Elucidating the molecular architecture of the skin and plant leaves, novel insights into the in-situ permeation of formulations
Publication Date
July 24, 2024
Creator
Abstract
It is estimated, approximately $5.6 billion dollars is invested globally in agrochemicals to enhance crop yields and improve crop quality. This is achieved by controlling invasive species from competing with or damaging the desired crop. While this is has led to financial benefits to farmers, there is a significant gap in the knowledge surrounding the molecular compositions of skin and leaves. This significantly impacts the fundamental understanding and development of optimised foliar delivery of agrochemical products including mandatory risk assessments for exposure to agricultural workers.
To understand the dermal absorption of compounds, a comprehensive understanding of the molecular architecture of the skin, particularly the primary barrier, the stratum corneum, is necessary. The research detailed in this thesis employs the OrbiSIMS in conjunction with an Ar3000+ gas cluster ion beam (GCIB) to initially investigate the molecular chemistry of the stratum corneum. This exploration entails studying the non-homogeneity of the barrier layer in terms of depth and lateral distributions. Through in situ depth profiling and SIMS-MFP filtering of the dataset, the identification of over 140 species across five compound classes (amino acids, fatty acids, ceramides, phospholipids, and triglycerides) was achieved. Additionally, the chemical gradients of pivotal components involved in the cholesterol sulfate cycle, including the major fatty acid palmitic acid, were unveiled. Ultimately, the study demonstrated the permeation of an anti-aging peptide, Pal-GHK, through human skin at relatively low concentrations (100 ppm).
To address the limitations of conventional techniques used in evaluating agrochemical permeation into skin tissue, the OrbiSIMS was utilised to map the depth distribution of model agrochemical formulation, CCZ EC, simultaneously at application rates relevant to real-life conditions. The localisation of the active ingredient, cyproconazole, along with the co-formulants of the formulation, was illustrated as a function of depth at varying exposure levels within the layers of the skin.
Similar to the skin, there is limited knowledge available concerning the chemical composition of leaves, specifically the barrier layer known as, cutin. The limited understanding significantly affects the comprehension of product function and the development of optimized pesticide delivery systems. A thorough understanding of the molecular composition of leaves would also contribute to the formulation of more targeted pesticides with fewer adverse human health effects. Employing the recently developed OrbiSIMS profiling method, this study identified the in situ precise localisations of over 90 individual species across seven compound classes (amino acids, fatty acids, aldehydes, vitamins, flavones, nucleic acids, and phospholipids) within wheat leaves. Key fatty acids and aldehydes related to cutin and epicuticular waxes were identified, including flavones and vitamins relevant to the underlying epidermis. Subsequently, the CCZ EC model formulation was applied at a 1 % v/v dilution, representative of what is typically applied to crops, for various exposure times. The entirety of the formulation was successfully depicted in a label-free manner at a relatively low concentration, revealing intricate differences in permeation characteristics at different time points.
The Franz cell method has a relatively low throughput, to address this issue the dermal absorption of a model agrochemical formulation containing the three active ingredients mefenoxam, isopyrazam, and cyproconazole was effectively demonstrated. Highlighting varied levels of permeation attributed to their distinct physicochemical properties. Similarly, the limitations of the Franz cell methodology become apparent when the test compound remains undetectable within the skin tissue post-procedure, leading to inefficiencies and cost-ineffectiveness. Therefore, 20 active ingredients spanning the pharmaceutical, cosmetic, and agrochemical sectors were screened using the OrbiSIMS to evaluate the method's sensitivity across a range of different chemistries.
The insights gained from this work holds substantial implications for attaining more precision and optimisation in pesticide delivery into plant systems. Simultaneously, the research can aid in the generation of a refined understanding of exposure risks for agricultural workers. Comprehensive knowledge of the molecular architecture of the skin has the potential to enhance drug delivery and diagnostics. Similarly, insights into the molecular composition of leaves can contribute to the advancement of pesticide development, fostering more effective and targeted formulations.
Item Type
ethesis
Thesis Type
PhD
Subjects (LC)
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
78176
UoN Repository URI
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Thesis Mohammed Haroon Khan.pdf
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Examined. Re-Submission/Final Version
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