Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images.
The purpose of this study was to evaluate the therapeutic efficacy and limitations of alpha-particle-emitting radiolabeled compounds by means of 2-dimensional histological images and distribution of activity on a microscopic level.


METHODS
A microdosimetric approach based on histological images is used to analyze the therapeutic effectiveness of alpha-particle-emitting (211)At and (213)Bi conjugated to 201B monoclonal antibody (mAb), which is reactive with murine lung blood vessels for the treatment of EMT-6 lung tumor colonies in nude mice. Autoradiography images were used to define the tissue morphology and activity distribution within lung tissues. Two animal groups were studied: Group A consisted of animals bearing small tumors (<130 micro m) and group B consisted of larger tumors (<600 micro m). Probability density functions (pdf) described the variability in average absorbed dose and survival probability among normal and tumor target cells and, in turn, were used to assess the survival fraction of tumor and normal tissue.


RESULTS
The average absorbed dose to tumor cells per unit cumulated activity concentration for animals in group A was 1.10 x 10(-3) and 1.37 x 10(-3) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively, and for animals in group B was 3.8 x 10(-4) and 5.6 x 10(-4) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively. The fraction of tumor cells that received a zero absorbed dose for animals in group A was 0.04% for (213)Bi and 0.2% for (211)At and for animals in group B was 25% for (213)Bi and 31% for (211)At. Both (213)Bi- and (211)At-labeled 201B mAb were effective therapies for animals with small tumors, where predicted therapeutic effectiveness was consistent with experimental findings; however, they were ineffective for animals with larger tumors.


CONCLUSIONS
Microdosimetric methods based on knowledge of tissue morphology and activity distribution on a small-scale level can be a useful tool for evaluating a priori the therapeutic efficacy and limitations of targeted alpha-particle endoradiotherapeutic strategies.
Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA. akaba001@mc.duke.edu
Gamal
G
Akabani
Stephen J
SJ
Kennel
Michael R
MR
Zalutsky
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D001246:Astatine / Q000627:therapeutic use*; D001729:Bismuth / Q000627:therapeutic use*; D002470:Cell Survival / Q000528:radiation effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D011874:Radiometry; D011879:Radiotherapy Dosage; D014407:Tumor Cells, Cultured
D011868:Radioisotopes; D001729:Bismuth; D001246:Astatine