Using the interactions of designed siRNA and DNA drug carrier systems with human blood plasma and its components for controlled drug delivery
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Abstract
The development of nanomaterials for biomedical application has become of great interest in the last decades. Especially in cancer therapy, the encapsulation of drugs in a carrier provides many advantages over administering active ingredients only. The nanomaterials are designed to guide the anti-cancer drug specifically to the tumor tissue. This way, the cytotoxic side effects that occur during chemotherapy can be reduced. In addition, the active compound itself can be protected from degradation.
But still, the application of nanomaterials in cancer treatment is limited due to some drawbacks in understanding and foreseeing the physiological responses a nanocarrier induces upon administration. So far, nanocarriers are usually applied intravenously. This means, that the carrier system immediately comes into contact with the human blood and the therein dissolved proteins. This results in the rapid formation of a protein corona on the nanomaterial´s surface that alters its chemical and physical properties in a significant manner.
In this study, the influence of single proteins as well as protein mixtures on the physicochemical properties of polystyrene particles as a model system is investigated. The single proteins as well as protein mixtures that are exempted from the most abundant proteins albumin and immunoglobulin G were obtained from the fractionation of human blood plasma. Incubation of the respective particles in defined protein fractions was used to form predetermined protein coronas that were further investigated in regards of stabilizing or destabilizing effects on a particle under in vivo conditions using dynamic light scattering. In addition, the effect of a given protein corona on cellular uptake by macrophages was monitored. This way, the possibility of stabilizing particles against aggregation via pre-coating was introduced.
The concept of pre-coating nanomaterials for tailoring their stability against aggregation was broadened in order to overcome the difficulties that occur because of a fluctuation in the blood serum proteome composition among different individuals.
Next, the focus was put on the transferability of different in vivo animal models to humans. It turned out, that the stability of polystyrene as well as dextran- and starch-coated particles against aggregation strongly depends on the protein source.
After screening the mentioned factors that influence the protein corona formation by the use of polystyrene particles as a model system, liposomes for siRNA delivery to the liver have been investigated and optimized regarding their stability against aggregation.
In summary, the closer look that is taken on the different factors that influence the physicochemical properties of a nanomaterial after exposure to human blood offers several opportunities of pre-in vivo screening methods for novel nanomaterials. In addition, it introduces possible ways of how the interactions between nanomaterials and proteins can be used for stabilization against aggregation.