Abstract
Purpose. The expression of folate receptor (FR) is amplified in many types of human cancers. Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model.
Methods. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed.
Results. Plasma folate level remained in the physiologic range relative to that in humans. F-L-DOX exhibited an extended systemic circulation time similar to that of L-DOX. Mice that received f-L-DOX showed greater tumor growth inhibition and a 31% higher (p < 0.01) increase in lifespan compared to those that received L-DOX. Meanwhile, free DOX given at the same dose resulted in significant toxicity and was less effective in prolonging animal survival.
Conclusions. FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
D. Goren, A. T. Horowitz, D. Tzemack, M. Tarshish, S. Zalipsky, and A. Gabizon. Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. Clin. Cancer Res. 6:1949-1957 (2000).
P. Garin-Chesa, I. Campbell, P. E. Saigo, J. L. Lewis Jr., L. J. Old, and W. J. Rettig. Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. Am. J. Pathol. 142:557-567 (1993).
J. F. Ross, P. K. Chaudhuri, and M. Ratnam. Differential #x00AEulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines—Physiologic and clinical implications. Cancer 73:2432-2443 (1994).
J. F. Ross, H. Wang, F. G. Behm, P. Mathew, M. Wu, R. Booth, and M. Ratnam. Folate receptor type Β is neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer 85:348-357 (1999).
J. J. Sudimack and R. J. Lee. Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev. 41:147-162 (2000).
J. A. Reddy and P. S. Low. Folate-mediated targeting of therapeutic and imaging agents to cancers. Crit. Rev. Ther. Drug Carrier Syst. 15:587-627 (1998).
R. J. Lee and P. S. Low. Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J. Biol. Chem. 269:3198-3204 (1994).
W. Guo, T. Lee, J. J. Sudimack, and R. J. Lee. Receptor-specific delivery of liposomes via folate-PEG-chol. J. Liposome Res. 10:179-195 (2000).
A. Gabizon. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest. 19:424-436 (2001).
R. J. Lee and P. S. Low. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Bio#x03A7;m. Biophys. Acta 1233:134-144 (1995).
A. Gabizon, A. T. Horowitz, D. Goren, D. Tzemach, F. Madelbaum-Shavit, M. M. Qazen, and S. Zalipsky. Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: in vitro studies. Bioconjug. Chem. 10:289-298 (1999).
X. Q. Pan, X. Zheng, G. Shi, H. Wang, M. Ratnam, and R. J. Lee. Strategy for the treatment of acute myelogenous leukemia based on folate receptor Β-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood 100:594-602 (2002).
X. Q. Pan, H. Wang, and R. J. Lee. Boron delivery to a murine lung carcinoma using folate receptor-targeted liposomes. Anticancer Res. 22:1629-1634 (2002).
M. J. Turk, D. J. Waters, G. Breur, W. R. Widmer, and P. S. Low. Folate-mediated targeting of liposomes to tumor cells and Mac-1 expressing cells in vivo. J. Control. Release 74:369-376 (2001).
J. C. Stewart. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal. Biochem. 104:10-14 (1980).
W. Guo, G. H. Hinkle, and R. J. Lee. 99mTc-HYNIC-folate, a novel receptor-based targeted radiopharmaceutical for tumor imaging. J. Nucl. Med. 40:1563-1569 (1999).
J. Plowman, D. J. Dykes, M. Hollingshead, L. Simpson-Herren, and M. C. Alley. Human tumor xenograft models in NCI drug development. In B. Teicher (ed.), Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Humana Press, Totowa, New Jersey, 1997, pp. 101-125.
R. L. Hong, C. J. Huang, Y. L. Tseng, V. F. Pang, S. T. Chen, J. J. Liu, and F. H. Chang. Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: is surface coating with polyethylene glycol beneficial? Clin. Cancer Res. 5:3645-3652 (1999).
J. Song, A. Medline, J. B. Mason, S. Gallinger, and Y.-I. Kim. Effects of dietary folate on intestinal tumorigenesis in the Apc Min mouse. Cancer Res. 60:5424-5440 (2000).
R. F. Branda, E. Nigels, A. R. Lafayette, and M. Hacker. Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats. Blood 92:2471-2476 (1998).
J. M. Lawrence, D. B. Petitti, M. Watkins, and M. A. Umekubo. Trends in serum folate after food fortification. Lancet 354:915-916 (1999).
R. L. Walzem and A. J. Clifford. Folate deficiency in rats fed diets containing free amino acids or intact proteins. J. Nutr. 118:1089-1096 (1988).
R. K. Jain. Delivery of molecular medicine to solid tumors:lessons from in vivo imaging of gene expression and function. J. Control. Release 73:7-25 (2001).
J. W. Park, K. Hong, D. B. Kirpotin, D. Papahadjopoulos, and C. C. Benz. Immunoliposomes for cancer treatment. Adv. Pharmacol. 40:399-435 (1997).
T. Shinoda, A. Takagi, A. Maeda, S. Kagatani, Y. Konno, and M. Hashida. In vivo fate of folate-BSA in non-tumor-and tumor-bearing mice. J. Pharm. Sci. 87:1521-1526 (1998).
J. L.-S. Au, S. H. Jang, and M. G. Wientjes. Clinical aspects of drug delivery to tumors. J. Control. Release 78:81-95 (2002).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pan, X.Q., Wang, H. & Lee, R.J. Antitumor Activity of Folate Receptor-Targeted Liposomal Doxorubicin in a KB Oral Carcinoma Murine Xenograft Model. Pharm Res 20, 417–422 (2003). https://doi.org/10.1023/A:1022656105022
Issue Date:
DOI: https://doi.org/10.1023/A:1022656105022