Abstract
Dye-loaded micelles of 10 nm diameter formed from amphiphilic graft copolymers composed of a hydrophobic poly(methyl methacrylate) backbone and hydrophilic poly(2-ethyl-2-oxazoline) side chains with a degree of polymerization of 15 were investigated concerning their cellular interaction and uptake in vitro as well as their interaction with local and circulating cells of the reticuloendothelial system in the liver by intravital microscopy. Despite the high molar mass of the individual macromolecules (Mn ≈ 20 kg mol-1), backbone end group modification by attachment of a hydrophilic anionic fluorescent probe strongly affected the in vivo performance. To understand these effects, the end group was additionally modified by the attachment of four methacrylic acid repeating units. Although various micelles appeared similar in dynamic light scattering and cryo-transmission electron microscopy, changes in the micelles were evident from principal component analysis of the Raman spectra. Whereas an efficient stealth effect was found for micelles formed from polymers with anionically charged or thiol end groups, a hydrophobic end group altered the micelles' structure sufficiently to adapt cell-type specificity and stealth properties in the liver.
Highlights
Targeting drugs to a desired tissue or cell-type is a common goal of modern pharmaceutical approaches
We identified a graft copolymer composed of 90 mol % of methyl methacrylate (MMA) and 10 mol % of EtOx15MA (P5) as an optimum for micellar encapsulation of the hydrophobic dye Disperse Orange 3.37 This statistical copolymer was selected as a potential micellar drug carrier to investigate their cell-type specificity in the liver
An efficient stealth effect introduced by a dense layer of multiple short OEtOx chains around a hydrophobic PMMA core was evident from a strongly reduced uptake of very small micelles in Kupffer cells
Summary
Targeting drugs to a desired tissue or cell-type is a common goal of modern pharmaceutical approaches. Carriers are used which employ active, passive, or a combination of both targeting strategies to enrich their payload in the desired environment.[1] For the encapsulation and the controlled release of numerous small molecules, polymeric drug carrier systems represent attractive vehicles for tissue-specific drug delivery.[2] Nanocarriers such as micelles below 50 nm in diameter were reported to be preferable in the use of tumor treatment.[3] Their small size leads to favorable tissue penetration properties, which allows them to reach even poorly perfused tissue, e.g., hypoxic tumor areas. The RES triggers an inflammatory response which decreases the effectiveness of further nanoparticle-based drug applications due to the generation of specific antibodies against these carriers.[5]
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