Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing

Hönzke, Stefan; Gerecke, Christian; Elpelt, Anja; Zhang, Nan; Unbehauen, Michael; Kral, Vivian; Fleige, Emanuel; Paulus, Florian; Haag, Rainer; Schäfer‐Korting, Monika; Kleuser, Burkhard; Hedtrich, Sarah

doi:10.1016/j.jconrel.2016.06.030

Cited by 36 publications

(36 citation statements)

References 64 publications

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“…By cleavage at the inter-shell site, this signal will lose intensity. The results of this analysis are plotted in Figure 6 and complement a previous study examining the degradation of the nanocarriers by skin lysate [22]. The graph shows degradation of more than 70% of all ester groups for all carriers after six days.…”

Section: Enzymatic Degradation Of Unloaded Carrierssupporting

confidence: 74%

“…Complementary to a previous biological study [22], here we present esterification as a promising alternative to amide formation for the synthesis of the CMS nanocarriers. Furthermore, the influence of different chain length, branching of inner shell, the type of chemical bond on melting point, and drug loading behavior of dexamethasone and tacrolimus are investigated.…”

Section: Introductionmentioning

confidence: 89%

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Biodegradable Core–Multishell Nanocarriers: Influence of Inner Shell Structure on the Encapsulation Behavior of Dexamethasone and Tacrolimus

et al. 2017

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Abstract:We here present the synthesis and characterization of a set of biodegradable core-multishell (CMS) nanocarriers. The CMS nanocarrier structure consists of hyperbranched polyglycerol (hPG) as core material, a hydrophobic (12,15,18,19, and 36 C-atoms) inner and a polyethylene glycol monomethyl ether (mPEG) outer shell that were conjugated by ester bonds only to reduce the toxicity of metabolites. The loading capacities (LC) of the drugs, dexamethasone and tacrolimus, and the aggregate formation, phase transitions, and degradation kinetics were determined. The intermediate inner shell length (C15) system had the best overall performance with good LCs for both drugs as well as a promising degradation and release kinetics, which are of interest for dermal delivery.

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Section: Enzymatic Degradation Of Unloaded Carrierssupporting

confidence: 74%

Section: Introductionmentioning

confidence: 89%

Biodegradable Core–Multishell Nanocarriers: Influence of Inner Shell Structure on the Encapsulation Behavior of Dexamethasone and Tacrolimus

et al. 2017

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“…19 For electron paramagnetic resonance (EPR), 3-carboxy-2,2,5,5-t etramethyl-1-pyrrolidinyloxy (PCA)-labeled Dx loaded on to a newer generation of CMS nanocarrier, which contains an ester bond instead of the amide bond (CMS E-15-350) but influences skin keratinocytes in a similar way as the amide-CMS nanocarrier. 20 Dx is a widely applied topical drug for the treatment of mucosal and skin inflammatory diseases. The attempt of this study was to show drug release from nanocarriers into oral mucosal tissues and, therefore, Dx was chosen to gain information according to earlier findings for skin tissue samples.…”

Section: Reagentsmentioning

confidence: 99%

Characterization of hyperbranched core‐multishell nanocarriers as an innovative drug delivery system for the application at the oral mucosa

Jäger

Obst

Lohan

et al. 2017

J of Periodontal Research

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Background and Objectives In the oral cavity, the mucosal tissues may develop a number of different pathological conditions, such as inflammatory diseases (gingivitis, periodontitis) and autoimmune disorders (eg, oral lichen planus) that require therapy. The application of topical drugs is one common therapeutic approach. However, their efficacy is limited. Dilution effects due to saliva hinder the adherence and the penetration of drug formulations. Therefore, the bioavailability of oral topical drugs is insufficient, and patients may suffer from disease over years, if not life‐long. Material and Methods In the present study, we characterized core‐multishell (CMS) nanocarriers for their potential use as drug delivery systems at oral mucosal tissues. For this purpose, we prepared porcine masticatory as well as buccal mucosa and performed Franz cell diffusion experiments. Penetration of fluorescently labeled CMS nanocarriers into the mucosal tissue was analyzed using confocal laser scanning microscopy. Upon exposure to CMS nanocarriers, the metabolic and proliferative activity of gingival epithelial cells was determined by MTT and sulforhodamine B assays, respectively. Results Here, we could show that the carriers penetrate into both mucosal tissues, while particles penetrate deeper into the masticatory mucosa. Electron paramagnetic resonance spectroscopy revealed that the 3‐carboxy‐2,2,5,5‐tetramethyl‐1‐pyrrolidinyloxy‐labeled glucocorticoid dexamethasone loaded on to the CMS nanocarriers was released from the carriers in both mucosal tissues but with a higher efficiency in the buccal mucosa. The release from the nanocarriers is in both cases superior compared to the release from a conventional cream, which is normally used for the treatment of inflammatory conditions in the oral cavity. The CMS nanocarriers exhibited neither cytotoxic nor proliferative effects in vitro. Conclusion These findings suggested that CMS nanocarriers might be an innovative approach for topical drug delivery in the treatment of oral inflammatory diseases.

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“…Although the importance of these studies is undoubted, the next step must be the assessment of the actual value of organ models for in vitro drug testing including the identification of valid readout parameters, definition of their limitations, and rigorous comparison against the relevant in vivo situation. So far, only a handful of studies have performed drug testing in skin models, and of these, only 1-2 drugs were included [56][57][58][59][60], the experimental settings varied significantly between them, and the choices of readout parameters have not been sufficiently justified.…”

Section: Current Applications Of Human-based Test Models In Pharmacolmentioning

confidence: 99%

3D organ models—Revolution in pharmacological research?

Weinhart

Hocke

Hippenstiel

et al. 2019

Pharmacological Research

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A B S T R A C T 3D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue models have been developed. In parallel, microfluidic organ-on-a-chip tissue cultures have gained increasing interest for their ability to house several organ models on a single device and interlink these within a human-like environment. In contrast to these advancements, the development of human disease models is still in its infancy. Although major advances have recently been made, efforts still need to be intensified. Human disease models have proven valuable for their ability to closely mimic disease patterns in vitro, permitting the study of pathophysiological features and new treatment options. Although animal studies remain the gold standard for preclinical testing, they have major drawbacks such as high cost and ongoing controversy over their predictive value for several human conditions. Moreover, there is growing political and social pressure to develop alternatives to animal models, clearly promoting the search for valid, cost-efficient and easy-to-handle systems lacking interspecies-related differences.In this review, we discuss the current state of the art regarding 3D organ as well as the opportunities, limitations and future implications of their use.

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Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing

Cited by 36 publications

References 64 publications

Biodegradable Core–Multishell Nanocarriers: Influence of Inner Shell Structure on the Encapsulation Behavior of Dexamethasone and Tacrolimus

Biodegradable Core–Multishell Nanocarriers: Influence of Inner Shell Structure on the Encapsulation Behavior of Dexamethasone and Tacrolimus

Characterization of hyperbranched core‐multishell nanocarriers as an innovative drug delivery system for the application at the oral mucosa

3D organ models—Revolution in pharmacological research?

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