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Exploring mesoporous silica nanoparticle interaction with gastrointestinal mucus using Molecular dynamic simulations

Terrmin

HT25

Beskrivning

Aim
The aim of this project is to utilize molecular dynamic simulations to deepen our understanding of the interactions between mesoporous silica nanoparticles (MSNs) and gastrointestinal mucus. By leveraging this knowledge, we aim to facilitate effective particle transport through the mucus barrier, enhancing targeted oral drug delivery to reach underlying cellular targets.

Objectives
The project is divided into three key stages:
1. Development of a coarse-grained (CG) mucus model.
• Construct a CG model incorporating various mucins and other critical components, like lipids and peptides.
• Verify the network-forming capacity of the CG model while comparing its pore size and solid-fluid volume fractions with experimental data.
2. Model validation through FITC-Dextran Diffusion Studies.
• Utilize experimental data to validate the CG model by studying FITC-dextran diffusion within the mucus.
• Perform simulations to calculate diffusion coefficients and exponents, ensuring a comparison with experimental diffusion data for validation purposes.
3. Development of mesoporous silica nanoparticles.
• Model the structure of MSNs.
• Investigate MSN diffusion within the validated mucus model using simulations to gather insights into their transport dynamics.

Background
Advanced drug delivery systems with targeted and controlled release of novel therapies directly to diseased tissue present potential for effective precision treatment. However, a common challenge is nanoparticles becoming trapped in mucus, hindering diffusion to target ligands. By optimizing the characteristics of MSNs—such as size, shape, and surface chemistry—we aim to achieve improved permeability through the gastrointestinal mucus.
Drug delivery development often relies on costly and time-consuming trial-and-error experiments. Molecular dynamics simulations present an efficient alternative, offering insights into the structural characteristics, interactions, and behaviours of drug delivery systems. [1-2] However, traditional all-atom simulations are often to computational heavy for simulation of large biomolecular complexes such as nanoparticles. Instead, coarse grained simulations, which simplify the molecular system by reducing the degrees of freedom, are useful for studying these systems.[3]

Methods
The simulations in this project will be performed using the Gromacs software package, with the CG Martini3 force field applied for the coarse-graining process. To construct the mucin structures, we will obtain data from AlphaFold, followed by using the Martinize tool to create coarse-grained representations. FITC dextran will be modelled employing the Martini3 carbohydrate models to ensure an accurate representation of its properties. The mesoporous silica nanoparticles will be modelled following protocols developed by Becirt et al. [4]

Expected Results
The project aims to develop a validated coarse-grained mucus model that accurately reflects experimental properties, enabling reliable predictions of mesoporous silica nanoparticle behaviour. These simulations are expected to enhance our understanding of diffusion dynamics in the mucus, aiding in the optimization of drug delivery systems.

Huvudområde

Läkemedelsutveckling

Ämne

Läkemedelsformulering och Molekylär galenisk farmaci

Typ

Beräkningsstudie

Företag

Uppsala university

Ort/Plats

Uppsala

Handledarens namn

Shakhawath Hossain

Handledarens e-post

shakhawath.hossain@uu.se

Institution

Institutionen för farmaci

Program

Masterprogram i läkemedelsmodellering

Kurs

Degree Project in Pharmaceutical Modelling within Pharmaceutics and Biopharmaceutics 45 c - 3FG001

Omfattning/hp

45hp