Journal
JOURNAL OF CONTROLLED RELEASE
Volume 218, Issue -, Pages 22-28Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2015.09.050
Keywords
Chemically modified RNA; Plasmid DNA; Polyethylenimine; Gene delivery; Bone morphogenetic protein-2; Bone regeneration
Funding
- NIDCR NIH HHS [R21 DE024206, 1R21DE024206-01A1] Funding Source: Medline
- NIEHS NIH HHS [P30 ES005605] Funding Source: Medline
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There exists a dire need for improved therapeutics to achieve predictable bone regeneration. Gene therapy using non-viral vectors that are safe and efficient at transfecting target cells is a promising approach to overcoming the drawbacks of protein delivery of growth factors. Here, we investigated the transfection efficiency, cytotoxicity, osteogenic potential and in vivo bone regenerative capacity of chemically modified ribonucleic acid (cmRNA) (encoding BMP-2) complexed with polyethylenimine (PEI) and made comparisons with PEI complexed with conventional plasmid DNA (encoding BMP-2). The polyplexes were fabricated at an amine (N) to phosphate (P) ratio of 10 and characterized for transfection efficiency using human bone marrow stromal cells (BMSCs). The osteogenic potential of BMSCs treated with these polyplexes was validated by determining the expression of bone-specific genes, osteocalcin and alkaline phosphatase as well as through the detection of bone matrix deposition. Using a calvarial bone defect model in rats, it was shown that PEI-cmRNA (encoding BMP-2)-activated matrices promoted significantly enhanced bone regeneration compared to PEI-plasmid DNA (BMP-2)-activated matrices. Our proof of concept study suggests that scaffolds loaded with non-viral vectors harboring cmRNA encoding osteogenic proteins may be a powerful tool for stimulating bone regeneration with significant potential for clinical translation. ((C)) 2015 Elsevier B.V. All rights reserved.
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