Abstract
3D-printed hydrogels are particularly advantageous as drug-delivery platforms but their loading with water-soluble active compounds remains a challenge requiring the development of innovative inks. Here, we propose a new 3D extrusion-based approach that, by exploiting the internal gelation of the alginate, avoids the post-printing crosslinking process and allows the loading of epirubicin-HCl (EPI). The critical combinations of alginate, calcium carbonate and d-glucono-δ-lactone (GDL) combined with the scaffold production parameters (extrusion time, temperature, and curing time) were evaluated and discussed. The internal gelation in tandem with 3D extrusion allowed the preparation of alginate hydrogels with a complex shape and good handling properties. The dispersion of epirubicin-HCl in the hydrogel matrix confirmed the potential of this self-crosslinking alginate-based ink for the preparation of 3D-printed drug-delivery platforms. Drug release from 3D-printed hydrogels was monitored, and the cytotoxic activity was tested against MCF-7 cells. Finally, the change in the expression pattern of anti-apoptotic, pro-apoptotic, and autophagy protein markers was monitored by liquid-chromatography tandem-mass-spectrometry after exposure of MCF-7 to the EPI-loaded hydrogels.
Highlights
Three-dimensional (3D) printing is a rapidly growing technology that offers many opportunities for manufacturing biomaterials with tunable properties
We studied the anti-apoptotic Bcl-2 and Bcl-xL class proteins; the pro-apoptotic p53, BAX, and BAD proteins; the executioner caspase 3 (CASP-3); the initiation caspase 9 (CASP-9); and the activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1), which are all proteins involved in the MCF-7 autophagy program as a mechanism of protection from cell death induced by EPI [38]
The loading test carried out using a model water-soluble drug as EPI confirmed the potential of this procedure for the preparation of 3D-printed hydrogels intended as drug delivery systems
Summary
Three-dimensional (3D) printing is a rapidly growing technology that offers many opportunities for manufacturing biomaterials with tunable properties. The computer-aided design (CAD) associated with this technology allows to achieve high automation/repeatability and precise control of microstructures, to prepare complex structures in a range of dimensions and material using the layer-by-layer deposition [2,3]. These features are advantageous in the preparation of modified release systems as the conventional drug-delivery platforms often restrict their application in the pharmaceutical industry, due to the incapability of adapting to individual pharmacokinetic traits. Hydrogels are one of the most feasible classes of ink materials for 3D printing, and this field has been rapidly advancing [5].
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