Nano-Shells and Stealth

The mononuclear phagocyte system is a system of phagocytic components which recognise, capture and remove foreign material from the body. Circulatory monocytes and fixed tissue macrophages (e.g. Kupffer cells) remove drug delivery systems from the bloodstream before degradation within macrophage-rich organs such as the liver, spleen and bone marrow. A reduction in phagocytic cell interaction increases the circulation time of the delivery system; a prerequisite for site specific drug accumulation.

The physicochemical properties of the nanocarrier e.g. surface charge, size, morphology and hydrophobicity/hydrophilicity determines the interaction with cells. Surface modification with hydrophilic polymers (surface engineered nanocarrier) can be used to render the nanocarrier non-recognisable (stealth-like) to phagocytic cell capture resulting in prolonged circulation time within the bloodstream.

 


By Morten Ebbesen

 

The schematic shows non-modified particles being captured by macrophage cells by a direct or protein-mediated (opsonisation) process. Steric hindrance by the hydrophilic polymer on the stealth system interupts these processes. Incorporation of ligands onto the nanocarrier surface can be used to redirect uptake into target cells.

 

 

 

 

 

 

Nano-shells and Surface Characterisation

Hydrophilic polymers such as poly (ethylene glycol) (PEG) have been frequently used to modify the surface of drug delivery vehicles, and to create a “stealth-like” nano-shell coat that reduces the MPS interaction. This is achieved through a) shielding of particle characteristics such as hydrophobicity and surface charge and b) creating a polymeric steric barrier for reducing protein opsonin adsorption. The effect of different PEG molecular weights, grafting method and densities has been studied; however, many studies rely on light scattering and light/electron microscopy for evaluating particle surface properties.

Different particle coatings with hydrophilic polymers such as pHPMA and PEG are carried out on model fluorescent polystyrene particles of different sizes and optimised with respect to the coating chemistry, composition, density and architecture. This is achieved using different aqueous conjugation techniques including “click” chemistry. Redox or enzymatic labile spacers will be built into the polymer design to facilitate site specific targeting.

Detailed surface characterization is important, and our approach is to use this to provide the basis for evaluating the interaction between particle surface and environment. Techniques such as XPS and ToF-SIMS, housed within the iNANO Center, give information about the elemental composition and chemical state of the particle surface, providing the relevant specificity and sensitivity for evaluating true coating characteristics.

Biological barriers to particle circulatory half-life are investigated in primary macrophages and protein adsorption determined by gel electrophoresis and MALDI-ToF analysis. Biodistribution is evaluated in murine models using the IVIS bioimager.

 

 By Morten Ebbesen

 

Defined polymer coats to investigate polymer properties and optimise nanoparticle performance.

Modification of surface architecture by varying graft density and molecular weight (blue) and mono or multivalent attachment (green) and incorporation of functional groups (red) influence cellular and protein interactions (yellow).

 

 

 

 

 

 

 

Collaborators:

David Oupicky, Department of Pharmaceutical Sciences, University of Nebraska Medical Center

Allan Hoffman, University of Washington

Moein Moghimi, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen

Dan Peer, Department of Cell Research & Immunology, Tel Aviv University

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