The receptor for
folic acid constitutes a useful target for
tumor-specific
drug delivery, primarily because: (1) it is upregulated in many human
cancers, including
malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the
folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3)
folate receptor density appears to increase as the stage/grade of the
cancer worsens. Thus,
cancers that are most difficult to treat by classical methods may be most easily targeted with
folate-linked
therapeutics. To exploit these peculiarities of
folate receptor expression,
folic acid has been linked to both low molecular weight drugs and
macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of
folic acid to macromolecules has been shown to enhance their delivery to
folate receptor-expressing
cancer cells in vitro in almost all situations tested.
Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid
tumors. Nevertheless, prominent examples do exist where
folate targeting has significantly improved the outcome of a macromolecule-based
therapy, leading to complete cures of established
tumors in many cases. This review presents a brief mechanistic background of
folate-targeted macromolecular
therapeutics and then summarizes the successes and failures observed with each major application of the technology.