Enhancing Drug-Induced Tissue Regeneration via a Polydopamine-Based Delivery System

A drug known as 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), which acts as a PHD (prolyl hydroxylase) inhibitor, has demonstrated the ability to promote tissue regeneration by enhancing metabolic activity through the upregulation of Hif-1α. This study introduces a novel approach to designing a drug delivery system aimed at optimizing the regenerative effects of 1,4-DPCA. By encapsulating 1,4-DPCA within polydopamine (PDA), which induces the production of reactive oxygen species (ROS), the combined effects of Hif-1α upregulation and the activation of cellular antioxidant defenses by localized ROS can significantly accelerate tissue regeneration. The hydrophobic properties of 1,4-DPCA make it suitable for encapsulation in the PDA carrier through a series of steps: initially, the drug forms aggregates due to its hydrophobic nature in the reaction solution, and subsequently, PDA components (dopamine hydrochloride) assemble around these aggregates, incorporating the drug into the core of PDA nanocarriers. This encapsulation process was validated using SEM, TEM, and XPS analyses. The ROS-generating capability of the developed drug delivery system (DDS) was confirmed via peroxide analysis. Further RT-qPCR and ELISA analyses showed that the released ROS and 1,4-DPCA contributed to the upregulation of antioxidant genes and Hif-1α, respectively. The synergy between these effects resulted in significantly enhanced bone tissue regeneration, as evidenced by a mouse calvarial defect model, where the bone regeneration was approximately six times greater than that of the untreated control group. Additionally, hemolysis and CCK-8 assay results indicated that the developed DDS is safe for in vivo injection, suggesting its potential for non-invasive applications. Considering that the tissue regeneration mechanisms activated by this DDS can be applied to various types of tissues, its applicability extends beyond bone defect-related conditions to other disease models requiring accelerated tissue regeneration.