Nanoparticle-Patterned Multicompartmental Chitosan Capsules for Oral Delivery of Oligonucleotides

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapeutics

Background:

• Oral administration of antisense therapy offers a promising route for gastrointestinal cancer treatment.
• Oligonucleotide instability and poor delivery hinder the clinical application of oral antisense therapy.
• Development of protective delivery systems is crucial for enhancing oral oligonucleotide efficacy.

Purpose of the Study:

• To synthesize and characterize size-dependent, multicompartmental oligonucleotide nanoparticle-patterned chitosan/phytic acid (ODN/CS/PA) capsules.
• To evaluate the protective capabilities of these capsules against enzymatic and acidic degradation.
• To assess the in vitro and in vivo delivery efficiency and therapeutic potential of encapsulated oligonucleotides.

Main Methods:

• Chitosan/phytic acid capsules were fabricated using a three-step self-assembly, nanoparticle encapsulation, and shell formation process.
• Capsule size and nanoparticle loading patterns were controlled via electrostatic extrusion with varying potentials.
• Nuclease digestion (DNase I) and simulated gastric fluid stability assays were performed.
• In vitro cellular delivery and protein expression inhibition in cancer cells were evaluated.
• In vivo biodistribution studies in rats were conducted following oral administration.

Main Results:

• Over 95% of encapsulated oligonucleotides were protected from DNase I digestion.
• Capsules provided 40-75% protection against simulated gastric fluid, dependent on capsule size.
• Controlled release correlated with enhanced cellular delivery, with large capsules showing a 32-fold increase compared to free nanoparticles.
• Oligonucleotide nanoparticles were successfully delivered to the small intestine and colon in rats.
• Inhibition of protein expression in cancer cells was confirmed.

Conclusions:

• Multicompartmental ODN/CS/PA capsules effectively protect oligonucleotides from degradation.
• These capsules facilitate efficient oral delivery of oligonucleotide nanoparticles to the gastrointestinal tract.
• The developed system shows significant potential for enhancing oral antisense therapy in gastrointestinal cancer treatment.