Understanding interactions of proteins with polymer-coated nanoparticles

Introduction

Polymer-coated nanoparticles are promising drug delivery vehicles. Multiple functionalities can be embedded into the nanoparticle structure to enable uptake of the drug-like molecules, their targeted delivery and controlled release. We have recently developed a magnetic nanoparticle-based delivery system for therapeutic proteins [1]. The success of this strategy critically depends on the interactions between proteins and nanoparticles as they determine the efficiency of encapsulation and release. However this area remains underexplored. We know that proteins often nonspecifically adsorb on the nanoparticles forming so-called protein corona on their surface, and that interactions of proteins with charge-stabilised nanoparticles sometimes results in denaturation [2]. However, we don’t know the factors that determine the speed, strength and reversibility of binding of proteins to the neutral polymers on the nanoparticle surface.

Objectives

• Investigate the effect of protein size, charge and glycosylation state on the binding to polyamide-coated nanoparticles;
• Obtain quantitative data on the rate and reversibility of protein-nanoparticle interactions;
• Investigate how polyamide properties (chain length, surface coverage) affect protein binding.

Experimental approach

Two types of nanoparticles will be used: magnetic iron oxide (low cost, easy to separate magnetically) and gold (very inert, easy to functionalise). The nanoparticles will be coated with monodisperse polyacrylamide polymers that will be prepared by living polymerisation. The end groups of the polymers will be functionalised to ensure attachment to the nanoparticle surface. Interactions between these nanoparticles and a range of commercially available proteins with different size/charge/glycosylation will be investigated using several analytical methods, such as isothermal calorimetry, surface plasmon resonance, fluorescent spectroscopy. In order to obtain molecular-level information on binding, proteins will be spin-labelled with stable free radicals, and binding will be monitored using EPR spectroscopy.

Novelty

This project will yield unprecedented information about the molecular nature of protein-nanoparticle interactions. This will not only help design better drug delivery systems, but will also inform other biological and medicinal applications of nanoparticles.

Scientific training

The project is very interdisciplinary and will benefit from the combined complementary expertise of the supervisors in physical organic chemistry, nanoparticles, biochemistry. The supervisors have a strong track record of joint supervision of PhD students and will provide training in all areas of the project.

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