Psoriasis: From Pathogenesis to Pharmacological and Nano-Technological-Based Therapeutics

Abstract

Research in the pathogenesis of inflammatory skin diseases, such as skin dermatitis and psoriasis, has experienced some relevant breakthroughs in recent years. The understanding of age-related factors, gender, and genetic predisposition of these multifactorial diseases has been instrumental for the development of new pharmacological and technological treatment approaches. In this review, we discuss the molecular mechanisms behind the pathological features of psoriasis, also addressing the currently available treatments and novel therapies that are under clinical trials. Innovative therapies developed over the last 10 years have been researched. In this area, advantages of nanotechnological approaches to provide an effective drug concentration in the disease site are highlighted, together with microneedles as innovative candidates for drug delivery systems in psoriasis and other inflammatory chronic skin diseases.

Keywords: biodegradable nanoparticles; clinical trials; microneedles; psoriasis; psoriasis versus atopic dermatitis; skin inflammatory diseases.

Figure 1

Plaque-type psoriasis pathogenesis principal hypothesis.

Figure 2

Pathophysiology in pustular psoriasis.

Figure 3

The physiological pathway of vitamin D synthesis and activation. (A) Ultraviolet radiation promotes the conversion of 7-dehydrocholesterol to pre–vitamin D₃, which isomerizes to vitamin D₃ (also called cholecalciferol) in the skin, due to sun heat. Diet supplements directly provide Vitamin D₃, also called ergocalciferol. In the liver, a 25-hydroxylation by CYP2R1 is carried out, thus leading to the formation of 25-hydroxyvitamin D₃. In the kidney, CYP27B1 further hydroxylates 25-hydroxyvitamin D₃ at the 1-α position, resulting in the formation of the active hormone 1α,25-dihydroxyvitamin D₃. The active form of vitamin D then enters into the cell via diffusion or endocytic receptor for transcription. Inside the cell, vitamin D binds to both vitamin D receptors at the nucleus and cell membrane. In the nucleus, both active forms of vitamin D and its receptor form a regulatory complex that finally leads to the beginning of the transcription process. In the cell membrane, binding to vitamin D receptors lead to several intracellular signal transductions. (B) An alternative pathway has been described. In this case, 25-hydroxyvitamin D₃ and 1α,25-dihydroxyvitamin D₃ metabolites are hydroxylated by other two cytochromes: on the one hand, a dominant gain-of-function mutation in CYP3A4, mainly located in the liver, leads to acceleration in vitamin D inactivation; on the other hand, hydroxylation by CYP24A1, mainly located in the mitochondria, gives rise to the formation of an active metabolite, 24R,25(OH)₂D₃. This molecule has been described to bind to FAM57B2 in fractured bones. This leads to the production of lactosylceramide (LacCer), which is essential for the callus formation and fracture healing.

Figure 4

(1) Application of microneedles, (2) insertion, (3) extraction. Types of microneedles: (a) solid microneedles, (b) coated microneedles, (c) dissolving microneedles, and (d) hollow mi-croneedles.