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The topical application of drugs allows for a local application in skin disease and can reduce side effects. Here we present biodegradable core-multishell (CMS) nanocarriers which are composed of a hyperbranched polyglycerol core functionalized with diblock copolymers consisting of polycaprolactone (PCL) and poly(ethylene glycol) (mPEG) as the outer shell. The anti-inflammatory drug Dexamethasone (Dexa) was loaded into these CMS nanocarriers. DLS results suggested that Dexa loaded nanoparticles mostly act as a unimolecular carrier system. With longer PCL segments, a better transport capacity is observed. In vitro skin permeation studies showed that CMS nanocarriers could improve the Nile red penetration through the skin by up to 7 times, compared to a conventional cream formulation. Interestingly, covalently FITC-labeled CMS nanocarriers remain in the stratum corneum layer. This suggests the enhancement is due to the release of cargo after being transported into the stratum corneum by the CMS nanocarriers. In addition, the hPG-PCL-mPEG CMS nanocarriers exhibited good stability, low cytotoxicity, and their production can easily be scaled up, which makes them promising nanocarriers for topical drug delivery., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Drug loaded dendritic core-multishell (CMS) nanocarriers are of especial interest for the treatment of skin diseases, owing to their striking dermal delivery efficiencies following topical applications. CMS nanocarriers are composed of a polyglycerol core, connected by amide-bonds to an inner alkyl shell and an outer methoxy poly(ethylene glycol) shell. Since topically applied nanocarriers are subjected to biodegradation, the application of conventional amide-based CMS nanocarriers (10-A-18-350) has been limited by the potential production of toxic polyglycerol amines. To circumvent this issue, three tailored ester-based CMS nanocarriers (10-E-12-350, 10-E-15-350, 10-E-18-350) of varying inner alkyl chain length were synthesized and comprehensively characterized in terms of particle size, drug loading, biodegradation and dermal drug delivery efficiency. Dexamethasone (DXM), a potent drug widely used for the treatment of inflammatory skin diseases, was chosen as a therapeutically relevant test compound for the present study. Ester- and amide-based CMS nanocarriers delivered DXM more efficiently into human skin than a commercially available DXM cream. Subsequent in vitro and in vivo toxicity studies identified CMS (10-E-15-350) as the most biocompatible carrier system. The anti-inflammatory potency of DXM-loaded CMS (10-E-15-350) nanocarriers was assessed in TNFα supplemented skin models, where a significant reduction of the pro-inflammatory cytokine IL-8 was seen, with markedly greater efficacy than commercial DXM cream. In summary, we report the rational design and characterization of tailored, biodegradable, ester-based CMS nanocarriers, and their subsequent stepwise screening for biocompatibility, dermal delivery efficiency and therapeutic efficacy in a top-down approach yielding the best carrier system for topical applications., (Copyright © 2016 Elsevier B.V. All rights reserved.)