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Purpose.
Octreotide (OCT) was reversibly lipidized to improve the pharmacological effect and to increase the plasma half-life and the liver retention of OCT for greater therapeutic potential in the treatment of liver cancers such as hepatocellular carcinoma.
Methods.
OCT was chemically modified using reversible aqueous lipidization (REAL) technology. REAL-modified OCT (REAL-OCT) was characterized with high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. A single dose of OCT or REAL-OCT or vehicle only was subcutaneously administered to male Sprague-Dawley rats, and the plasma growth hormone (GH) levels were measured after an intravenous injection of 2.5 μg/kg of growth hormone releasing factor (GRF) to assess the ability of REAL-OCT on GH inhibition. Radio-iodinated Tyr3-OCT (TOC) and REAL-TOC were used for pharmacokinetic studies.
Results.
At 0.1 mg/kg, REAL-OCT inhibited the GRF-induced GH surge in rats for a greater than 24-h period in comparison to the 6-h period for OCT. The distribution and elimination half-life for 125I-REAL-TOC were 1.4 h and 6.6 h, respectively, which were significantly longer than those of 125I-TOC. Sustained high blood concentrations and reduced in vivo degradation were observed for 125I-REAL-TOC. In addition, 125I-REAL-TOC appeared to be targeted to the liver with persistent high liver retention.
Conclusions.
REAL-OCT has a significantly enhanced pharmacological effect, and this is most likely due to the favorable changes in the pharmacokinetic parameters upon lipidization. The observed liver targeting effect of REAL-TOC suggests that REAL-OCT might be advantageous over OCT in treating liver cancers.
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References
1. S. W. Lamberts, A. J. van der Lely, W. W. de Herder, and L. J. Hofland. Octreotide. N. Engl. J. Med. 334:246–254 (1996).
2. E. A. Kouroumalis. Octreotide for cancer of the liver and biliary tree. Chemotherapy 47:150–161 (2001).
3. D. N. Samonakis, J. Moschandreas, T. Arnaoutis, P. Skordilis, C. Leontidis, I. Vafiades, and E. Kouroumalis. Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol. Rep. 9:903–907 (2002).
4. M. Raderer, M. H. Hejna, C. Muller, G. V. Kornek, A. Kurtaran, I. Virgolini, W. Fiebieger, G. Hamilton, and W. Scheithauer. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int. J. Oncol. 16:1197–1201 (2000).
5. J. T. Siveke, C. Folwaczny, and C. Herberhold. Complete regression of advanced HCC with long acting octreotide. Gut 52:1531 (2003).
6. C. Scarpignato and I. Pelosini. Somatostatin analogs for cancer treatment and diagnosis: an overview. Chemotherapy 47:1–29 (2001).
7. C. Bousquet, E. Puente, L. Buscail, N. Vaysse, and C. Susini. Antiproliferative effect of somatostatin and analogs. Chemotherapy 47:30–39 (2001).
8. P. Dasgupta, A. Singh, and R. Mukherjee. N-terminal acylation of somatostatin analog with long chain fatty acids enhances its stability and anti-proliferative activity in human breast adenocarcinoma cells. Biol. Pharm. Bull. 25:29–36 (2002).
9. P. Dasgupta, A. T. Singh, and R. Mukherjee. Lipophilization of somatostatin analog RC-160 improves its bioactivity and stability. Pharm. Res. 16:1047–1053 (1999).
10. P. Dasgupta, A. T. Singh, and R. Mukherjee. Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its anti-proliferative activity on human oral carcinoma cells in vitro. Life Sci. 66:1557–1570 (2000).
11. W. C. Shen, J. Wang, and D. Shen. Reversible lipidization for the delivery of peptide and protein drugs. In S. Frøkjær, L. Christrup, and P. Krogsgaard-Larsen (eds.), Peptide and Protein Drug Delivery, Munksgaard, Copenhagen, 1998, pp. 397–408.
12. L. Honeycutt, J. Wang, H. Ekrami, and W. C. Shen. Comparison of pharmacokinetic parameters of a polypeptide, the Bowman-Birk protease inhibitor (BBI), and its palmitic acid conjugate. Pharm. Res. 13:1373–1377 (1996).
13. J. Wang, D. Shen, and W. C. Shen. Preparation, purification, and characterization of a reversibly lipidized desmopressin with potentiated anti-diuretic activity. Pharm. Res. 16:1674–1679 (1999).
