Self-Assembly of DNA–Minocycline Complexes by Metal Ions with Controlled Drug Release

Abstract

Here we reported a study of metal ions-assisted assembly of DNA-minocycline (MC) complexes and their potential application for controlling MC release. In the presence of divalent cations of magnesium or calcium ions (M²⁺), MC, a zwitterionic tetracycline analogue, was found to bind to phosphate groups of nucleic acids via an electrostatic bridge of phosphate (DNA)-M²⁺-MC. We investigated multiple parameters for affecting the formation of DNA-Mg²⁺-MC complex, including metal ion concentrations, base composition, DNA length, and single- versus double-stranded DNA. For different nitrogen bases, single-stranded poly(A)₂₀ and poly(T)₂₀ showed a higher MC entrapment efficiency of DNA-Mg²⁺-MC complex than poly(C)₂₀ and poly(G)₂₀. Single-stranded DNA was also found to form a more stable DNA-Mg²⁺-MC complex than double-stranded DNA. Between different divalent metal ions, we observed that the formation of DNA-Ca²⁺-MC complex was more stable and efficient than the formation of DNA-Mg²⁺-MC complex. Toward drug release, we used agarose gel to encapsulate DNA-Mg²⁺-MC complexes and monitored MC release. Some DNA-Mg²⁺-MC complexes could prolong MC release from agarose gel to more than 10 days as compared with the quick release of free MC from agarose gel in less than 1 day. The released MC from DNA-Mg²⁺-MC complexes retained the anti-inflammatory bioactivity to inhibit nitric oxide production from pro-inflammatory macrophages. The reported study of metal ion-assisted DNA-MC assembly not only increased our understanding of biochemical interactions between tetracycline molecules and nucleic acids but also contributed to the development of a highly tunable drug delivery system to mediate MC release for clinical applications.