Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.DOI: http://dx.doi.org/10.7554/eLife.27081.001

The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research.

A synthetic route for oxidation-sensitive core− multishell (osCMS) nanocarriers was established, and their drug loading and release properties were analyzed based on their structural variations. The nanocarriers showed a drug loading of 0.3−3 wt % for the anti-inflammatory drugs rapamycin and dexamethasone and the photosensitizer meso-tetra-hydroxyphenylporphyrin (mTHPP). Oxidative processes of the nanocarriers were probed in vitro by hydrogen peroxide, and the degradation products were identified by infrared spectroscopy supported by ab initio calculations, yielding mechanistic details on the chemical changes occurring in redox-sensitive nanocarriers. Oxidationtriggered drug release of the model drug Nile Red measured and assessed by time-dependent fluorescence spectroscopy showed a release of up to 80% within 24 h. The drug delivery capacity of the new osCMS nanocarriers was tested in ex vivo human skin with and without pretreatments to induce local oxidative stress. It was found that the delivery of mTHPP was selectively enhanced in skin under oxidative stress. The number and position of the thioether groups influenced the physicochemical as well as drug delivery properties of the carriers.

A synthetic route for redox-sensitive and non-sensitive core multi-shell (CMS) carriers with sizes below 20 nm and narrow molecular weight distributions was established. Cyclic voltammetric measurements were conducted characterizing the redox potentials of reduction-sensitive CMS while showcasing its reducibility through glutathione and tris(2-carboxyethyl)-phosphine as a proof of concept. Measurements of reduction-initiated release of the model dye Nile red by time-dependent fluorescence spectroscopy showed a pronounced release for the redox-sensitive CMS nanocarrier (up to 90% within 24 h) while the non-sensitive nanocarriers showed no release in PBS. Penetration experiments using ex vivo human skin showed that the redox-sensitive CMS nanocarrier could deliver higher percentages of the loaded macrocyclic dye meso-tetra (m-hydroxyphenyl) porphyrin (mTHPP) to the skin as compared to the non-sensitive CMS nanocarrier. Encapsulation experiments showed that these CMS nanocarriers can encapsulate dyes or drugs with different molecular weights and hydrophobicity. A drug content of 1 to 6 wt% was achieved for the anti-inflammatory drugs dexamethasone and rapamycin as well as fluorescent dyes such as Nile red and porphyrins. These results show that redox-initiated drug release is a promising strategy to improve the topical drug delivery of macrolide drugs.

A water-soluble, core-multishell (CMS) nanocarrier based on a new hyperbranched polyester core building block was synthesized and characterized towards drug transport and degradation of the nanocarrier. The hydrophobic drug dexamethasone was encapsulated and the enzyme-mediated biodegradability was investigated by NMR spectroscopy. The new CMS nanocarrier can transport one molecule of dexamethasone and degrades within five days at a skin temperature of 32˝C to biocompatible fragments.

Spin-labeling active compounds is a convenient way to prepare them for EPR spectroscopy with minimal alteration of the target molecule. In this study we present the labeling reaction of dexamethasone (Dx) with either TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or PCA (3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy) with high yields. According to NMR data, both labels are attached at the primary hydroxy group of the steroid. In subsequent spin-stability measurements both compounds were applied onto HaCaT cells. When the signal of Dx-TEMPO decreased below the detection limit within 3 h, the signal of Dx-PCA remained stable for the same period of time.

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