(A-9) Quercetin microneedle patch for treating chemotherapy-induced peripheral neuropathic pain

Introduction:: Although chemotherapeutic drugs are extremely effective tool to arrest the progress of malignancy, they can also affect normal cells and body structure, causing deleterious side effects. Due to their neurotoxicity, chemotherapy induced neuropathic pain (CINP) is the most common neurological syndrome in patients undergoing antineoplastic therapy. The toxicity is agent-dependent and may occur either with a high single does or after cumulative administration. Severe CINP can be hazardous in cancer patients as it can interrupt treatment schedule by necessitating dose reduction or even cessation of chemotherapy, thus decreasing the probability of survival. Numerous pharmacological agents, such as antioxidants, neuroprotective agents, anti-inflammatory compounds, anticonvulsants, and antidepressants, have been tested in clinical trials. However, none have consistently demonstrated beneficial and analgesic effects in large randomized, double-blind, placebo-controlled trials. Therefore, it is necessary to develop more efficient drug management approaches and exploit potent therapeutic agents. Here we develop a minimum-invasive microneedle patch to sustainably deliver a neuroprotective agent, quercetin (QCT), for the treatment of CINP.


Materials and Methods:: In our previous studies, we have fabricated multi-functional hydrogel system based on phenylboronic acid modified hyaluronic acid (HA-PBA) and the poly (vinyl alcohol) (PVA) for controllable delivery of neuron growth factors and neuroprotective agents [1, 2]. The HA-PBA-PVA drug delivery system exhibited therapeutic effects to promote nerve regeneration, reduce neuroinflammation, relieve neuropathic pain and improve functional outcome after traumatic peripheral nerve injury. Here, we mixed HA-PBA and QCT to form HA-PBA-QCT. A dual layer microneedle patch was made by consisting of the HA-PBA-QCT tips and HA/PVA substrate. The HA-PBA-QCT microneedle patch would be applied to limb terminal skin in mice for the treatment with CINP.


Results, Conclusions, and Discussions:: HA-PBA can bind with QCT to form microgel composite, i.e., HA-PBA-QCT (Fig 1. A, B and C). The HA-PBA-QCT was embedded into the tips of microneedle patch (Fig 1. D). In addition, the HA-PBA-based microneedles can penetrate parafilm layers and mouse dorsal skins (Fig 1. E, F and G). Moreover, we found that HA-PBA-QCT microneedle prolonged QCT release period compared with the HA/QCT microneedle. Furthermore, incorporation of PVA in the substrate decreased the dissipation rate of the needle tips after insertion into an agarose gel.
We successfully developed a dual layer microneedle patch which can attach to and penetrate skin tissue, and further sustainedly release the encapsulated QCT from the needle tips. The release kinetics of QCT is dependent on the interaction between QCT and HA-PBA as well as the formation of HA-PBA-PVA hydrogel after insertion into a moisture environment. The microneedle patch is minimum-invasive and easily applicable to skin tissue. As many chemotherapeutic agents can induce neuroinflammation and damage nerve terminals at skin, consequently leading to CINP, we will investigate its analgesic functions during CIPN in a mice model.


Acknowledgements (Optional): : This work was funded by NIH/NIAMS R21R21AR078439, University of Nebraska Collaboration Initiative Grant, Nebraska Stem Cell Research Project Grant.


References (Optional): : [1] Kong Y, et. al. (2021). Applied Materials Today, 24, 101090; [2] Kong Y, et al. (2023). Journal of Controlled Release, 357, 319-332.