Journal
BIOMATERIALS
Volume 52, Issue -, Pages 148-160Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.02.007
Keywords
Targeted delivery system; MicroRNA; Osteoclast; Bone resorption
Funding
- Hong Kong Baptist University [FRG2/13-14/006]
- Hong Kong General Research Fund [12102914, HKBU 478312]
- Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University [RC-IRMS/13-14/02, RC-IRMS/13-14/03]
- Research Committee of Hong Kong Baptist University [30-12-286, FRG2/12-13/027]
- Science and Technology Innovation Commission of Shenzhen Municipality [SCM-2013-SZTIC-001]
- Natural Science Foundation Council [81272045, 81401833]
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Dysregulated microRNAs in osteoclasts could cause many skeletal diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNAs modulators targeting osteoclasts with minimal off-target effects. Bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts. Considering that the eight repeating sequences of aspartate (D-Asp(8)) could preferably bind to highly crystallized hydroxyapatite, we developed a targeting system by conjugating D-Asps peptide with liposome for delivering microRNA modulators specifically to bone resorption surfaces and subsequently encapsulated antagomir-148a (a microRNA modulator suppressing the osteoclastogenic miR-148a), i.e. (D-Asp(8))-liposome-antagomir-148a. Our results demonstrated that D-Asp(8) could facilitate the enrichment of antagomir-148a and the subsequent down-regulation of miR-148a in osteoclasts in vivo, resulting in reduced bone resorption and attenuated deterioration of trabecular architecture in osteoporotic mice. Mechanistically, the osteoclast-targeted delivery depended on the interaction between bone resorption surfaces and D-Asp(8). No detectable liver and kidney toxicity was found in mice after single/multiple dose(s) treatment of (D-Asp(8))-liposome-antagomir-148a. These results indicated that (D-Asp(8))-liposome as a promising osteoclast-targeting delivery system could facilitate clinical translation of microRNA modulators in treating those osteoclast-dysfunction-induced skeletal diseases. (C) 2015 Elsevier Ltd. All rights reserved.
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