Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

Abstract

Background: Molecules taken up by olfactory and trigeminal nerve neurons directly access the brain by the nose-to-brain pathway. In situ-forming mucoadhesive gels would increase the residence time of intranasal material, favoring the nose-to-brain delivery. In this first approach, brain radioactivity after intranasal administration of 32 P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined. Materials:32 P-siRNA dendriplexes were incorporated into in situ-forming mucoadhesive gels prepared by blending thermosensitive poloxamer (23% w/w) with mucoadhesive chitosan (1% w/w, PxChi) or carbopol (0.25% w/w, PxBCP). Rheological properties, radiolabel release profile, and local toxicity in rat nasal mucosa were determined. The best-suited formulation was intranasally administered to rats, and blood absorption and brain distribution of radioactivity were measured. Results:The gelation temperature of both formulations was 23°C. The PxChi liquid showed non-Newtonian pseudoplastic behavior of high consistency and difficult manipulation, and the gel retained 100% of radiolabel after 150 minutes. The PxCBP liquid showed a Newtonian behavior of low viscosity and easy manipulation, while in the gel phase showed apparent viscosity similar to that of the mucus but higher than that of aqueous solution. The gel released 35% of radiolabel and the released material showed silencing activity in vitro. Three intranasal doses of dendriplexes in PxCBP gel did not damage the rat nasal mucosa. A combination of 32 P-siRNA complexation with dendrimers, incorporation of the dendriplexes into PxCBP gel, and administration of two intranasal doses was necessary to achieve higher brain radioactivity than that achieved by intravenous dendriplexes or intranasal naked siRNA. Conclusion:The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the mediation of a direct brain delivery.

Inhibition of microRNA-210 provides neuroprotection in hypoxic–ischemic brain injury in neonatal rats

“…The intranasal delivery is a powerful, non-invasive method to directly deliver chemicals and peptides to the brain, which is not obstructed by the blood-brain barrier, avoids fast systemic clearance, and limits potential secondary effects. It has been used to deliver chemicals, peptides, oligonucleotides, proteins and stem cells into the brain (Cai et al, 2011; Cooper et al, 2013; Kim et al, 2012; Perez et al, 2012; Rat et al, 2011; van Velthoven et al, 2013; Yang et al, 2013a; Yang et al, 2013b). A recent study demonstrated that silencing miR-134 with intranasal administration of miR-134 antagomir LNA in each nostril produced neuroprotective and prolonged seizure-suppressive effects in mice (Jimenez-Mateos et al, 2012).…”

Formulations for Intranasal Delivery of Pharmacological Agents to Combat Brain Disease: A New Opportunity to Tackle GBM?

“…The potential of mucoadhesive gel formulations was also displayed by Perez et al . [89]. They coupled radioactive siRNA to PAMAM dendrimers to form dendriplexes, and formulated these particles into mucoadhesive gels containing either 1% (w/w) chitosan or 0.25% (w/w) carbopol 974P NF TM .…”

Intranasal, siRNA Delivery to the Brain by TAT/MGF Tagged PEGylated Chitosan Nanoparticles

“…Another study by the same research group showed intranasal siRNA delivery against HMGB1 gene, using PAMAM dendrimer formulation to cause neuroprotection in the postischemic brains of Sprague-Dawley rats [ 52 ]. Another study showed the intranasal delivery of radioactive 32 P-siRNA dendriplexes complexed in mucoadhesive gels with maximum expression in the olfactory bulb [ 23 ]. These applications are in accordance to the study performed by our group, suggesting intranasal delivery is a well established route to deliver nanoparticle formulations targeting brain and causing a therapeutic effect.…”