Topical Delivery of ROS-Responsive Methotrexate Prodrug Nanoassemblies by a Dissolvable Microneedle Patch for Psoriasis Therapy

Abstract

Purpose Oxidative stress, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and adenosine signaling are factors associated with psoriatic inflammation. Topical delivery of methotrexate (MTX) has become an option to overcome the side effects caused by systemic therapy in psoriasis, leading to the suppression of NF-κB activation through boosting adenosine release. However, thickened psoriatic skin is the primary restriction against local drug delivery. Methods In this study, a ROS responsive MTX prodrug (MTX-TK-HA) was synthesized with the feature of CD44 mediated active targeting to hyperproliferative keratinocytes. MTX prodrug and PLA-mPEG were formulated by nano-precipitation method to develop the MTX-TK-HA/PLA-mPEG nanoassemblies. To achieve painless transdermal delivery, a dissolving microneedle was applied for direct loading of these nanoassemblies by micromolding technique. The particle size, zeta potential, ROS-responsiveness, permeability, and mechanical strength of nanoassemblies and microneedle arrays were determined, respectively. Then, MTT assay, immunoblot analysis, ELISA assay, flow cytometry, and histological staining were utilized to thoroughly evaluate the efficacy of nanoassemblies-loaded microneedles in an imiquimod-induced psoriatic mouse model. Results Nanoassemblies-loaded microneedle arrays were capable of significantly penetrating imiquimod-induced psoriatic epidermis in mice. The efficient topical delivery of these nanoassemblies was achieved by potent mechanical strength and hyaluronic acid as the dissolvable matrix for microneedle arrays. CD44-mediated endocytosis enabled the intracellular uptake of nanoassemblies in keratinocytes, and methotrexate was released from MTX-TK-HA with ROS stimuli, followed by suppressing the proliferation of epidermal cells via NF-κB pathway blockade. Conclusion In a psoriatic mouse model, nanoassemblies loaded microneedle arrays relieve inflammatory skin disorders via regulation of adenosine and NF-κB signaling. Our study offered a rational design for the transdermal delivery of hydrophobic agents and defined an effective therapeutic option for psoriasis treatment.

Nanocarrier-Integrated Microneedles: Divulging the Potential of Novel Frontiers for Fostering the Management of Skin Ailments

“…A H&E staining study showed that treatment with nano MNs alters the pathogenesis of psoriasis, which confirms the therapeutic efficacy of nano MNs. 184 7.3. Melanoma.…”

“…Photographs illustrated that treatment with nano MNs demonstrates rapid and efficient improvement in psoriatic skin. A H&E staining study showed that treatment with nano MNs alters the pathogenesis of psoriasis, which confirms the therapeutic efficacy of nano MNs …”

Design and Evaluation of Tretinoin Fatty Acid Vesicles for the Topical Treatment of Psoriasis

“…Animal skin samples were collected, fixed in 4% paraformaldehyde and deparaffinised. After deparaffinisation and rehydration, sections were subjected to haematoxylin and eosin (H&E) immersion staining and microscopic examination [46]. The spleen is the largest part of the immune system of the human body.…”

Development of a Deep Eutectic Solvent-Assisted Kaempferol Hydrogel: A Promising Therapeutic Approach for Psoriasis-like Skin Inflammation

“…This is followed by an up-regulation of inflammatory products derived from keratinocytes, ultimately contributing to keratinocyte proliferation. , Apart from the immune factor, the antioxidant system acts as a defense mechanism against reactive oxygen species (ROS). Psoriasis has also been linked to dysregulation of the antioxidant system and increased ROS production. − …”