Date of Award

2024-12-01

Degree Name

Doctor of Philosophy

Department

Biomedical Engineering

Advisor(s)

Thomas Boland

Abstract

Continuous overactivation of myofibroblasts leads to excessive deposition of profibrotic proteins, which in turn causes tissue stiffness and, ultimately, organ failure. One of those proteins, Cadherin-11 (CDH11), is reported to be overexpressed in the tissue of fibrotic skin, specifically on myofibroblasts. Similarly, chronic inflammation drives fibrosis progression in autoimmune-related illnesses like systemic sclerosis (SSc). Therefore, it is hypothesized that CDH11 could be a target for cell-specific delivery of antifibrotic therapies to fibrotic skin tissue. Here, a CDH11 peptide conjugated liposome loaded with Tofacitinib, a JAK inhibitor, was developed to understand the potential of targeted therapies to treat skin fibrosis. The physical characterization of the developed LPS was evaluated and analyzed for their therapeutic efficacy in vitro using dermal fibroblasts and in vivo using a skin fibrosis mouse model. The findings from the experiments confirmed that CDH11 targeted LPS have specificity for myofibroblasts, enhancing the cellular internalization of tofacitinib-loaded LPS in fibrotic cells and tissue, and demonstrated downstream effects inhibiting fibrotic disease progression. The research work here represents a novel LPS delivery approach exhibiting promising potential to treat skin fibrosis.

Language

en

Provenance

Recieved from ProQuest

File Size

71 p.

File Format

application/pdf

Rights Holder

Elfa Beaven

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