title: Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs).
abstract: BACKGROUND
  Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA.
  
  
  RESULTS
  Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature.
  
  
  CONCLUSIONS
  This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Shann S
authors.initials: SS
authors.lastname: Yu
authors.forename: Randy L
authors.initials: RL
authors.lastname: Scherer
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Ortega
authors.forename: Charleson S
authors.initials: CS
authors.lastname: Bell
authors.forename: Conlin P
authors.initials: CP
authors.lastname: O'Neil
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.forename: Todd D
authors.initials: TD
authors.lastname: Giorgio
mesh_terms: D003432:Cross-Linking Reagents / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000138:chemical synthesis*; D003911:Dextrans / Q000737:chemistry*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008823:Micelles; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry; D013440:Sulfides / Q000138:chemical synthesis*
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D003911:Dextrans; D058185:Magnetite Nanoparticles; D008823:Micelles; D013440:Sulfides; C097921:ferumoxtran-10; C515871:poly(ethylene glycol)-stabilized poly(propylene sulfide); D011092:Polyethylene Glycols