Orally administered antisense therapy has been introduced as an effective approach for treating cancer in the gastrointestinal tract. However, its practical application has been limited by the instability of oligonucleotides and their inefficient delivery. To overcome these problems, we synthesized size-dependent, oligonucleotide nanoparticle-patterned chitosan/phytic acid (ODN/CS/PA) capsules with protective shields via a three-step process of self-assembly, nanoparticle encapsulation, and shell formation. The multicompartmental capsule size and oligonucleotide nanoparticle-loading pattern were controlled by applying different potentials during the electrostatic extrusion process used for nanoparticle encapsulation. Over 95% of encapsulated oligonucleotides were protected from nuclease digestion (DNase I) and, depending on their size, showed 40-75% protection against simulated gastric fluid. Their controlled release from capsules correlated with the cellular delivery of released nanoparticles and the inhibition of protein expression in cancer cells. Specifically, large capsules showed approximately 32-fold greater delivery to cancer cells than nonencapsulated nanoparticles. We also confirmed delivery of oligonucleotide nanoparticles to the small intestine and colon of rats following oral administration. These findings demonstrate that the multicompartmental ODN/CS/PA capsules can facilitate efficient oral delivery of oligonucleotides for cancer treatment.
Keywords: cancer; chitosan; multicompartmental delivery system; oligonucleotide; oral delivery; phytic acid.