# Novel Small-Molecule Treatment and Emerging Biological Therapy for Poriasis
## 2 Small Molecules
### Immunosuppressants
#### 2.2.1 Hydrogel
(**B**) The CLSM imaging shows the skin penetration of MTX-ZA at 0.5 h, 2 h, 6 h, and 24 h. MTX-ZA was labeled using Nile red (red color). Cytokatin 17 and Kallikrein 7 (KLK7) antibodies (green) were used to distinguish the stratum corneum (SC) layer, hair follicles (HFs), visible epidermal (VE), and dermis (DE). The nuclei were dyed with DAPI (blue). White arrows indicate the Nile red-labeled MTX-ZA. Scale bar: 50 nm. Reproduced from Ref. [50]. (**C**) NS MAP and powder MAP morphology via SEM (scanning electron microscope) and digital image. The red arrows and boxes indicate the partially enlarged figures of the microstructure of microneedles (**D**). The skin dissolution state of NS MAPs at 0 min, 5 min, 10 min, and 15 min. Scale bar: 2 mm. Reproduced with permission from Ref. [51]. [PERSON] et al. developed a thermally responsive hydrogel utilizing an ionic liquid microemulsion for the topical administration of MTX. Poly(N-isopropylacrylamide) (PNIPAM) hydrogels are commonly employed in temperature-sensitive drug delivery systems because they present low critical solution temperatures. Incorporating fibroin protein into the hydrogel structure improves its mechanical strength and adhesive capabilities. The permeability of the MTX/IL-ME hydrogel surged to a plateau of 32% at 16 h compared with 5.1% for the MTX/PBS hydrogel, indicating that the drug permeability of IL-ME increased by six times. Additionally, the MTX/IL-ME hydrogel demonstrated significant antibacterial effects, reducing intracellular Staphylococcus aureus colony counts by 95.6%. In cell viability experiments, cells co-incubated with the MTX/IL-ME hydrogel showed survival rates of 88% at 24 h and 81% at 48 h, indicating that the ionic liquid-based microemulsion hydrogel exhibits characteristics of enhanced permeability, antibacterial activity, and good biocompatibility [52]. [PERSON] et al. prepared Eudragit E100 nanoparticles that contain amino-cationic groups to enhance cell uptake and protect the nanoparticles, thus avoiding the proton sponge effect to deliver MTX. The nanoparticles were embedded into chitosan-based hydrogels. In vitro permeability tests revealed that the concentration of the drug preserved in the skin was limited to 19.95 \(\pm\) 1.04 ug/cm\({}^{2}\), with the epidermis retaining 81.33% of the drug over a 24 h period [53]. [PERSON] et al. used a thin film hydration method to prepare the niosomes in order to improve the solubility of cyclosporine (CyA) and add Carbopol 940 to form a gel. A drug retention study revealed that the deposition of cyclosporine in the stratum corneum and the viable layers was 50.57%, compared with 10.13% of cyclosporine suspension in 24 h. In terms of histopathology, the PASI scores of mice treated with cyclosporine-loading niosome gel decreased significantly [54]. They also prepared a microemulsion-based cyclosporine gel consisting of an oil phase (isopropyl), surfactant (Tween 80), and co-surfactant (isopropyl alcohol). After selecting the best surfactant mixture ratio, microemulsion was added to carbomer gel for local application. Compared with a suspension, the cumulative drug release percentage was improved from 4.2 \(\pm\) 0.31% to 14.71 \(\pm\) 0.31%. The amount of cyclosporine retained in the epidermis and viable layers also increased from 12.36 \(\pm\) 2.2% to 42.36 \(\pm\) 6.5%, leading to the sustainable treatment of psoriasis [55].