The receptor for folic acid is an established tumor marker, showing elevated expression in many epithelial cancers, including cancers of the ovary, cervix, endometrium, kidney, brain and head and neck. When folic acid is covalently linked to another molecule or particle, it may still bind with high affinity (KD -1 0-9M) to the folate receptor (FR), but will lose all affinity for the reduced folate carrier (a transport protein that mediates folate uptake by many nonmalignant cells). Folate conjugates are, therefore, bound and internalized only by FR-expressing cells. Because of FR upregulation on cancer cells, folate ligation has been hypothesized to convert the vitamin into a molecular """"""""Trojan Horse"""""""" that can facilitate targeting and delivery of attached therapeutic or imaging agents into malignant cells. While results from cell culture studies have been very encouraging, few quantitative data are available to permit an assessment of the therapeutic potential of folatemediated drug targeting in human patients. In our first two aims, we propose to first obtain this quantitative information. In the last two aims, we will test the therapeutic potential of the strategy in mouse tumor models. First, we will measure the in vivo recycling rate of FR in several relevant cancer models. Together with published data on the levels of FR expression in various human cancers, this recycling information should enable a more quantitative estimate of the total uptake and delivery capacity of the folate-mediated targeting pathway. Second, we will address how the size of a folate conjugate impacts its accessibility to cancer cells in vivo. Recent data indicate that the ability of folate conjugates to bind to and decorate cells throughout a tumor mass may be limited by molecular size. Quantitative data on this matter will be required to guide the design of folate-linked therapeutics. Third, we will synthesize and test folate-conjugated cytotoxic drugs for therapeutic efficacy in vivo. And finally, we will define the molecular and cellular bases of a novel folate-targeted immunotherapy that we have already shown can eradicate established tumors in mice without damaging normal tissues.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Therapeutics Subcommittee 1 (ET)
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Forry, Suzanne L
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Purdue University
Schools of Arts and Sciences
West Lafayette
United States
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Bandara, N Achini; Bates, Cody D; Lu, Yingjuan et al. (2017) Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer. Mol Cancer Ther 16:461-468
Sega, Emanuela I; Lu, Yingjuan; Ringor, Michael et al. (2008) Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy. Int J Radiat Oncol Biol Phys 71:559-66
Hartmann, Lynn C; Keeney, Gary L; Lingle, Wilma L et al. (2007) Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer 121:938-42
Lu, Yingjuan; Sega, Emanuela; Low, Philip S (2005) Folate receptor-targeted immunotherapy: induction of humoral and cellular immunity against hapten-decorated cancer cells. Int J Cancer 116:710-9
Sandoval, Ruben M; Kennedy, Michael D; Low, Philip S et al. (2004) Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy. Am J Physiol Cell Physiol 287:C517-26
Turk, Mary Jo; Waters, David J; Low, Philip S (2004) Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett 213:165-72
Lu, Yingjuan; Sega, Emanuela; Leamon, Christopher P et al. (2004) Folate receptor-targeted immunotherapy of cancer: mechanism and therapeutic potential. Adv Drug Deliv Rev 56:1161-76
Lu, Yingjuan; Low, Philip S (2003) Targeted immunotherapy of cancer: development of antibody-induced cellular immunity. J Pharm Pharmacol 55:163-7
Kennedy, Michael D; Jallad, Karim N; Lu, June et al. (2003) Evaluation of folate conjugate uptake and transport by the choroid plexus of mice. Pharm Res 20:714-9
Lu, Yingjuan; Low, Philip S (2003) Immunotherapy of folate receptor-expressing tumors: review of recent advances and future prospects. J Control Release 91:17-29

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