title: Role of lipid-soluble complexes in targeted tumor therapy.
abstract: 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 (111)In, 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 micro Ci) (111)In-8-hydroxyquinoline ((111)In-oxine) or (111)In-mercaptopyridine-N-oxide ((111)In-Merc) in 200 micro L solution intratumorally through a multihole needle. Tumors in some mice were dissected, and 20- micro m-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 (111)In. Additionally, tumor cells were labeled with (111)In-oxine and homogenized, and (111)In associated with cell components was determined using polyacrylamide gel electrophoresis. Radiation dose that could be delivered to adjacent tissues was estimated. The (111)In absorbed dose as a function of radial position r in a 1-g tumor was theoretically compared with those of beta-emitting radionuclides (90)Y and (177)Lu.
  
  
  RESULTS
  More than 85% of (111)In remained in tumors, bound to cell cytoplasmic components of apparent molecular weights 250 and 6 kDa. (111)In in tumors was uniformly distributed. Only 2% of the injected (111)In 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 gamma-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 (111)In and (177)Lu compared favorably, but not that of (90)Y.
  
  
  CONCLUSIONS
  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 (111)In-oxine appears to be a feasible, effective, safe, and promising treatment for cancer.
authors.affiliation: Department of Radiology, Thomas Jefferson University, 1020 Locust Street, Suite 359JAH, Philadelphia, PA 19107, USA. Mathew.Thakur@mail.tju.edu
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Thakur
authors.forename: Ron
authors.initials: R
authors.lastname: Coss
authors.forename: Roger
authors.initials: R
authors.lastname: Howell
authors.forename: Donka
authors.initials: D
authors.lastname: Vassileva-Belnikolovska
authors.forename: Jeff
authors.initials: J
authors.lastname: Liu
authors.forename: Sampath P
authors.initials: SP
authors.lastname: Rao
authors.forename: Greg
authors.initials: G
authors.lastname: Spana
authors.forename: Phyllis
authors.initials: P
authors.lastname: Wachsberger
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Leeper
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D016503:Drug Delivery Systems / Q000379:methods; D005240:Feasibility Studies; D006801:Humans; D015552:Injections, Intralesional / Q000379:methods; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015125:Oxyquinoline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D012995:Solubility; D013871:Thiones; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D008055:Lipids; D009942:Organometallic Compounds; D011725:Pyridines; D019275:Radiopharmaceuticals; D013871:Thiones; C032950:indium oxine; D015125:Oxyquinoline; C008704:pyrithione