Nanoparticles have attracted significant attention as drug carriers because their chemistry and structure can be tuned to target certain tissues, control drug release and decrease the dose required for effective therapeutic intervention. Nanogels have the additional advantage of being mechanically deformable, enabling their passage through tight junctions like the blood-brain barrier. However, the hydrophilicity of nanogels limits their ability to uptake most anti-psychotic drugs like haloperidol, which are highly hydrophobic and thus have poor bioavailability as well as negative side effects at therapeutic doses. Herein, we present a method to synthesize hydrophobized nanogels using protein-repellent poly(oligoethylene glycol methacrylate) (POEGMA) to promote long-term circulation. The nanogels were synthesized by precipitation polymerization using either butyl methacrylate (BMA) or methyl methacrylate (MMA) as the hydrophobic comonomer. All nanogel formulations have diameters &lt;100 nm with narrow polydispersities (&lt;0.1). Quantification of drug uptake indicated that (1) MMA nanogels load more haloperidol than the more hydrophobic BMA nanogels and (2) increasing the fraction of hydrophobic monomer too high decreases the amount of drug encapsulated, suggesting that both nanogel swelling and drug partitioning are important in drug loading. <i>In vivo</i> response was assessed by administering drug-loaded nanogels via intraperitoneal injection or intranasally to male Sprague-Dawley rats. Catalepsy was examined by placing the front paws on a bar and scoring the length of time the rats held this position (Figure 1), while locomotion suppression was studied using computerized cages that record multidirectional movements. Both BMA and MMA nanogel formulations induced catalepsy and showed locomotion impairment; however, BMA nanogels consistently produced higher scores than MMA nanogels despite having lower drug loading, a result attributed to their smaller size and thus improved transport to the brain via the intranasal route. Thus, hydrophobically-modified nanogels offer attractive properties for treating brain diseases.

Hydrophobically-modified poly(oligoethylene glycol methacrylate)-based nanogels for the delivery of anti-psychotic drugs to the brain

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.