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Role of Lipid-Soluble Complexes in Targeted Tumor Therapy

¹ Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
² Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
³ University of Medicine and Dentistry of New Jersey, Newark, New Jersey
⁴ National Center of Clinical and Transfusional Haematology, Sofia, Bulgaria

Radionuclide therapy remains a promising arsenal against cancer. However, low tumor uptake, high radiation dose to normal organs, and subsequent adverse effects are challenging problems. This study assessed the therapeutic significance of lipid-soluble compounds of ¹¹¹In, which passively diffuse through the cell membrane, bind to cytoplasmic components, and remain cell bound until decay. Methods: Athymic nude mice bearing human colorectal, prostate, or breast cancer received 11.1–14.8 MBq (300–400 µCi) ¹¹¹In-8-hydroxyquinoline (¹¹¹In-oxine) or ¹¹¹In-mercaptopyridine-N-oxide (¹¹¹In-Merc) in 200 µL solution intratumorally through a multihole needle. Tumors in some mice were dissected, and 20-µm-thick sections were autoradiographed. In additional mice, tumor diameter was measured daily, mice were imaged and weighed, and blood samples were drawn for determination of neutrophil counts for up to 28 d after injection. Some mice were sacrificed at predetermined times for quantitative tissue distribution of ¹¹¹In. Additionally, tumor cells were labeled with ¹¹¹In-oxine and homogenized, and ¹¹¹In associated with cell components was determined using polyacrylamide gel electrophoresis. Radiation dose that could be delivered to adjacent tissues was estimated. The ¹¹¹In absorbed dose as a function of radial position r in a 1-g tumor was theoretically compared with those of ß-emitting radionuclides ⁹⁰Y and ¹⁷⁷Lu. Results: More than 85% of ¹¹¹In remained in tumors, bound to cell cytoplasmic components of apparent molecular weights 250 and 6 kDa. ¹¹¹In in tumors was uniformly distributed. Only 2% of the injected ¹¹¹In was in the liver, kidneys, and carcass. Statistical analysis showed that on day 28, control tumors grew >100%, whereas treated tumors either had growth arrest or grew only slowly (17%). The estimated radiation dose per megabecquerel (millicurie) injected was 90 Gy/g (9,000 rad/g), of which 64% was from conversion electrons, 16% from Auger electrons, 20% from -photons and x-rays, respectively. Radiation dose to adjacent normal organs was 5%–10% of the radiation dose to the tumor and negligible to the liver and kidneys. Neutrophil counts remained unchanged. Mouse body weight was ±10% of the initial weight. The radiation dosimetry for ¹¹¹In and ¹⁷⁷Lu compared favorably, but not that of ⁹⁰Y. Conclusion: Treatment is independent of receptor density, heterogeneity, or the hypoxic status of cells. It is applicable to treat all known and accessible tumor types, and it delivers a negligible radiation dose to vital organs and only 5%–10% of the radiation dose to organs adjacent to the tumor. Intratumoral administration of ¹¹¹In-oxine appears to be a feasible, effective, safe, and promising treatment for cancer.

Key Words: targeted radionuclide therapy