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.

Keywords: CMS nanocarriers; anti-inflammatory drugs; cyclic voltammetry; dexamethasone; disulfide; rapamycin; redox; skin penetration; stimuli responsive.

Scheme 1

Synthesis of redox-sensitive CMS (rsCMS) 1a and non-redox sensitive nanocarrier (ccCMS) 1b. The following conditions were used: (i) NEt₃, MsCl, CH₂Cl₂, 0 °C– room temperature (r.t.), 17 h, (ii) NH₃ (25%) aq, 2 d, (iii) NaOH, I₂, KI, MeOH, 17 h, r.t., (iv) PEG₇₅₀-NH₂, bulk, high vacuum, 120 °C, 3 h, (v) (1) N-hydroxysuccinimide, ethyl(dimethylaminopropyl)carbodiimide, 2-Morpholinoethanesulfonic acid pH 6, 0 °C, r.t. (2) hPG-NH₂, 24 h, r.t.

Figure 1

Cyclic voltammetric measurement of rsCMS 1a in dry DMSO at a scan rate of 100 mV/s, three rounds.

Figure 2

Kinetics of stimulus-triggered release of Nile red (NR) from rsCMS 1a measured with fluorescence spectroscopy over 24 h; NR release was followed by fluorescence intensity decay at NR emission maximum wavelength.

Figure 3

Penetration of ccCMS 1b and rsCMS 1a nanocarriers in ex vivo human skin and delivery of the loaded dye meso-tetra (m-hydroxyphenyl) porphyrin (mTHPP). (A) Representative images of skin sections from rsCMS 1a and ccCMS 1b nanocarrier-treated samples. Bars = 50 µm. (B) Summary of the mean fluorescence intensity (MFI) and standard errors from three different donors (d1-d3). Statistical analysis was performed to compare rsCMS 1a values with those of ccCMS 1b nanocarriers in the same skin layers. The stars show significant differences (* p < 0.05; ** p < 0.01; *** p < 0.001).