Polymeric micelles are ideal carriers for solubilization and targeting applications using hydrophobic drugs. Stability of colloidal aggregates upon injection into the bloodstream is mandatory to maintain the drugs' targeting potential and to influence pharmacokinetics. In this review we analyzed and discussed the most relevant stress mechanisms that polymeric micelles and related colloidal carriers encounter upon injection, including (1) dilution, (2) interactions with blood components, and (3) immunological responses of the body. In detail we analyzed the opsonin-dysopsonin hypothesis that points at a connection between a particles' protein-corona and its tissue accumulation by the enhanced permeability and retention (EPR) effect. In the established theory, size is seen as a necessary condition to reach nanoparticle accumulation in disease modified tissue. There is, however, mounting evidence of other sufficient conditions (e.g., particle charge, receptor recognition of proteins adsorbed onto particle surfaces) triggering nanoparticle extravasation by active mechanisms. In conclusion, the analyzed stress mechanisms are directly responsible for in vivo success or failure of the site-specific delivery with colloidal carrier systems.
Superparamagnetic iron oxide nanoparticles (SPIONs) used as MRI contrast agents or for theranostic applications encounter a complex mixture of extracellular proteins that adsorb on the SPION surface forming a protein corona. Our goal was to understand how cellular binding and T2 relaxation times are affected by this protein corona. Our studies focused on carboxymethyl dextran-modified SPIONs, chosen for their similarity to Resovist SPIONs used to detect liver lesions. Using a combination of fluorescence microscopy and flow cytometry, we find that the cellular binding of SPIONs to both macrophages and epithelial cells is significantly inhibited by serum proteins. To determine if this decreased binding is due to the iron oxide core or the carboxymethyl dextran surface coating, we functionalized polystyrene nanoparticles with a similar carboxymethyl dextran coating. We find a comparable decrease in cellular binding for the carboxymethyl dextran-polystyrene nanoparticles indicating that the carbohydrate surface modification is the key factor in SPION-cell interactions. NMR measurements showed that T2 relaxation times are not affected by corona formation. These results indicate that SPIONs have a decreased binding to cells under physiological conditions, possibly limiting their use in theranostic applications. We expect these results will be useful in the design of SPIONs for future diagnostic and therapeutic applications.
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