Multiscale Framework for Imaging Radiolabeled Therapeutics

Mol Pharm. 2015 Dec 7;12(12):4554-60. doi: 10.1021/acs.molpharmaceut.5b00392. Epub 2015 Nov 5.


The resistance of a tumor to a drug is the result of bulk properties of the tumor tissue as well as phenotypic variations displayed by single cells. Here, we show that radioisotopic detection methods, commonly used for tracking the tissue distribution of drug compounds, can be extended to the single-cell level to image the same molecule over a range of physical scales. The anticancer drug rituximab was labeled with short-lived radionuclides ((89)Zr/(64)Cu) and its accumulation at the organ level was imaged using PET in a humanized transgenic mouse model of non-Hodgkin's lymphoma. To capture the distribution of the drug at a finer scale, tissue sections and single living cells were imaged using radioluminescence microscopy (RLM), a novel method that can detect radionuclides with single-cell resolution. In vivo PET images (24 h postinjection) showed that [(89)Zr]rituximab targeted the intended site of human CD20 expression, the spleen. Within this organ, RLM was used to resolve radiotracer accumulation in the splenic red pulp. In a separate study, RLM highlighted marked differences between single cells, with binding of the radiolabeled antibody ranging from background levels to 1200 radionuclides per cell. Overall, RLM images demonstrated significantly higher spatial resolution and sensitivity than conventional storage-phosphor autoradiography. In conclusion, this combination of PET and RLM provides a unique opportunity for exploring the molecular mechanism of drugs by tracking the same molecule over multiple physical scales, ranging from single living cells to organs substructures and entire living subjects.

Keywords: autoradiography; positron emission tomography; radioisotope; single cell pharmacokinetics.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD20 / metabolism
  • Antineoplastic Agents / pharmacology*
  • Autoradiography / methods
  • Disease Models, Animal
  • Humans
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Mice
  • Mice, Transgenic
  • Positron-Emission Tomography / methods
  • Radioisotopes / administration & dosage
  • Radioisotopes / metabolism*
  • Radiopharmaceuticals / administration & dosage
  • Radiopharmaceuticals / metabolism*
  • Rituximab / metabolism*
  • Rituximab / pharmacology*
  • Tissue Distribution


  • Antigens, CD20
  • Antineoplastic Agents
  • Radioisotopes
  • Radiopharmaceuticals
  • Rituximab