Starch Nanoparticle/Carboxymethyl Chitosan Nanoassemblies for Intranasal Delivery of Antipsychotic Drugs to the Brain

Delivering antipsychotic drugs intranasally (IN) offers promising benefits over systemic delivery by increasing the residence time, bioavailability, and efficacy of a drug while reducing off-target toxicity. To effectively use this pathway for prolonged drug delivery, vehicles are required that can initially adhere to the nasal mucosa but then transport through the mucosa, the nasal epithelium, and ultimately to the brain. Herein, a nanogel-based nanoassembly is described with the capacity to switch its size from 150 to 20 nm under intranasal conditions to deliver the antipsychotic drug (haloperidol, HP) to the brain. The nanoassembly was fabricated by imine cross-linking between carboxymethyl chitosan (CMCh) and hydrophobized aldehyde-functionalized starch nanoparticles (SNP-OSA-CHO) within a water-in-oil emulsion. Nanoassemblies could efficiently load HP (up to 80% encapsulation efficiency), release up to 55% of the drug in nasal epithelium-simulated conditions over 5 days, and showed good cytocompatibility with striatal and nasal epithelial cells. In vivo, HP-loaded nanoassemblies suppressed rat locomotion for 4 h relative to normal rat behavior, longer than SNP-OSA-CHO-loaded HP (2 h) or free HP (3 h) dosed at the same drug concentration. Biodistribution results suggest that nanoassemblies are mucopenetrative, while free SNP-OSA-CHO are primarily mucoadhesive, correlating with the extended attenuation time of acute amphetamine-induced hyperlocomotion achieved with the nanoassemblies. These results, coupled with the flexibility of the small nanoparticle component of the nanoassembly for delivering diverse drug payloads, suggest the potential utility of nanoassemblies for IN drug delivery.