Degradable poly(ethylene glycol) (PEG)-based hydrogels for spatiotemporal control of siRNA/nanoparticle delivery

J Control Release. 2018 Oct 10:287:58-66. doi: 10.1016/j.jconrel.2018.08.002. Epub 2018 Aug 3.

Abstract

Despite great therapeutic potential and development of a repertoire of delivery approaches addressing degradation and cellular uptake limitations, small interfering RNA (siRNA) exhibits poorly controlled tissue-specific localization. To overcome this hurdle, siRNA was complexed to nanoparticles (siRNA/NP) embedded within poly(ethylene glycol)-poly(lactic acid)-dimethacrylate (PEG-PLA-DM) hydrogels with the hypothesis that hydrolytic degradation of ester bonds within the PLA crosslinks would provide tunable, sustained siRNA/NP release. Hydrogels formed from macromers with increasing PLA repeats (e.g., 0 or non-degradable to 5 PLA repeats flanking PEG cores) and mixtures of nondegradable PEG-DM (0 PLA) and degradable PEG-PLA5-DM macromers were investigated. Hydrogels formed only with fully degradable crosslinks degraded rapidly over 6-14 days with limited control over siRNA/NP release. However, hydrogels formed with mixtures of nondegradable and 20%, 50%, and 100% degradable macromers resulted in siRNA/NP release over 3 to 28 days. Subsequently, gene silencing mediated by released siRNA/NP from 20% and 50% degradable hydrogels was sustained for ~28 days. Furthermore, in vivo imaging showed that hydrogel degradation controlled siRNA/NP localization, with sustained siRNA/NP release from 0%, 20% and 50% degradable hydrogels over 28, 21, and 15 days. A model, which accounts for hydrogel degradation rate and siRNA/NP diffusion, was developed to enable rational design of siRNA/NP delivery depots. Overall, this study shows that siRNA/NP release can be sustained via encapsulation in hydrogels with tunable degradation kinetics and modeled for a priori design of delivery depots.

Keywords: Biomaterials; Controlled delivery; Degradable hydrogel; siRNA delivery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Delayed-Action Preparations / chemistry
  • Female
  • Hydrogels / chemistry*
  • Methacrylates / chemistry*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Polyesters / chemistry*
  • Polyethylene Glycols / chemistry*
  • RNA Interference
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacokinetics

Substances

  • Delayed-Action Preparations
  • Hydrogels
  • Methacrylates
  • Polyesters
  • RNA, Small Interfering
  • monomethoxypolyethyleneglycol-polylactide block copolymer
  • poly(ethylene glycol)-dimethacrylate
  • Polyethylene Glycols
  • poly(lactide)