A Folate Receptor-a–Specific Ligand That Targets Cancer Tissue and Not Sites of Inflammation

Folic acid has been frequently exploited to target attached drugs to cells that overexpress a folate receptor (FR). Unfortunately, folic acid and folate-linked drugs bind equally well to both major isoforms of the FR—that is, FR-a, which is primarily expressed on malignant cells, and FR-b, which is upregulated on activated monocytes and macrophages. Because both major isoforms of FR can be expressed simultaneously in the same organism, folic acid cannot enable selective targeting of therapeutic and imaging agents to either tumor masses or sites of inflammation. In an effort to develop a targeting ligand that can selectively deliver attached imaging and therapeutic agents to tumor cells, we constructed a reduced and alkylated form of folic acid, N5, N10-dimethyl tetrahydrofolate (DMTHF) that exhibits selectivity for FR-a.Methods: DMTHF–99mTc was injected into mice bearing FR-a–expressing tumor xenografts and imaged by g-scintigraphy. The selectivity for FR-a over FR-b i