Dual-Drug Loaded Separable Microneedles for Efficient Rheumatoid Arthritis Therapy

Abstract

Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)—an inhibitor of IL-6R—and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/Apt1-67@MN) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/Apt1-67@MN was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy.

Targeting Tumor Necrosis Factor Receptor 1 with Selected Aptamers for Anti-Inflammatory Activity

“…Among the three types of aptamers, apt2-apt1 had the most substantial blocking effect on NF-κB, which is consistent with its best performance in the L929 cell-binding test (Figures and S16). There is still room for further improvement of the aptamers for better anti-inflammatory activity compared with zafirlukast (Figure D,E), which may be achieved by combining them with other drugs for a synergistic effect or by optimizing their binding affinity and specificity in the future. − …”

Dissolving and Swelling Hydrogel-Based Microneedles: An Overview of Their Materials, Fabrication, Characterization Methods, and Challenges

“…Similar results were seen for MeHA-loaded tips for the co-delivery of tocilizumab (TCZ)-an inhibitor of interleukin-6 receptors (IL-6R) and an aptamer, Apt1-67. The inhibition rates of IL-6 and tumor necrosis factor-α (TNF-α) were slightly higher for the SC administration; however, the loaded MNs were superior in relieving arthritis symptoms, including synovial hyperplasia, inflammatory cell infiltration, and joint cavity roughness [143].…”

“…skin [139,141,143,152,181], whereas Lau et al (2017) inserted dissolvable MNs in the abdominal skin of a mouse. Similarly, rat dorsal skin was utilized for in vivo skin insertions [62,86,118,163].…”

“…Notably, rodent skin models have found applications as in vivo representations for studying HG microneedle penetration. In vivo MN penetration in mice skin models was mainly performed on depilated dorsal skin [139,141,143,152,181], whereas Lau et al (2017) inserted dissolvable MNs in the abdominal skin of a mouse. Similarly, rat dorsal skin was utilized for in vivo skin insertions [62,86,118,163].…”

Co-Delivery of Loxoprofen and Tofacitinib by Photothermal Microneedles for Rheumatoid Arthritis Treatment

“…The natural polymers hyaluronic acid (HA) and chondroitin sulfate (CS) [ 21 ], as the main components of human joint synovial fluid [ 22 ], are widely used in arthritis treatment and can also be used as materials for preparing dissolving MNs [ 23 , 24 ]. In the treatment of RA, MNs are ideal drug delivery vehicles to directly deliver drugs into the joints [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”