Redox-Responsive Nanocarrier for Controlled Release of Drugs in Inflammatory Skin Diseases

Abstract

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.

Novel Adhesive Nanocarriers Based on Mussel-Inspired Polyglycerols for the Application onto Mucosal Tissues

“…As the amount of naturally dissolvable NR is negligible, 1% is essentially the amount of encapsulated NR. A drug concentration of 1 wt% was found in all NR-loaded CMS nanocarriers, which correlates with the drug loading of nanocarriers with similar structures [ 42 , 43 ].…”

Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model

“…For the rsCMS0 carrier, similar drug loading was reached with all methods. Effects of the different drug loading methods were studies using the model drugs Pheophorbide A and meso-tetra (m-hydroxyphenyl) porphyrin and are described in Rajes et al 30 In the present study, Rapa was loaded on the nanocarriers by horn sonication of the CMS carrier stock solution in the presence of 50 wt% Rapa. To remove non-encapsulated drug, the suspension was centrifuged at 570 × g and the supernatant kept.…”

“…The detailed synthesis of rsCMS and osCMS nanocarriers is reported in previous publications. 30 , 31 Briefly, the CMS nanocarriers investigated in this study were prepared as follows: The rsCMS0 was synthesized by oxidating mercaptoundecanoic acid to disulfanediyldiundecanoic acid. This was then reacted with methoxy poly (ethylene glycol) amine through peptide coupling.…”

“…To remove non-encapsulated drug, the suspension was centrifuged at 570 × g and the supernatant kept. The drug loading was measured by HPLC as described previously 30 and was approximately 5 wt% for both nanocarriers. For skin penetration experiments, the CMS nanocarriers were loaded with the fluorescent dye Atto Oxa12 NHS ester (AttoOxa, ATTO-TEC, Siegen, Germany).…”

“…The core of these CMS nanocarriers is a hyperbranched polyglycerol, whereas the inner shell is given by linear disulfide or thioether chains and the outer shell is formed by methoxy poly (ethylene glycol) groups. The rsCMS nanocarriers were prepared by introducing disulfide groups in the inner shell, 30 while thioether groups were inserted to obtain the osCMS nanocarriers. 31 The rsCMS nanocarriers have been shown to release the loaded cargo upon partial degradation following the reaction of free thiol groups (like glutathione) with the disulfide groups.…”