In vivo stability of supramolecular host-guest complexes monitored by dual-isotope multiplexing in a pre-targeting model of experimental liver radioembolization

J Control Release. 2019 Jan 10;293:126-134. doi: 10.1016/j.jconrel.2018.11.020. Epub 2018 Nov 25.

Abstract

Introduction: Cyclodextrin (CD)-based supramolecular interactions have been proposed as nanocarriers for drug delivery. We previously explored the use of these supramolecular interactions to perform targeted hepatic radioembolization. In a two-step procedure the appropriate location of the diagnostic pre-targeting vector can first be confirmed, after which the therapeutic vector will be targeted through multivalent host-guest interactions. Such a procedure would prevent therapeutic errors that come from a mismatch between diagnostic and therapeutic procedures. In the current study we explored the use of dual-isotope imaging to assess the in vivo stability of the formed complex and individual components.

Methods: Dual-isotope imaging of the host and guest vectors was performed after labeling of the pre-targeted guest vector, being adamantane (Ad) functionalized macro-aggregated albumin (MAA) particles, with technetium-99 m (99mTc-MAA-Ad). The host vector, Cy50.5CD9PIBMA39, was labeled with indium-111 (111In-Cy50.5CD9PIBMA39). The in situ stability of both the individual vectors and the resulting [MAA-Ad-111In-Cy50.5CD9PIBMA39] complexes was studied over 44 h at 37 °C in a serum protein-containing buffer. In vivo, the host vector 111In-Cy50.5CD9PIBMA39 was administered two hours after local deposition of 99mTc-MAA-Ad in mice. Dual-isotope SPECT imaging and quantitative biodistribution studies were performed between 2 and 44 h post intravenous host vector administration.

Results: The individual vectors portrayed <5% dissociation of the radioisotope over the course of 20 h. Dissociation of [MAA-Ad-111In-Cy50.5CD9PIBMA39] complexes remained within a 10-20% range after incubation in serum. In vivo dual-isotope SPECT imaging of host-guest interactions revealed co-localization of the tracer components. Quantitative assessment of the biodistribution revealed that the hepatic accumulation of the host vector nearly doubled between 2 h and 44 h post-injection (from 14.9 ± 6.1%ID/g to 26.2 ± 2.1%ID/g).

Conclusions: Assessment of intra-hepatic host-guest complexation was successfully achieved using dual isotope multiplexing, underlining the complex stability that was found in situ (up to 44 h in serum). Overall, the results obtained in this study highlight the potential of supramolecular chemistry as a versatile platform that could advance the field of nanomedicine.

Keywords: Dual-labeling; Interventional radiology; Pre-targeting; Radioembolization; Supramolecular chemistry; Theranostics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins
  • Animals
  • Embolization, Therapeutic*
  • Indium Radioisotopes
  • Liver*
  • Maleic Anhydrides
  • Mice
  • Polymers
  • Radiopharmaceuticals
  • Technetium
  • beta-Cyclodextrins

Substances

  • Albumins
  • Indium Radioisotopes
  • Maleic Anhydrides
  • Polymers
  • Radiopharmaceuticals
  • beta-Cyclodextrins
  • poly(isobutylene-alt-maleic anhydride)
  • macro aggregates of albumin
  • Technetium
  • Indium-111