Synthetic microRNA cassette dosing: Pharmacokinetics, tissue distribution and bioactivity

Hongyan Wang, Ming Chiu, Zhiliang Xie, Michael Chiu, Zhongfa Liu, Ping Chen, Shujun Liu, John C. Byrd, Natarajan Muthusamy, Ramiro Garzon, Carlo M. Croce, Guido Marcucci, Kenneth K. Chan

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from the same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2′-methoxyphosphorothioate-miRs (2′-MeOPSmiR16-1, 2′-MeOPSmiR29b and 2′-MeOPSantagomiR155) were administered iv to C57BL/6 mice as a mixture, each at 7.5 mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR's biotargets were monitored sequentially after dosing up to 24 h. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2′-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 min and lowest total body clearance of 0.0054 L/min·kg, whereas 2′-MeOPSmiR29b has the shortest gamma half-life of 510.6 min and highest total body clearance of 0.042 L/min·kg. The tissue concentrations of all three 2′-MeOPS-modified miR(s)/antagomiR were measurable from 5 min to at least 24 h after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of the most sensitive tissues with respect to downregulation of mRNA and protein levels of four measured biotargets (e.g., Bcl-2, Mcl-1, DNMT3a and DNMT3b) despite its relatively low miR/antagomiRs levels. We conclude that cassette dosing is applicable to 2′-MeOPS- modified synthetic miRs that are tissue-deliverable and biofunctional without any additional formulation requirement. This study supports future exploration of miR-involved combination therapies.

Original languageEnglish (US)
Pages (from-to)1638-1644
Number of pages7
JournalMolecular pharmaceutics
Volume9
Issue number6
DOIs
StatePublished - Jun 4 2012
Externally publishedYes

Keywords

  • 2′-MeOPSmiRs
  • cassette dosing
  • pharmacodynamic
  • pharmacokinetics
  • tissue distribution

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