Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Synthesis and Characterization of the Tumor Targeting Mitoxantrone-Insulin Conjugate

  • Liu, Wen-Sheng (Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, West China School of Pharmacy, Sichuan University) ;
  • Yuan-Huang (Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, West China School of Pharmacy, Sichuan University) ;
  • Zhang, Zhi-Rong (Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, West China School of Pharmacy, Sichuan University)
  • Published : 2003.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Anticancer drugs have serious side effects arising from their poor malignant cells selectivity, Since insulin receptors highly express on the cytomembrane of some kind of tumor cells, using insulin as the vector was expected to reduce serious side effects of the drugs. The objective of this study was to evaluate the tumor targeting effect of the newly synthesized mitoxantrone-insulin conjugate (MIT-INS) with the drug loading of 11.68%. In vitro stability trials showed MIT-INS were stable in buffers with different pH (2-8) at $37^{\circ}C$ within 120 h (less than 3% of free MIT released), and were also stable in mouse plasma within 48 h (less than 1 % of free MIT released). In vivo study on tumor-bearing mice showed that, compared with MIT [75.92 $\mu g \cdot$ h/g of the area under the concentration-time curve (AUC) and 86.85 h of mean residence time (MRT)], the conjugates had better tumor-targeting efficiency with enhanced tumor AUC of 126.53 1l9 h/g and MTR of 151.95 h. The conjugate had much lower toxicity to most other tissues with targeting indexes ($TI^c$) no larger than 0.3 besides good tumor targeting efficiency with $TI^c$ of 1.67. The results suggest the feasibility to promote the curative effect in ca.ncer chemotherapy by using insulin as the vector of anti-cancer drugs.

Keywords

References

  1. Ehninger, G., Schuler, U., and Porksch, B., Pharmacokinetics and metabolism of Mitoxantrone. Clin. Pharmacokine., 18, 365-80 (1990) https://doi.org/10.2165/00003088-199018050-00003
  2. Hanafusa, T., Yumoto, Y., and Nouso, K., Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett., 176, 149-158 (2002) https://doi.org/10.1016/S0304-3835(01)00736-4
  3. Huynh, H., Chow, P. K., and Ooi, L. L., A possible role for insulin-like growth factor-binding protein-3 autocrine/ paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ., 13, 115-122 (2002)
  4. Koutions, G., Stathopoulos, G. P., and Dontas, I., The effect of Doxrubicine and its analogue mitoxantrone on cardiac muscle and on serum lipids: an experimental study. Anticancer Res., 22, 815-820 (2002)
  5. Kurtaran, A., Li, S. R., and Raderer, M., Technetium-99mgalactocyl-neoglycoalyco- albumin combined with iodine-123 Tyr(A14) insulin visualized human hepatocellular carcinomas. J. Nucl. Med., 36, 1875-1881 (1995)
  6. Oka, Y., Waterland, R. A., and Killian, J. K., M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology, 35, 1153-1163 (2002) https://doi.org/10.1053/jhep.2002.32669
  7. Ou, X. H. and Kuang, A. R., The use of insulin as carrier in targeted therapy. J. Biomedical Engineering, 17, 87-90 (2000)
  8. Tanaka, S., Sugimachi, K., and Maehara, S., Oncogenic signal transduction and therapeutic strategy for hepatocellular carcinoma. Surgery, 131, S142-147 (2002) https://doi.org/10.1067/msy.2002.119495
  9. Theresa, M. A., Ligand-targeted therapeutics in anticancer therapy. Nature, 2, 750-761 (2002)
  10. Von Horn, H., Tally, M., and Hall, K., Expression levels of insulin-like growth factor binding proteins and insulin receptor isoforms in hepatoblastomas. Cancer Lett., 162, 253-260 (2001) https://doi.org/10.1016/S0304-3835(00)00668-6
  11. Wang, J. X., Sun, X., and Zhang, Z. R., Enhanced brain targeting by synthesis of 3,5-dioctanoyl-5-fluoro-2-deoxyuridine and incorporation into solid lipid nanoparticles. European J. Pharmaceutics Biopharmaceutics, 54, 285-290 (2002) https://doi.org/10.1016/S0939-6411(02)00083-8
  12. Zhang, Z. R. and Zhang, Q. Z., Comparison of liver targeting effect of mitoxantrone-bovine serum albumin-microspheres with galactosyl-mitoxantrone-bovine serum albumin-microspheres. Chi. J. Hospital Pharmacy, 19, 140-141 (1999)