Double-Layer Microneedle Patch Loaded with HA-PBA-QCT for Management of Paclitaxel-Induced Peripheral Neuropathic Pain

Chemotherapy-induced neuropathic pain (CINP) is a common adverse effect of antineoplastic drugs, often leading to dose reduction, treatment delays, or cessation of chemotherapy. Chemotherapy agents, like paclitaxel (PTX), damage the somatosensory nervous system by inducing neuroinflammation and oxidative stress, resulting in the sensitization of sensory neurons. Quercetin (QCT), known for its anti-inflammatory, antioxidant, and neuroprotective properties, is investigated for various neurological disorders. This work creates phenylboronic acid-modified hyaluronic acid (HA-PBA) gels with incorporated QCT and fabricates a double-layer microneedle (MN) patch using an HA-PBA-QCT complex in the needles and HA/polyvinyl alcohol (PVA) as the substrate. The crosslinking between PVA and HA-PBA-QCT enables a controlled, sustained release of QCT upon application. This work applies these QCT-loaded microneedle (QMN) patches to the instep skin of PTX-treated mice, which exhibits mechanical allodynia and cold hyperalgesia. Biweekly applications of the QMN patches significantly reduce pain responses. This analgesic effect is associated with the modulation of satellite glial cell activity, decreased macrophage infiltration, and reduced TNF-alpha and IL-6 levels in dorsal root ganglia (DRGs). Additionally, the treatment improves cellular antioxidant capacity, indicated by upregulated Nrf2 and catalase in DRGs. Overall, these findings suggest that double-layer QMN patches offer long-term anti-inflammatory and antioxidant benefits, potentially alleviating CINP in patients.