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Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification
Yangwu Chen1,2,3,4, Weiliang Shen1,2,3,4, Chenqi Tang1,2,3,4
1Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Heterotopic ossification (HO) in connective tissues like tendons and ligaments severely damages tissue structure. The pathogenesis of HO remains unclear but may involve mTOR. The results presented here indicate that tendon stem/progenitor cells do not undergo osteochondrogenic differentiation when mTOR signaling is inactivated by gene knockout or rapamycin (RAPA) treatment. Meanwhile, it is necessary to deliver RAPA to the injured sites and avoid disturbing the normal tendon. A RAPA delivery system, developed using collagen hybrid peptide (CHP) to modify the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles, targeted RAPA specifically to pathological tendon collagen. The CHP-PLGA-RAPA nanoparticles showed excellent pathological collagen affinity, sustained-release ability, and bioactivity. In a mouse model of tendon HO, CHP-PLGA-RAPA nanoparticles specifically bound to pathological tendon and strongly suppressed HO progression. The mTOR signaling pathway appears to be a viable therapeutic target for tendon HO, and CHP-PLGA nanoparticles may be valuable for the treatment of tendon-related diseases.
Insights
Targeting mTOR signaling with rapamycin (RAPA) nanoparticles effectively inhibits heterotopic ossification (HO) in tendons. This novel delivery system shows promise for treating tendon injuries and preventing pathological bone formation.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Orthopedics
Background:
- Heterotopic ossification (HO) in connective tissues like tendons and ligaments causes significant structural damage.
- The exact mechanisms driving HO pathogenesis are not fully understood but may involve the mTOR signaling pathway.
Purpose of the Study:
- To investigate the role of mTOR signaling in tendon stem/progenitor cell differentiation.
- To develop and evaluate a targeted drug delivery system for rapamycin (RAPA) to treat tendon HO.
- To assess the efficacy of RAPA-loaded nanoparticles in a mouse model of tendon HO.
Main Methods:
- Tendon stem/progenitor cells were treated with gene knockout or rapamycin (RAPA) to inactivate mTOR signaling.
- A novel drug delivery system using collagen hybrid peptide (CHP)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CHP-PLGA-RAPA) was developed for targeted RAPA delivery.
- The therapeutic effect of CHP-PLGA-RAPA nanoparticles was evaluated in a mouse model of tendon HO.
Main Results:
- Inactivation of mTOR signaling prevented osteochondrogenic differentiation of tendon stem/progenitor cells.
- CHP-PLGA-RAPA nanoparticles demonstrated high affinity for pathological tendon collagen, sustained RAPA release, and maintained bioactivity.
- In vivo studies showed that CHP-PLGA-RAPA nanoparticles specifically targeted pathological tendon sites and significantly suppressed HO progression in mice.
Conclusions:
- The mTOR signaling pathway is a promising therapeutic target for managing tendon HO.
- CHP-PLGA nanoparticles represent a valuable platform for targeted drug delivery in treating tendon-related diseases, particularly HO.
- This approach offers a strategy to deliver therapeutics to injured sites while minimizing disruption to healthy tendon tissue.
