Self-assembled thermoresponsive poly(glycidyl ether) brushes on polystyrene culture dishes facilitate the fabrication of vascular human cell sheets.

Cancer nanomedicines are typically stealthed by a poly(ethylene glycol) layer that is important to obtain extended blood circulation and elevated tumor accumulation. PEG stealth, however, also leads to poor tumor cell selectivity and uptake thereby reducing treatment efficacy. Here, we report that biodegradable micelles with sheddable dendritic polyglycerol sulfate (dPGS) shells show an unusual tumor targetability and chemotherapy in vivo. The self-assembly of dPGS-SS-poly(ε-caprolactone) amphiphilic block copolymer with an M of 4.8-3.7 kg mol affords negatively charged and small sized micelles (dPGS-SS-PCL Ms). dPGS-SS-PCL Ms reveal a low cytotoxicity, decent doxorubicin (DOX) loading, and accelerated drug release under a reductive condition. Notably, DOX-loaded dPGS-SS-PCL Ms exhibit a high tolerable dosage of more than 40 mg kg, a long plasma half-life of ca. 2.8 h, and an extraordinary tumor accumulation. Intriguingly, therapeutic results demonstrate that DOX-loaded dPGS-SS-PCL Ms induce complete tumor suppression, significantly improved survival rate, and diminishing adverse effects as compared to free drug (DOX·HCl) in MCF-7 human mammary carcinoma models. Dendritic polyglycerol sulfate with a superior tumor homing ability appears to be an attractive alternative to PEG in formulating targeted cancer nanomedicines.

The fabrication of cell sheets is a major requirement for bottom-up tissue engineering purposes (e.g., cell sheet engineering) and regenerative medicine. Employing thermoresponsive polymer coatings as tissue culture substrates allows for the mild, temperature-triggered detachment of intact cell sheets along with their extracellular matrix (ECM). It has been shown before that biocompatible, thermoresponsive poly­(glycidyl ether) monolayers on gold substrates can be utilized to harvest confluent cell sheets by simply reducing the temperature to 20 °C. Herein, we report on the first poly­(glycidyl ether)-based coating on an application-relevant tissue culture plastic substrate. We devised a simple, substrate-geometry-independent method to functionalize polystyrene (PS) surfaces from dilute ethanolic solution via the physical adsorption process of a thermoresponsive poly­(glycidyl ether) block copolymer (PGE) bearing a short, hydrophobic, and photoreactive benzophenone (BP) anchor block. Subsequently, the PGE-coated PS is UV-irradiated for covalent photoimmobilization of the polymer on the PS substrate. Online monitoring of the adsorption process via QCM-D measurements and detailed characterization of the resulting coatings via AFM, ellipsometry, and water contact angle (CA) measurements revealed the formation of an ultrathin PGE layer with an average dry thickness of 0.7 ± 0.1 nm. Adhesion and proliferation of human dermal fibroblasts on PGE-coated PS and tissue culture PS (TCPS) were comparable. For temperature-triggered detachment, fibroblasts were cultured in PGE-coated PS culture dishes at 37 °C for 24 h until they reached confluency. Intact cell sheets could be harvested from the thermoresponsive substrates within 51 ± 17 min upon cooling to 20 °C, whereas sheets could not be harvested from uncoated PS and TCPS control dishes. Live/dead staining and flow cytometry affirmed a high viability of the fibroblasts within the cell sheets. Hence, ultrathin layers of thermoresponsive poly­(glycidyl ether)­s on hydrophobic PS substrates are functional coatings for cell sheet fabrication.

Thermoresponsive coatings that exhibit "switchable" protein-and cell-adhesive properties are frequently used for the fabrication of cell sheets. Among other architectures, polymer brush coatings have shown to be especially viable due to their distinct phase transition behavior, which can be tailored via a manifold of adjustable brush characteristics, such as the (co)monomer composition, polymer chain length, and grafting density. Brush coatings based on poly(glycidyl ether)s (PGEs) have shown to efficiently mediate cell sheet fabrication when tethered to various tissue culture substrates. Herein, we report the phase transition of self-assembled PGE brushes with respect to polymer molecular weight (M: 10 and 22 kDa) and grafting density (0.07−0.5 chains nm −2 ) on gold model substrates studied by quasi-static QCM-D temperature ramp measurements. The brush grafting density can be tuned via the applied grafting conditions, and all brushes investigated feature broad phase transition regimes (ΔT ∼15 °C) with volume phase transition temperatures (VPTTs) close to the cloud point temperatures (CPTs) of the PGEs in solution. We further demonstrate that brush coatings with a low grafting density (0.07−0.12 chains nm −2 ) exhibit a continuous brush-to-mushroom transition, whereas brushes with medium grafting densities (0.3−0.5 chains nm −2 ) undergo a brush-to-brush transition comprising vertical phase separation during the phase transition progress. These insights help to understand the transition behavior of thin, thermoresponsive brushes prepared via grafting-to strategies and contribute to their rational design for improved functional surfaces.