Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin

Edlich, Alexander; Gerecke, Christian; Giulbudagian, Michael; Neumann, Falko; Hedtrich, Sarah; Schäfer‐Korting, Monika; Ma, Nan; Calderón, Marcelo; Kleuser, Burkhard

doi:10.1016/j.ejpb.2016.12.016

Cited by 23 publications

(15 citation statements)

References 44 publications

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“…Though we saw no robust evidence of tNG penetration past the SC in our skin equivalents at our tested time-points and concentrations, there is some evidence that this may be possible in ex vivo human skin, and that very small amounts of tNGs are actively taken up by dendritic cells of the VE, something that could prove valuable to the treatment of inflammatory skin diseases. 62 , 63 …”

Section: Resultsmentioning

confidence: 99%

“…To date, it has been shown that both tNG_pNIPAM and tNG_tPG induce no specific toxicity in murine LC's or human keratinocytes. 63 , 64 However, a lack of cytotoxicity does not exclude immunogenicity. Though nanoparticle induced immunogenicity is desirable in certain instances -vaccine formulations for example 65 , 66 - further immune cell activation in inflammatory skin diseases is not.…”

Section: Resultsmentioning

confidence: 99%

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Breaking the Barrier - Potent Anti-Inflammatory Activity following Efficient Topical Delivery of Etanercept using Thermoresponsive Nanogels

et al. 2018

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Topical administration permits targeted, sustained delivery of therapeutics to human skin. Delivery to the skin, however, is typically limited to lipophilic molecules with molecular weight of < 500 Da, capable of crossing the stratum corneum. Nevertheless, there are indications protein delivery may be possible in barrier deficient skin, a condition found in several inflammatory skin diseases such as psoriasis, using novel nanocarrier systems.Methods: Water in water thermo-nanoprecipitation; dynamic light scattering; zeta potential measurement; nanoparticle tracking analysis; atomic force microscopy; cryogenic transmission electron microscopy; UV absorption; centrifugal separation membranes; bicinchoninic acid assay; circular dichroism; TNFα binding ELISA; inflammatory skin equivalent construction; human skin biopsies; immunohistochemistry; fluorescence microscopy; western blot; monocyte derived Langerhans cells; ELISAResults: Here, we report the novel synthesis of thermoresponsive nanogels (tNG) and the stable encapsulation of the anti-TNFα fusion protein etanercept (ETR) (~150 kDa) without alteration to its structure, as well as temperature triggered release from the tNGs. Novel tNG synthesis without the use of organic solvents was conducted, permitting in situ encapsulation of protein during assembly, something that holds great promise for easy manufacture and storage. Topical application of ETR loaded tNGs to inflammatory skin equivalents or tape striped human skin resulted in efficient ETR delivery throughout the SC and into the viable epidermis that correlated with clear anti-inflammatory effects. Notably, effective ETR delivery depended on temperature triggered release following topical application.Conclusion: Together these results indicate tNGs hold promise as a biocompatible and easy to manufacture vehicle for stable protein encapsulation and topical delivery into barrier-deficient skin.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Breaking the Barrier - Potent Anti-Inflammatory Activity following Efficient Topical Delivery of Etanercept using Thermoresponsive Nanogels

et al. 2018

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“…dPG-PNIPAM nanogels showed to be uptaken by HaCaT and NHK cells through endocytosis, and localize predominantly within lysosomal compartments [ 47 ]. Moreover, we demonstrated with dendritic cells that polyglycerol-based thermoresponsive nanogels experience a shift in the specific uptake pathway, depending on if the nanogels are on the swelling or in the shrunken state (below or above the VPTT) [ 51 ]. The study points to caveolae-mediated endocytosis as being the major uptake mechanism at 37 °C, which is above the VPTT of the nanogels.…”

Section: Discussionmentioning

confidence: 99%

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Winter

Navarro

et al. 2020

Cancers

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Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.

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“…More specifically, nanogels are soft when applied on skin surface and can penetrate deep in the stratum corneum (SC), where local temperature increase induces a change of conformation that results in the release of the incorporated active compound. The investigated nanogels were shown to enhance SC hydration [21,22,23] and exhibited promising drug delivery properties [24] along with low cytotoxicity [25,26].…”

Section: Introductionmentioning

confidence: 99%

Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels

et al. 2019

Self Cite

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Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.

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Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin

Cited by 23 publications

References 44 publications

Breaking the Barrier - Potent Anti-Inflammatory Activity following Efficient Topical Delivery of Etanercept using Thermoresponsive Nanogels

Breaking the Barrier - Potent Anti-Inflammatory Activity following Efficient Topical Delivery of Etanercept using Thermoresponsive Nanogels

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels

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