Synthesis and Validation of Functional Nanogels as pH‐Sensors in the Hair Follicle

Abstract

Patzelt et al. have described the size-dependent uptake of 100-1000 nm sized nanoparticles into the HF. Mediumsized nanoparticles (500-700 nm) achieved a maximum in penetration depth, [4] due to the surface structure of the hair and the hair follicle. Particles that are of the same size thickness of the keratin cells (530 nm in human hair and 320 nm in porcine hair) can be easily transported into the HF. The movements of the hair acts as a pumping system. Thus, the optimum size is also dependent on the species. [5,6] But even if the particles penetrate into the HF, they will not pass the follicular barrier. Consequently, the particles could be used as a transport system for drugs. Particles in the required nanoscale range can be produced in various ways. [7][8][9] A possibility to achieve particles in the nanometer range is the synthesis of nanogels which exist of crosslinked polymer chains and form 3D nanosized networks. [10,11] They can be prepared by mini [12][13][14][15] and microemulsion. [16,17] In this case reactive macromolecules are templated into stabilized droplets and then reacted to the desired nanoparticles. However, high energy input by ultrasonication or large amounts of surfactants are needed to stabilize the droplet reactors. To avoid these harsh In the present study, a pH responsive dendritic polyglycerol nanogel (dPG-NG) is developed to measure the pH values inside the hair follicle (HF) using an ex vivo porcine ear model. The macromolecular precursors are labeled with a pH sensitive indodicarbocyanine dye (pH-IDCC) and a control dye (indocarbocyanine dye: ICC) and crosslinked via a mild and surfactantfree Thiol-Michael reaction using an inverse nanoprecipitation method. With this method, it is possible to prepare tailor-made particles in the range of 100 nm to 1 µm with a narrow polydispersity. The dPG-NGs are characterized using dynamic light scattering, nanoparticle tracking analysis, and atomic force microscopy. Systematic analysis of confocal microscope images of histological sections of the skin enables accurate determination of the pH gradient inside the HF. The results show that these novel pH-nanosensors deeply penetrate the skin via the follicular pathway and the pH of the pig hair follicles increase from 6.5 at the surface of the skin to 7.4 in deeper areas of the HF. The pH-nanosensor shows no toxicity potentials.

Determination of the pH Gradient in Hair Follicles of Human Volunteers Using pH-Sensitive Melamine Formaldehyde-Pyranine Nile Blue Microparticles

“…The obtained pH gradients shown in Figure 3 b and Figure 4 b are in accordance with pH gradients measured on hair follicles in porcine ear skin biopsy sections using pH-responsive dendritic polyglycerol nanogel [ 21 ].…”

“…The subjects 1–6 showed some clear pH shifting from about 6.35 to 7.01 at the sheath region to 5.86 to 6.35 at the external hair shaft. The average difference is about 0.58, is slightly lower than measured for porcine hairs [ 21 ]. Beside these results, the subjects 7 and 8 did not show any significant changes, although single hairs showed similar gradient trends.…”

“…pH-responsive dendritic polyglycerol nanogels (100 nm–1 µm) conjugated with a pH-sensitive dye and a control dye were recently developed which enabled to determine the pH gradient within the HF of ex vivo porcine ear skin to a depth of ≈530 µm in laser scanning microscopic images of skin sections. The pH gradient in the follicular ducts ranged from pH 6.50 on the skin surface, to pH 7.44 near the point of deepest nanogel penetration, with a sharp increase in pH over the first 300 µm [ 21 ]. pH changes corresponding to HF found in diseased skin have not yet been elucidated to date.…”

A Facile, One-Pot, Surfactant-Free Nanoprecipitation Method for the Preparation of Nanogels from Polyglycerol–Drug Conjugates that Can Be Freely Assembled for Combination Therapy Applications

“…Several preparations of NGs using PG have been reported by the Haag and Calderón groups [21,22,23,24,25,26,27,28] and encapsulation of bioactive molecules including anticancer drugs into PG NGs as well as their in vitro release has been extensively investigated. However, encapsulation can cause unwanted leakage and release of the payload before reaching the target site.…”

From Polymers to Functional Biomaterials

“…The article nicely demonstrates that the dPG‐NGs penetrate the skin via the follicular pathway and are able to monitor the topical or intradermal pH in an ex vivo porcine ear model. The presented nanogel platform seems to provide a suitable basis for the development of intrafollicular drug delivery …”