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Development of human artificial colonic mucus (HACM) for drug diffusion study with incorporation of extracellular DNA

Terrmin

HT24

Beskrivning

Aim
To select appropriate polymer for HACM formulation which mimics native human colonic mucus diffusivity properties
Background
Translation of in vitro research into in vivo clinical relevance is currently still an issue, with time and effort spent in drug discovery and pre-clinical step (Matthews et al. 2016). Development of efficient drug testing platform is necessary in accordance to ethical 3Rs principles and SDGs 2030 of UN. Among various gastrointestinal tract as target for oral drug delivery, the colon has biological properties which serves as hurdles for drug delivery system such as pH, transit time, colonic microbiota, and mucus barrier (Naeem et al. 2020). In this study, we would like to focus on the characteristics of mucus barrier which might influence drug diffusion. By establishing a relevant in vitro biosimilar mucus model for drug testing, a proper estimate of in vivo delivery system can be configured. Among major components of colonic mucus, the presence of extracellular DNA (exDNA) role in structural integrity has not been well elucidated. Several studies mentioned elevation of exDNA in the mucus during pathogenesis of various diseases, such as cystic fibrosis, however its effects on the drug diffusion still remains in question. This study also aims to understand the role of exDNA in colonic mucus barrier properties.
Methods
• Human Artificial Colonic Mucus prototypes formulation
• Testing of HACM viscosity & storage modulus with rheometer
• Permeability studies of several model drugs using Transwell / Snapwell
• Surface charge measurement using DLS
• Confocal microscopy of FRAP/MPT
• Cryo-SEM image acquisition and analysis
• ExDNA isolation and preparation
• pH meter and micro-osmometer
• Other prospective methods might be performed depending on research progress and time
• Opportunities to learn more about microbes, PK simulation and 3D-printing is also available
My task
- Literature study
- Write project plan and report
- Perform the experiments involving HACM synthesize, and evaluate with pH meter, micro-osmometer, rheometer, DLS, FRAP/MPT, plate reader, HPLC, UPLC-MS sample preparation and permeation studies in Transwell/Snapwell system
Expected results:
• Viscosity and storage modulus profile of HACM
• Surface charge profile of HACM
• Permeability profile of several drug compound
• Diffusion profile of several drug compound
• Established HACM as model for in vitro colonic drug testing
• Improved understanding whether exDNA is necessary for formulation or not

Huvudområde

Läkemedelsutveckling

Ämne

Läkemedelsformulering och Molekylär galenisk farmaci

Typ

Laborativ studie

Företag

Uppsala Universitet

Ort/Plats

Uppsala

Handledarens namn

Marco Tjakra

Handledarens e-post

marco.tjakra@farmaci.uu.se

Institution

Institutionen för farmaci

Program

Masterprogram i läkemedelsutveckling

Kurs

Degree project in Drug Discovery and Development 45 c -3FK044

Omfattning/hp

45hp