Interplay of the Assembly Conditions on Drug Transport Mechanisms in Polyelectrolyte Multilayer Films

[Image: see text] The layer-by-layer film deposition is a suitable strategy for the design and functionalization of drug carriers with superior performance, which still lacks information describing the influence of assembly conditions on the mechanisms governing the drug release process. Herein, traditional poly(acrylic acid)/poly(allylamine) polyelectrolyte multilayers (PEM) were explored as a platform to study the influence of the assembly conditions such as pH, drug loading method, and capping layer deposition on the mechanisms that control the release of calcein, the chosen model drug, from PEM. Films with 20–40 bilayers were assembled at pH 4.5 or 8.8, and the drug loading process was carried out during- or post-film assembly. Release data were fitted to three release models, namely, Higuchi, Ritger–Peppas, and Berens–Hopfenberg, to investigate the mechanism governing the drug transport, such as the apparent diffusion and the relaxation time. The postassembly drug loading method leads to a higher drug loading capacity than the during-assembly method, attributed to the washing out of calcein during film assembly steps in the latter method. Higuchi’s and Ritger–Peppas’ model analyses indicate that the release kinetic constant increased with the number of bilayers for the postassembly method. The opposite trend is observed for the during-assembly method. The Berens–Hopfenberg release model enabled the decoupling of each drug transport mechanism’s contribution, indicating the increase of the diffusion contribution with the number of bilayers for the postassembly method at pH 4.5 and the increase of the polymer relaxation contribution for the during-assembly method at pH 8.8. Deborah’s number, which represents the ratio of the polymer relaxation time to the diffusion time, follows the trends observed for the relaxation contribution for the conditions investigated. The deposition of the capping phospholipid layer over the payload also favored the polymer relaxation contribution in the drug release, featuring new strategies to investigate the drug release in PEM.