Microparticulate poly(vinyl alcohol) hydrogel formulations for embedding and controlled release of polyethylenimine...

Nucleic acid-based therapeutics offer enormous potential in the treatment of various pathologies. For DNA or RNA delivery, nanoparticle systems based on lipids or polymers have been developed. However, colloidal instability in solution, poor storage properties especially as dry powder and little stability against an aggressive environment, e.g. after oral application, are major issues. Furthermore, there is an urgent need for sustained release systems that allow for fine-tuned, long-term temporal and spatial nanoparticle release. In this paper, we describe the embedding of polymeric nanoparticles for gene delivery, namely polyethylenimine (PEI)-based polyplexes and their corresponding liposome-modified analogues (lipopolyplexes), into microparticulate poly (vinyl alcohol) (PVA) hydrogels. Various parameters are modified, and major differences are found. PVA is explored with two different molecular weights and at different concentrations, furthermore different emulsifiers and acetone for extraction are employed, and the protocol is performed with or without repetitive freeze/thaw cycles for physical PVA crosslinking. We thereby establish Nanoparticles-in-Microparticle Delivery Systems (NiMDS) that are extensively characterized and shown to allow prolonged storage as easy-to-handle formulation (dry powder) without loss of nanoparticle activity. Unexpectedly, the nanoparticles' PVA encapsulation/release alters important physicochemical nanoparticle properties and biological activities in a favourable way. Furthermore, we also demonstrate the nanoparticle release to be dependent on the microstructure of the PVA matrix, which is determined by the degree of physical crosslinking through a defined number of freeze/thaw cycles. We show that these defined physically crosslinked PVA hydrogels thus represent sustained release devices for fine-tuned, long-term nanoparticle release in possible therapeutic applications.

The present paper for the first time describes the embedding of polymeric PEI-based polyplexes and lipopolyplexes into poly(vinyl alcohol) (PVA) hydrogels, to establish novel Nanoparticles-in-Microparticle Delivery Systems (NiMDS). Through modification of various parameters including different PVA molecular weights and concentrations, different emulsifiers and defined numbers of freeze-thaw cycles for physical PVA crosslinking, sustained release devices are also obtained. Beyond favourable alterations of important physicochemical/biological nanoparticle properties and the possibility for prolonged storage as easy-to-handle formulation (dry powder), we show that these NiMDS also allow the tailormade, fine-tuned, long-term release of fully active nanoparticles in possible therapeutic applications.