title: Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing.
abstract: 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.
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hönzke
authors.affiliation: Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gerecke
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Elpelt
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Unbehauen
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Vivian
authors.initials: V
authors.lastname: Kral
authors.affiliation: DendroPharm GmbH, Berlin, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Fleige
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Paulus
authors.affiliation: Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.affiliation: Institute of Nutritional Science, Department of Toxicology, University of Potsdam, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany. Electronic address: sarah.hedtrich@fu-berlin.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hedtrich
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D050091:Dendrimers / Q000737:chemistry*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D053758:Nanoparticles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D012871:Skin Diseases / Q000188:drug therapy / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D050091:Dendrimers; D004337:Drug Carriers; D011108:Polymers; C043941:polyglycerol; D011092:Polyethylene Glycols; D003907:Dexamethasone; C028210:monomethoxypolyethylene glycol; D005990:Glycerol
keywords: Biocompatibility; Dendritic core-multishell nanocarriers; Dermal drug delivery; Dexamethasone; Inflammatory skin disease; Skin model