This thesis summarizes the research conducted in the field of core-multishell nanocarriers for the application in dermal drug delivery. While the CMS nanocarrier as a platform for drug delivery has been established by several publications, the goal of my thesis was to specialize the CMS nanocarrier as a bioresponsive nanocarrier for applications in the skin. The skin is a yet poorly characterized biological environment regarding its chemistry, especially in the state of disease. However, the penetration and successful delivery of the fluorescent model drug nile red into deeper skin layers, compared to a standard nile red cream, has been stated in a previous study. The increased penetration was the starting point for the general hypothesis on the CMS nanocarrier being a potential drug delivery platform. However, the fate of the nanocarrier inside the skin was identified as a potential toxicity issue. Hence, the first project of this PhD work aimed at establishing a biodegradable CMS nanocarrier. Based on a diacid and a triol, a hyperbranched polyester as the core molecule of a CMS nanocarrier was synthesized and used as a macroiniiator for the ring-opening polymerization of Epsilon-caprolactone. Surrounded by a water-soluble mPEG outer shell, this nanocarrier showed a complete enzymatic degradation in seven days, while surprisingly, hydrolysis of the ester-based CMS nanocarrier did not take place under physiologically relevant conditions. The low molecular weight of the core molecule and the low branching of the resulting CMS nanocarrier are hypothesized to be the reason for the poor drug loading capacity of this biodegradable nanocarrier. Aiming at the redox-barrier of skin, we hypothesized the natural gradient of reductants and oxidants in the skin to be a suitable trigger for stimulus-initiated release of drugs at sites of inflammation. A complementary set of a reduction-sensitive and an oxidationsensitive CMS nanocarrier has been synthesized. Based on a hyperbranched polyglycerol as a core building block, and a water-soluble mPEG outer shell, the alkyl inner shell contained either a disulfide moiety, or a thioether moiety. The reduction-sensitive disulfide-containing rsCMS and its oxidation-sensitive thioether-containing osCMS counterpart were tested for the triggered release of the encapsulated dye nile red in vitro. A physiologically relevant concentration of 10 mM GSH was not able to trigger a fast release of NR, possibly due to the limited reduction capacity of GSH in the absence of redox-mediating enzymes. However, the reductant TCEP led to 90 % release in 24 h. The incubation of osCMS with 1 % H2O2 triggered a sustained release of 80 % NR over the same period. Skin penetration experiments of NR@rsCMS on ex vivo human skin supported our hypothesis on the natural GSH gradient in the skin. Also, the synthesis of an EPR-labelled dexamethasone was established, and the PCA-labelled version will be used in future studies on the distribution of ROS in skin as the trigger for stimulated release of drugs from osCMS.
