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Construction of a PLGA based, targeted siRNA delivery system for treatment of osteoporosis
Deniz Sezlev Bilecen1,2, Jose Carlos Rodriguez-Cabello3, Hasan Uludag4
1a BIOMATEN, Middle East Technical University (METU), Center of Excellence in Biomaterials and Tissue Engineering , Ankara , Turkey.
Abstract:
Osteoporosis, a systemic skeletal disorder, occurs when bone turnover balance is disrupted. With the identification of the genes involved in the pathogenesis of the disease, studies on development of new treatments has intensified. Short interfering RNA (siRNA) is used to knockdown disease related gene expressions. Targeting siRNA in vivo is challenging. The maintenance of therapeutic plasma level is hampered by clearance of siRNA from the body. Targeted systems are useful in increasing the drug concentration at the target site and decreasing side effects. Aim of the present study was to develop an injectable siRNA delivery system to protect siRNA during systemic distribution and target the siRNA to bone tissue using a thermoresponsive, genetically engineered, elastin-like recombinamer (ELR), designed to interact with the mineral component of bone. The delivery system consisted of DNAoligo as a siRNA substitute complexed with the cationic polymer, polyethyleneimine (PEI), at N/P ratio of 20. The complex was encapsulated in poly(lactic acid-co-glycolic acid) (PLGA) nanocapsules. PLGA capsules were characterized by SEM, TEM and XPS. FTIR was used to show the preferential attachment of ELR to HAp. Encapsulation efficiency of the complex in PLGA nanocapsules was 48%. The release kinetics of the complex fits the Higuchi release kinetics.
Insights
This study developed an injectable nanocapsule system for targeted osteoporosis treatment using short interfering RNA (siRNA). The system protects siRNA and delivers it to bone tissue, enhancing therapeutic delivery.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Molecular Biology
Background:
- Osteoporosis disrupts bone turnover, necessitating novel treatments.
- Short interfering RNA (siRNA) offers gene knockdown but faces in vivo delivery challenges.
- Targeted delivery systems are crucial for enhancing therapeutic efficacy and reducing side effects.
Purpose of the Study:
- To develop an injectable siRNA delivery system for osteoporosis.
- To protect siRNA during systemic circulation and target it to bone tissue.
- To utilize a thermoresponsive elastin-like recombinamer (ELR) for bone-mineral interaction.
Main Methods:
- siRNA substitute (DNAoligo) complexed with polyethyleneimine (PEI).
- Complex encapsulated in poly(lactic acid-co-glycolic acid) (PLGA) nanocapsules.
- Characterization using SEM, TEM, XPS, and FTIR; release kinetics analyzed.
Main Results:
- PLGA nanocapsules demonstrated successful encapsulation of the DNAoligo-PEI complex (48% efficiency).
- FTIR confirmed preferential attachment of ELR to hydroxyapatite (HAp), indicating bone targeting potential.
- Release kinetics followed Higuchi model, suggesting controlled release.
Conclusions:
- The developed injectable nanocapsule system shows promise for targeted siRNA delivery in osteoporosis.
- The ELR-functionalized PLGA nanocapsules offer a strategy for enhanced bone targeting.
- This approach could improve therapeutic outcomes for osteoporosis by improving siRNA delivery.
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