Immunomodulatory effects of nanoparticles in a mouse model of skin allergy

Thesis (Ph. D.)--University of Rochester. Department of Biomedical Engineering, 2016.Topical treatments containing nanoparticles (NPs), also known as cosmeceuticals, is a fast growing market including products for hair damage, anti-wrinkle lotions, hyperpigmentation and photoaging and is expected to be valued at $31.84 billion by 2016. NPs incorporated in cosmeceuticals as well as drug delivery systems include liposomes, nanocapsules, lipid NPs, nanocrystals, dendrimers, nanogold, nanosilver, cubosomes, niosomes and fullerenes. The penetration of NPs through the skin is anticipated to depend on their physiochemical properties like size, shape, surface charge and composition as well as the skin barrier status. Understanding the factors that affect NP penetration through skin and their interaction with the cellular components in the epidermis and dermis are critical for the tailoring and design of NP-based topical and transdermal therapeutics. Various ex vivo and in vivo animal models have been used to quantify NP penetration, their systemic transport and immunomodulatory effects (direct immune suppression and targeted delivery). Skin is also the main route to allergen sensitization and provides innate as well as adaptive immune functions to maintain homeostasis. Skin antigen presenting cells (APCs) generate an adaptive immune response following allergen exposure as in the case of Allergic Contact Dermatitis (ACD), a type IV hypersensitivity response. Common ACD allergens include urushiol in poison ivy and nickel in jewelry. APCs sensitize effector CD4+ and CD8+ T cells in the lymph nodes against topical allergens at the point of first contact (sensitization phase) and a subsequent exposure can cause pruritic rash and/or swelling generated by the antigen-specific T cells (elicitation phase). Over 2800 chemicals have the potential to cause an allergic reaction in the skin and an estimated 15-20% of the population in North America suffers from contact allergy. The goal of the current treatment methods (steroids and antihistamines) is to reduce symptoms of ACD that include swelling, redness, barrier dysfunction, pruritus (itch), and induration (tissue hardening). Hence, there is an unmet need for an effective over-the-counter topical therapeutic for treating inflammatory skin conditions like ACD. In this thesis, we demonstrate through both ex vivo and in vivo skin models that several factors like application vehicles, skin processing conditions and exposure models can impact NP penetration through skin and their potential uptake by skin immune cells. We also discuss the development of a topical therapeutic containing NPs in a mouse model of ACD called Contact Hypersensitivity Response (CHS) model. We discovered that some NPs like gold NPs (AuNP), silver NPs (AgNP) and silica NPs (SiNP) have an intrinsic ability to suppress the inflammatory response in the elicitation phase of the allergic response with a common workplace sensitizer called dinitrofluorobenzene (DNFB). These NPs when applied within a 2 hour window of exposure to a chemical allergen (DNFB) reduce the influx of immune cells (neutrophils and T cells) and mitigate mast cell degranulation in the tissue that leads to an altered cytokine milieu thereby generating an immunosuppressive effect. These findings suggest an opportunity to develop an NP based therapeutic for treating/preventing skin allergies. Future studies seek to examine the extensibility of our findings to other Th1 and Th2 sensitizing agents like 2-deoxyurushiol and to develop a cellular and molecular level understanding of the immunosuppressive mechanism