm infants. Current interventions, such as mechanical ventilation and supplemental oxygen, often yield suboptimal outcomes, necessitating the exploration of novel therapeutic modalities. The administration of Dexamethasone (DEX), while effective in reducing mechanical ventilation dependency, is hindered by its severe long-term neurodevelopmental impacts and crystalline structure leading to poor solubility.<br/><br/>In response, our study pioneers an advanced drug delivery system involving the encapsulation of DEX within poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), subsequently coupled to red blood cells (RBCs). This approach aims to produce a polymer-matrix-stabilized amorphous form of DEX, ensuring sustained and localized pulmonary release. By leveraging these DEX-loaded NPs (DEX-NPs) in combination with RBCs, we aim to optimize drug circulation time, biodistribution, and targeted lung delivery, thereby attenuating systemic adverse effects of DEX.<br/><br/>We employed the nanoprecipitation method to synthesize drug-free and DEX-loaded NPs, thoroughly characterizing their size, polydispersity index, zeta potential, encapsulation efficiency, and DEX stabilization capability. Our results demonstrate that these polymeric NPs effectively encapsulate and stabilize DEX up to 3 mg, with higher amounts leading to crystallinity. Solvent, polymer, and drug compatibility studies indicated that PLGA stabilizes about 15% of its weight in DEX (~3 mg) with acetone or acetone: DMSO as solvents. Notably, acetone and DMSO blend markedly improved encapsulation efficiency and drug stability in PLGA nanoparticles.<br/>In addition to these findings, we successfully coupled various types of NPs to mouse RBCs, examining the efficiency of this coupling and the biocompatibility of the resultant constructs. This element of our research was critical in assessing the feasibility and safety of the NP-RBC conjugates for <i>in vivo</i> applications. Our <i>in vitro </i>toxicity assessments across various cell lines revealed that while plain NPs exhibited limited toxicity, DEX-NPs showed higher cytotoxicity at concentrations above 0.05 mg/mL. <i>In vivo</i> studies on term-born neonate CD-1 mouse pups highlighted the superior lung targeting of NP-hitchhiked RBCs compared to free NPs.<br/><br/>This study emphasizes the potential of DEX-PLGA NP-RBC conjugates in revolutionizing BPD treatment. Our findings not only advocate for the targeted pulmonary delivery of therapeutics but also set a foundation for subsequent investigations into the efficacy and safety of this novel approach in the context of neonatal lung diseases.