Biokinetic and dosimetric studies of 188Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical.


METHODS
(188)Re-HA was prepared by a direct labelling method to produce a ReO(O-COO)(2)-type coordination complex. (188)Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of (188)Re-HA was determined.


RESULTS
A stable complex of (188)Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T(1/2)alpha=21 min). Four hours after administration, (188)Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47+/-5.11% of the injected dose). The liver MTD in mice was approximately 40 Gy after 7.4 MBq of (188)Re-HA injection.


CONCLUSIONS
(188)Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.
Meléndez-Alafort
Laura
L
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, 35131 Padua, Italy.
Nadali
Anna
A
Zangoni
Elena
E
Banzato
Alessandra
A
Rondina
Maria
M
Rosato
Antonio
A
Mazzi
Ulderico
U
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D011868:Radioisotopes; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012211:Rhenium / Q000737:chemistry*; D014018:Tissue Distribution
D001798:Blood Proteins; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012211:Rhenium; D006820:Hyaluronic Acid