Barriers in Systemic Delivery and Preclinical Testing of Synthetic microRNAs in Animal Models: an Experimental Study on miR-215-5p Mimic

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Publikace nespadá pod Filozofickou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.
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MACHÁČKOVÁ Táňa VYCHYTILOVÁ Petra SOUČKOVÁ Kamila LAGA Richard ANDROVIC Ladislav MIXOVA Gabriela SLABÝ Ondřej

Rok publikování 2021
Druh Článek v odborném periodiku
Časopis / Zdroj Physiological research
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.biomed.cas.cz/physiolres/pdf/2021/70_481.pdf
Doi http://dx.doi.org/10.33549/physiolres.934571
Klíčová slova miRNA; miR-215-5p; Animal model; Systemic delivery
Popis Mus musculus is the most commonly used animal model in microRNA research; however, little is known about the endogenous miRNome of the animals used in the miRNA-targeting preclinical studies with the human xenografts. In the presented study, we evaluated the NOD/SCID gamma mouse model for the preclinical study of systemic miR-215-5p substitution with a semitelechelic poly[N-(2-hydroxypropyl)methacrylamide]-based carrier conjugated with miR-215-5pmimic via a reductively degradable disulfide bond. Murine mmu-miR-215-5p and human hsa-miR-215-5p have a high homology of mature sequences with only one nucleotide substitution. Due to the high homology of hsa-miR-215-5p and mmu-hsa-miR-2155p, a similar expression in human and NOD/SCID gamma mice was expected. Expression of mmu-miR-215 in murine organs did not indicate tissue-specific expression and was highly expressed in all examined tissues. All animals included in the study showed a significantly higher concentration of miR-215-5p in the blood plasma compared to human blood plasma, where miR-215-5p is on the verge of a reliable detection limit. However, circulating mmu-miR-215-5p did not enter the human xenograft tumors generated with colorectal cancer cell lines since the levels of miR-215-5p in control tumors remained notably lower compared to those originally transfected with miR-215-5p. Finally, the systemic administration of polymer-miR-215-5p-mimic conjugate to the tail vein did not increase miR-215-5p in NOD/SCID gamma mouse blood plasma, organs, and subcutaneous tumors. It was impossible to distinguish hsa-miR-215-5p and mmu-miR-215-5p in the murine blood and organs due to the high expression of endogenous mmu-miR-215-5p. In conclusion, the examination of endogenous tissue and circulating miRNome of an experimental animal model of choice might be necessary for future miRNA studies focused on the systemic delivery of miRNA-based drugs conducted in the animal models.
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