Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy

摘要

Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H2O2. The dual -responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNF alpha 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer drug conjugates.