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We have recently demonstrated that the specific inhibition of nuclear factor-κB by a decoy oligonucleotide (dec-ODN) delivered through inhalable large porous particles (LPP) made of poly(lactic-co-glycolic acid) (PLGA) may be highly beneficial for long-term treatment of lung inflammation. Nevertheless, besides chronic inflammation, multifunctional systems aimed to control also infection are required in chronic lung diseases, such as cystic fibrosis (CF). In this work, we tested the hypothesis that engineering PLGA-based LPP with branched poly(ethylenimine) (PEI) may improve LPP properties for pulmonary delivery of dec-ODN, with particular regard to the treatment of Pseudomonas aeruginosa lung infections. After getting insight into the role of PEI on the technological properties of PLGA-based LPP for delivery of dec-ODN, the putative synergistic effect of PEI free or PEI released from LPP on in vitro antimicrobial activity of tobramycin (Tb) and aztreonam (AZT) against P. aeruginosa was elucidated. Meanwhile, cytotoxicity studies on A549 cells were carried out. Results clearly demonstrate that the dry powders have promising aerosolization properties and afford a prolonged in vitro release of both dec-ODN and PEI. The encapsulation of PEI into LPP results in a 2-fold reduction of the minimum inhibitory concentration of AZT, while reducing the cytotoxic effect of PEI. Of note, the developed ODN/PLGA/PEI LPP persisted at lung at least for 14 days after intratracheal administration in rats where they can provide sustained and combined release of dec-ODN and PEI. dec-ODN will likely act as an anti-inflammatory drug, while PEI may enhance the therapeutic activity of inhaled antibiotics, which are commonly employed for the treatment of concomitant lung infections.

Poloxamer thermoresponsive gels are widely explored in controlled drug delivery. Nevertheless, these gels possess inadequate mechanical properties, poor bioadhesiveness, and high permeability to water. To overcome these issues, we blended mucoadhesive hyaluronic acid (HA) with poloxamer analogs. This study aimed to investigate the features affecting the microscopic properties of the gels, which determine their macroscopic properties and capability to control/sustain protein release. Results showed that HA hampers water-poloxamer interactions, thus, strongly influencing physicochemical properties of poloxamer gels. This leads to gels with improved mechanical properties in which the diffusion kinetics of macromolecular active molecules are drastically slowed down. Poloxamer-HA gels can sustain the delivery of proteins, such as insulin, and may allow the modulation of its release kinetics by modifying HA content within the gels in the administration sites in which the active molecule release mechanism is mainly governed by its diffusion.

The aim of this work was to design a biodegradable delivery system for oligonucleotides providing both a sustained release and an improved intracellular penetration. To this purpose oligonucleotide/polyethylenimine (ON/PEI) complexes at nitrogen to phosphate (N/P) molar ratios of about 15 or 40 were encapsulated into poly(lactide-co-glycolide) microspheres by the multiple emulsion-solvent evaporation technique. ON/PEI complexes were efficiently entrapped inside microspheres. The introduction of salts within the external aqueous phase allowed an improvement of microsphere characteristics. In particular, the use of sodium chloride led to a reduced microsphere porosity and a more homogeneous ON distribution inside the polymeric matrix. These effects were attributed to the reduced flux of water from the external aqueous phase toward the internal aqueous droplets, due to the osmotic effect of sodium chloride. Both, the reduced porosity and the improved ON distribution inside the matrix, were considered responsible for the lower burst effect and the slower ON release rate from microsphere prepared with sodium chloride. ON/PEI complexes encapsulated inside microspheres were also protected toward enzymatic degradation in fetal calf serum. Interestingly, ON/PEI complexes slowly released from microspheres efficiently penetrated inside HeLa cells and oligonucleotides were preferentially located in the nucleus.