14. J. Wang, D. Chow, H. Heiati, and W. C. Shen. Reversible lipidization for the oral delivery of salmon calcitonin. J. Control. Rel. 88:369–380 (2003).
15. W. A. Murphy, C. A. Meyers, and D. H. Coy. Potent, highly selective inhibition of growth hormone secretion by position 4 somatostatin analogs. Endocrinology 109:491–495 (1981).
16. L. Bokser and A. V. Schally. Delayed release formulation of the somatostatin analog RC-160 inhibits the growth hormone (GH) response to GH-releasing factor-(1-29)NH2 and decreases elevated prolactin levels in rats. Endocrinology 123:1735–1739 (1988).
17. P. J. McConahey and F. J. Dixon. Radioiodination of proteins by the use of the chloramine-T method. Methods Enzymol. 70:210–213 (1980).
18. T. Karashima, R. Z. Cai, and A. V. Schally. Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release. Life Sci. 41:1011–1019 (1987).
19. V. J. Hruby. Conformational restrictions of biologically active peptides via amino acid side chain groups. Life Sci. 31:189–199 (1982).
20. S. Siehler, K. Seuwen, and D. Hoyer. [125I][Tyr3]octreotide labels human somatostatin sst2 and sst5 receptors. Eur. J. Pharmacol. 348:311–320 (1998).
21. S. W. Lamberts, J. C. Reubi, W. H. Bakker, and E. P. Krenning. Somatostatin receptor imaging with 123I-Tyr3-Octreotide. Z. Gastroenterol. 28:20–21 (1990).
22. W. H. Bakker, E. P. Krenning, W. A. Breeman, J. W. Koper, P. P. Kooij, J. C. Reubi, J. G. Klijn, T. J. Visser, R. Docter, and S. W. Lamberts. Receptor scintigraphy with a radioiodinated somatostatin analogue: radiolabeling, purification, biologic activity, and in vivo application in animals. J. Nucl. Med. 31:1501–1509 (1990).
23. M. Lemaire, M. Azria, R. Dannecker, P. Marbach, A. Schweitzer, and G. Maurer. Disposition of sandostatin, a new synthetic somatostatin analogue, in rats. Drug Metab. Dispos. 17:699–703 (1989).
24. T. Yamada, Y. Kato, H. Kusuhara, M. Lemaire, and Y. Sugiyama. Characterization of the transport of a cationic octapeptide, octreotide, in rat bile canalicular membrane: possible involvement of P-glycoprotein. Biol. Pharm. Bull. 21:874–878 (1998).
25. G. Fricker, V. Dubost, D. Schwab, C. Bruns, and C. Thiele. Heterogeneity in hepatic transport of somatostatin analog octapeptides. Hepatology 20:191–200 (1994).
26. Z. Kan, P. A. McCuskey, K. C. Wright, and S. Wallace. Role of Kupffer cells in iodized oil embolization. Invest. Radiol. 29:990–993 (1994).
27. N. C. Phillips and M. S. Tsao. Liposomal muramyl dipeptide therapy of experimental M5076 liver metastases in mice. Cancer Immunol. Immunother. 33:85–90 (1991).
28. D. M. Nott, J. Y. Baxter, J. S. Grime, D. W. Day, T. G. Cooke, and S. A. Jenkins. Effects of a somatostatin analogue (SMS 201-995) on the growth and development of hepatic tumour derived by intraportal injection of Walker cells in the rat. Br. J. Surg. 76:1149–1151 (1989).
29. N. Davies, H. Kynaston, J. Yates, B. A. Taylor, and S. A. Jenkins. Octreotide, the reticuloendothelial system, and experimental liver tumour. Gut 36:610–614 (1995).
30. N. Davies, J. Yates, H. Kynaston, B. A. Taylor, and S. A. Jenkins. Effects of octreotide on liver regeneration and tumour growth in the regenerating liver. J. Gastroenterol. Hepatol. 12:47–53 (1997).
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Yuan, L., Wang, J. & Shen, WC. Reversible Lipidization Prolongs the Pharmacological Effect, Plasma Duration, and Liver Retention of Octreotide. Pharm Res 22, 220–227 (2005). https://doi.org/10.1007/s11095-004-1189-z
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DOI: https://doi.org/10.1007/s11095-004-1189-z