In Vitro and In Vivo Antipsoriatic Efficacy of Protected and Unprotected Sugar-Zinc Phthalocyanine Conjugates.

Psoriasis, a chronic immune-mediated skin disorder affecting over 125 million people globally, is characterized by abnormal keratinocyte proliferation and immune cell infiltration. Photodynamic therapy (PDT) remains underutilized in the treatment of psoriasis despite its potential as a promising and effective therapeutic approach. This study aimed to explore the efficacy of zinc phthalocyanine (ZnPc) and its sugar conjugates as potential antipsoriatic agents. We successfully synthesized protected and unprotected sugar-conjugated zinc phthalocyanines and evaluated their potential against cytokine-stimulated HaCaT keratinocytes, as well as an established IMQ psoriasis-like in vivo model. Tetrasubstituted protected glucose-ZnPc (Glu-4-ZnPc-P) demonstrated superior phototoxicity (IC50 = 2.55 µM) compared to unprotected glucose conjugate (IC50 = 22.7 µM), protected galactose-ZnPc (IC50 = 7.13 µM), and free ZnPc in cytokine-stimulated HaCaT cells (IC50 = 5.84 µM). Cellular uptake analysis revealed that IL-17A, a cytokine that plays a central role in the pathogenesis of psoriasis, enhanced unprotected Glu-4-ZnPc uptake by 56.3%, while GLUT1 inhibitor BAY-876 reduced its accumulation by 23.8%. Intracellular ROS generation following Glu-4-ZnPc-P-PDT was significantly increased after stimulation with IL-17A, correlating with in vitro photocytotoxicity. In vivo PDT using Glu-4-ZnPc-P exhibited significant improvement in Psoriasis Area and Severity Index (PASI), inhibiting splenomegaly and restoring normal skin morphology. This study highlights sugar-conjugated zinc phthalocyanines as potential candidates for targeted PDT in psoriasis, providing a basis for further clinical investigations.

The Impact of Proinflammatory Cytokines and Imiquimod on GLUT1 in HaCaT Keratinocytes - a Potential Anti-Psoriatic Therapeutic Target?

BACKGROUND/AIMS: Glucose metabolism has been proven as an essential process for proliferating keratinocytes, which highlights the importance of glucose transporter-1 (GLUT1) not only in the onset of psoriasis but also in the progression and severity of this inflammation-driven disease. In this study, we attempted to find a connection between proinflammatory cytokines (IL-6, IL-17, IL-23, IL-36, TNF-α), a skin inflammation inducing agent - imiquimod (IMQ) and GLUT1 expression. METHODS: Human keratinocyte HaCaT cell line was incubated with exogenous cytokines: IL-6, IL-17A, IL-23, IL-36, TNF-α at a final concentration of 100 ng/ml, or with 1 µM of IMQ, for 48 h. Following the stimulation, glucose uptake and GLUT1 expression were evaluated. The activity of GLUT1 was measured in the presence of a selective GLUT1 inhibitor, BAY-876. The expression of GLUT1 was examined by immunofluorescence and quantified by qPCR, Western blotting and densitometry. RESULTS: The results from qPCR analysis showed that the administration of exogenous IL-6, IL-17, IL-23 and IL-36 to HaCaT cells resulted in upregulation of GLUT1-encoding SLC2A1 gene, while TNF-α had no significant effect. The same results were confirmed by immunofluorescence analysis, as the fluorescent intensity of GLUT1 was elevated following cytokine and IMQ stimulation. Western blot and densitometry showed that all examined cytokines, as well as IMQ, increased GLUT1 expression. HaCaT cells displayed an improved intracellular 2-deoxy-D-glucose (2-DG) uptake and GLUT1 activity after stimulation by exogenous cytokines and IMQ. The highest uptake of 2-DG was observed after IL-23 stimulation (1.93x) and the lowest after TNF-α stimulation (1.07x). BAY-876 inhibited the 2-DG uptake compared to control. CONCLUSION: Our findings suggest that cytokines and IMQ may play a key role in regulating GLUT1 expression in HaCaT cells. We believe that GLUT1 overexpression could potentially be utilized in the targeted treatment of psoriasis.

An Update on Photodynamic Therapy of Psoriasis-Current Strategies and Nanotechnology as a Future Perspective.

Psoriasis (PS) is an immune-mediated skin disease with substantial negative effects on patient quality of life. Despite significant progress in the development of novel treatment options over the past few decades, a high percentage of patients with psoriasis remain undertreated and require new medications with superior long-term efficacy and safety. One of the most promising treatment options against psoriatic lesions is a form of phototherapy known as photodynamic therapy (PDT), which involves either the systemic or local application of a cell-targeting photosensitizing compound, followed by selective illumination of the lesion with visible light. However, the effectiveness of clinically incorporated photosensitizers in psoriasis treatment is limited, and adverse effects such as pain or burning sensations are frequently reported. In this study, we performed a literature review and attempted to provide a pooled estimate of the efficacy and short-term safety of targeted PDT in the treatment of psoriasis. Despite some encouraging results, PDT remains clinically underutilized. This highlights the need for further studies that will aim to evaluate the efficacy of a wider spectrum of photosensitizers and the potential of nanotechnology in psoriasis treatment.