Development of multivalent radioimmunonanoparticles for cancer imaging and therapy

Arutselvan Natarajan, Cheng Y. Xiong, Cordula Gruettner, Gerald L Denardo, Sally J. DeNardo

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Background: Noninvasive, focused hyperthermia can be achieved by using an externally applied alternating magnetic field (AMF) if effective concentrations of nanoparticles can be delivered to the target cancer cells. Targeting agents, for example, monoclonal antibodies or peptides, linked to magnetic iron oxide nanoparticles (NP), represent a promising strategy to target cancer cells and hyperthermia. Methods: We have developed a new radioconjugate NP ( 111In-DOTA-di-scFv-NP), using recombinantly generated antibody fragments, di-scFv-c, for the imaging and therapy of anti-MUC-1-expressing cancers, because aberrant MUC-1 is abundantly expressed on the majority of human epithelial cancers. Anti-MUC-1 di-scFv-c (50 kDa) were engineered, generated, and selected to link maleimide functionalized nanoparticles (NP-M). DOTA chelate was conjugated with di-scFv-c for radionuclide chelation to trace the radioimmunonanoparticles (RINPs) in vivo. Results: Heat-inducing NP-M were prepared with maleimide density >15 per particle for site-specific thiolation. The specific activity of the RINP was 4-5 μCi 111In/mg with >10 molecules of di-scFv per NP. We characterized the RINP by polyacrylamide gel electrophoresis, cellulose acetate electrophoresis, size-exclusion chromatography, and tumor-cell binding. RINP had a >90% di-scFv conjugated to NP and an immunoreactivity >80% relative to unmodified di-scFv-c on HBT 3477 and DU145 tumor cells. Pharmacokinetics and whole-body autoradiography studies demonstrated that a 5% injecetd dose was targeted in tumor after 24 hours. Conclusions: Further development of this new preparation of RINP may provide uniquely high tumor-targeting NP for AMF-driven tumor hyperthermia with less spleen and kidney accumulation.

Original languageEnglish (US)
Pages (from-to)82-91
Number of pages10
JournalCancer Biotherapy and Radiopharmaceuticals
Volume23
Issue number1
DOIs
StatePublished - Feb 1 2008

    Fingerprint

Keywords

  • di-scFv-c
  • Immunoreactivity
  • Maleimide functionalization
  • MUC-1
  • Nanoparticle
  • Site-specific conjugation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

Cite this