PLGA is a biodegradable and biocompatible polymer that has a long history of safe use for both medical applications and drug delivery. Many therapeutic macromolecules such as peptides, proteins, and nucleic acids have been encapsulated into PLGA microparticles or nanoparticles to achieve a prolonged and controlled release profiles to reduce the frequency of administration.28 SiRNA also has been successfully entrapped into the matrix of PLGA with relatively high loading efficiency,16 and the siRNA-loaded PLGA nanoparticles were further spray-dried with mannitol into inhalable nanocomposite microparticles.29 The integrity and biological activity of siRNA was successfully preserved during the spray-drying process and the physicochemical properties of the particles are suitable for inhalation. However, this system did not show significant gene silencing efficiency on lung cancer cell lines probably due to the anionic surface charge of PLGA nanoparticles and too slow release rate of payload. The incorporation of some cationic polymer or lipid such as dioleoyltrimethylammoniumpropane (DOTAP) showed to be a promising strategy to potentiate the gene silencing capability, and again it was demonstrated by the same group that spray-drying is an excellent technique to formulate siRNA nanoparticles into inhalable dry powders, thus enabling local delivery of biologically active siRNA directly to the lung tissue.30 Nevertheless, their results also clearly indicated that the excellent safety profile of PLGA had been compromised with the incorporation of DOTAP. A DOTAP of 5% (w/w) did not affect the cell viability in the tested DOTAP/PLGA concentration range, whereas nanoparticles modified with more than 5% (w/w) DOTAP reduced the cell viability in a nanoparticle- and DOTAP-concentration-dependent way. Therefore, it was essential to understand the delivery dynamics of this DOTAP/PLGA hybrid nanocarriers (lipid-polymer hybrid nanoparticles, LPNs) to improve their design for therapeutic applications. Recently, Foged et al. investigated the carrier structure-function relationship of LPNs.31 The results suggested that the siRNA-loaded LPNs are characterized by a core-shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in TE buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core-shell structure influenced the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA-DOTAP lipoplexes from the LPNs. Based on these results, a model for the nanostructural characteristics of the LPNs was suggested, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix.
Another strategy to address the low transfection efficiency of PLGA nanoparticles is to modify the structure of PLGA to endow it some favorable properties. For example, the polyester of tertiary-amine-modified polyvinyl alcohol backbones grafted PLGA showed faster degrading rate than PLGA. It is also biodegradable and achieved 80%-90% knockdown of a luciferase reporter gene in vitro.32 It will be interesting to see the performance of these PLGA-based siRNA delivery systems in vivo.