Oral CTB-Pro-IGF-1 Bioencapsulated in Plants Enhances Jaw Bone Regeneration in Rat Osteoradionecrosis

Jaw osteoradionecrosis (ORN) is a debilitating complication of head and neck cancer radiotherapy, characterized by exposed, necrotic bone that fails to heal. Current treatments are often invasive and lack definitive efficacy, leaving patients with chronic pain and functional impairment. Insulin-like Growth Factor-1 (IGF-1) is a potent anabolic peptide known for its critical role in bone formation and tissue repair, acting primarily through the IGF-1R to stimulate osteoblast proliferation and differentiation. However, systemic delivery of IGF-1 can be challenging due to its short half-life and potential for off-target effects. This study explores a novel, orally delivered, plant-bioencapsulated form of IGF-1 to address the need for an effective, non-invasive therapy for ORN.

Researchers induced jaw osteoradionecrosis (ORN) in a pre-clinical rat model by administering 50 Gy radiation followed by minor trauma to the jaw. They then evaluated the efficacy of an orally delivered, aglycosylated IGF-1 with an E-peptide (CTB-Pro-IGF-1), bioencapsulated in lettuce chloroplasts. Expression levels of CTB-Pro-IGF-1 in lettuce were assessed across different plant ages and generations. Pharmacokinetic analyses determined serum levels after oral administration. Irradiated and control rats received oral gavage of 560 μg of CTB-Pro-IGF-1 daily for 2 weeks. Bone regeneration was subsequently evaluated using in vivo microCT, ex vivo microCT, and histological analyses of jaw tissue.

The plant-based expression system for CTB-Pro-IGF-1 proved robust, with expression levels in lettuce significantly increasing with plant age (52, 60, and 72 days; p < 0.05) and remaining stable across several generations (T2, T3; p < 0.05). Pharmacokinetic studies revealed that orally administered CTB-Pro-IGF-1 reached maximum serum levels within 6 hours and was eliminated within 24 hours, crucially without altering endogenous IGF-1 levels, suggesting a targeted action.

Histological and microCT analyses confirmed complete bone regeneration in the treated animals, a stark contrast to the untreated controls which showed persistent osteoradionecrosis. This complete healing was observed across multiple assessment modalities, indicating a profound therapeutic effect. The findings suggest that the bioencapsulated peptide successfully navigated the digestive system to exert its anabolic effects on bone tissue, promoting comprehensive repair in a challenging injury model.