Graduation Date

Summer 8-18-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Psoriasis is a chronic inflammatory skin disease that is often associated with systemic comorbidities and impaired skin barrier function. There are several treatment options including topical treatment with immunosuppressants, phototherapy, and systemic therapies using small molecules and biological agents. However, none of them can be regarded as a perfect solution due to their toxicity during chronic use. Recently, the CXCR4/SDF-1 axis was found to play an important role in the pathogenesis of psoriasis. AMD3100, a small molecule CXCR4 antagonist can selectively bind to CXCR4 and inhibit skin inflammation, reduce angiogenesis and infiltration of inflammatory cells. Unfortunately, AMD3100 can only be administered systemically.

In this study, we aimed to develop CXCR4 inhibitor that can be applied topically in psoriasis as a way of reducing overall systemic toxicity of CXCR4 inhibition. We developed PAMD, a polycation based on AMD3100, as a topical drug to treat psoriasis. PAMD offers a great platform for chemical modification, drug combination, and the ability to form nanocarriers. Psoriasis is a skin disease therefore, it is desirable to deliver PAMD via a topical route to target the disease locally and improve safety and patient compliance. Stratum corneum (SC) is the foremost layer of skin, which acts as the main barrier to protect internal organs and limit the delivery of most drug molecules. Various attempts have been reported to increase skin penetration, including both passive and active iv methods. The mechanism of skin absorption is dependent on size, charge, and partition coefficients of the penetrant.

Based on previous reports on the role of hydrophobicity and charge on skin penetration of polymers, our approach relied on modifying the PAMD with citraconic anhydride for a negative charge and oleic acid for lipophilicity. The best performing negatively charged PAMD demonstrated low toxicity in HaCaT cells in vitro, and high retention and deep penetration in both healthy and psoriatic skin models. The favorable level of penetration may be due to the acidic skin environment and the intercellular transportation within SC, facilitated by the attraction of the polymer and diffusion respectively. IMQ-induced psoriasis mouse model was attenuated by a topical application of PAMD, PAMD.COO-, and subcutaneous injection of AMD3100. This observation provided evidence supporting that blockade of CXCR4/SDF-1 cascade reduces skin inflammation related to the decreased mRNA levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. The topical application of CXCR4 antagonistic polymers exhibited comparable in vivo therapeutic effects as systemic administration of AMD3100. Moreover, the penetration of the polymer had no influence on anti-psoriatic activity in mice.

Available for download on Thursday, August 08, 2019

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