Use of Oily Contrast Medium for Selective Drug Targeting to Tumor: Enhanced Therapeutic Effect and X-Ray Image1

Highly malignant rabbit tumor (VX-2) was implanted at the periphery of the liver in 63 rabbits. Selective delivery of the anticancer agent copoly(styrenemaleic acid) conjugated to neocarzinostatin (SMANCS), which was dissolved in an oil contrast medium (Lipiodol), was performed by injection via the proper hepatic artery. The anticancer effect was also evaluated by various parameters. By using low-kVp X-ray examination of the resected rabbit liver, Lipiodol was found to distribute throughout the entire liver arterial lumina and was retained there for about 24 hr, but disappeared from the normal liver arterial lumina gradually. However, Lipiodol was retained in the tumor tissue and vessels for at least 7 days, whereas it was undetectable in any other organs. A radioactive analogue of Lipiodol, a chloroiodinated fatty acid, was prepared by using [14C]linoleic acid. This analogue was used in the study of the distribution by low-kVp X-ray examination, Sudan III staining, and autoradiography. Li piodol remained in the tumor vessels as well as the tumor cells. The use of the radioisotope yielded a quantitative profile of Lipiodol accumulation in tumor tissues; approximately 1000 times more at 15 min and 100 times more at 3 days after the injection than that of most other organs or plasma. Its major excretion route appeared to be through the bile and then the feces. The biological activity of SMANCS was also determined and was found to be significant in both tumor and liver even 7 days after injection. No activity was found in any other organ or tissue. The relatively high biological activity of SMANCS in the nontumorous liver adjacent to the tumor may be the result of contin uous drug release from SMANCS-Lipiodol in the tumor tissue. By histolÃ3gica! examination, massive tumor necrosis and infiltra tion of the inflammatory cells were found in the rabbits treated with SMANCS-Lipiodol. In the rabbits treated with Lipiodol alone, necrosis of the tumor was only minimal, and no infiltration of inflammatory cells was observed. Survival periods of the treated rabbits (n = 14) were signifi cantly longer than those of controls (n = 10); 23.1 ±5.5 (S.D.) days versus 16.1 ±2.9 days (p < 0.005), respectively, even though only one injection was used for this highly malignant tumor. Mean tumor size for both groups at laparotomy was 163.3 ±83.0 sq mm and 160.5 ±76.5 sq mm, respectively (not significant). At death, the mean tumor size was 517.1 ±664.7 sq mm in the treated rabbits and 1897.5 ±665.0 sq mm in the nontreated (mock operation) control rabbits (p < 0.005). Thus, 1A part of this work was supported by a grant from the Ministry of Health and Welfare of Japan. 2 Recipient of an Award from The Japanese Foundation for Multidisciplinary Treatment of Cancer, and a Science Grant from the Ministry of Education, Science, and Culture of Japan. To whom requests for reprints should be addressed. Received August 25, 1983; accepted February 8, 1984. the anticancer effect of SMANCS-Lipiodol was obvious even after a single dose.