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Abstract
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.
Copyright 2002 Elsevier Science B.V.