The native transportation protein serum albumin represents an attractive nano-sized transporter for drug delivery applications due to its beneficial safety profile. Existing albumin-based drug delivery systems are often limited by their low drug loading capacity as well as noticeable drug leakage into the blood circulation. Therefore, a unique albumin-derived core-shell doxorubicin (DOX) delivery system based on the protein denaturing-backfolding strategy was developed. 28 DOX molecules were covalently conjugated to the albumin polypeptide backbone via an acid sensitive hydrazone linker. Polycationic and pegylated human serum albumin formed two non-toxic and enzymatically degradable protection shells around the encapsulated DOX molecules. This core-shell delivery system possesses notable advantages, including a high drug loading capacity critical for low administration doses, a two-step drug release mechanism based on pH and the presence of proteases, an attractive biocompatibility and narrow size distribution inherited from the albumin backbone, as well as fast cellular uptake and masking of epitopes due to a high degree of pegylation. The IC50 of these nanoscopic onion-type micelles was found in the low nanomolar range for Hela cells as well as leukemia cell lines. In vivo data indicate its attractive potential as anti-leukemia treatment suggesting its promising profile as nanomedicine drug delivery system.
The ability of pathogenic staphylococci to form biofilms facilitates colonization and the development of chronic infections. Therapy is hampered by the high tolerance of biofilms towards antibiotic treatment and the immune system. We found evidence that lysogenic Staphylococcus aureus cells in a biofilm and in planktonic cultures spontaneously release phages into their surroundings. Phages were detected over a much longer period in biofilm cultures than in planktonic supernatants because the latter were degraded by secreted proteases. Phage release in planktonic and biofilm cultures was artificially increased by adding mitomycin C. Two morphologically distinct phages in the S. aureus strain used in this work were observed by electron microscopy. We postulate that phage-release is a frequent event in biofilms. The resulting lysis of cells in a biofilm might promote the persistence and survival of the remaining cells, as they gain a nutrient reservoir from their dead and lysed neighboring cells. This might therefore be an early differentiation and apoptotic mechanism.
A convenient approach for the synthesis of narrowly dispersed polypeptide copolymers of defined compositions is presented. The controlled denaturation of the proteins serum albumin and lysozyme followed by an in situ stabilization with polyethylene(oxide) chains yields polypeptide side chain copolymers of precisely defined backbone lengths as well as the presence of secondary structure elements. Supramolecular architectures are formed in solution because of the presence of hydrophobic and hydrophilic amino acids along the polypeptide main chain. Polypeptide copolymers reported herein reveal excellent solubility and stability in aqueous media and no significant cytotoxicity at relevant concentrations, and they can be degraded via proteolysis, which is very attractive for biomedical applications. This "semi-synthetic chemistry" approach is based on a novel and convenient concept for producing synthetic polypeptides from native protein resources, which complements traditional polypeptide synthesis and expression approaches and offers great opportunities for the preparation of diverse polypeptides with unique architectures.
Quantum dots (QDs) coated with an albumin-derived copolymer shell exhibit significant photoresponsiveness to DNA loading and have great potential for investigating gene delivery processes. The QDs reported herein are positively charged, have attractive optical properties, and are noncytotoxic and notably stable in live cells. Their complex formation with plasmid DNA leads to proportionally decreased photoluminescence and efficient gene transfection is observed. Therefore, they are suitable for live-cell bioimaging and mechanistic studies of nonviral gene delivery. Fluorescence correlation spectroscopy is applied for the first time to investigate individual QDs diffusing in large endosomes inside living cells, and serves as a valuable tool to study the physical properties of QDs inside live cells. The data obtained in this study strongly support the notable stability of these QDs, even in cell endosomes.
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