Conspectus
Active targeting
uses molecular fragments that bind receptors overexpressed
on cell surfaces to deliver cargoes, and this selective delivery to
diseased over healthy tissue is valuable in diagnostic imaging and
therapy. For instance, targeted near-infrared (near-IR) dyes can mark
tissue to be excised in surgery, and radiologists can use active targeting
to concentrate agents for positron emission tomography (PET) in tumor
tissue to monitor tumor metastases. Selective delivery to diseased
tissue is also valuable in some treatments wherein therapeutic indexes
(toxic/effective doses) are key determinants of efficacy. However,
active targeting will only work for cells expressing the pivotal cell
surface receptor that is targeted. That is a problem because tumors,
even ones derived from the same organ, are not homogeneous, patient-to-patient
variability is common, and heterogeneity can occur even in the same
patient, so monotherapy with one actively targeted agent is unlikely
to be uniformly effective. A particular category of fluorescent heptamethine
cyanine-7 (Cy-7) dyes, here called tumor seeking dyes, offer a way to circumvent this problem because they selectively accumulate in any solid tumor. Furthermore, they persist in tumor tissue for several days, sometimes longer
than 72 h. Consequently, tumor seeking dyes are near-IR fluorescent
targeting agents that, unlike mAbs (monoclonal antibodies), accumulate
in any solid lesion, thus overcoming tumor heterogeneity,
and persist there for long periods, circumventing
the rapid clearance problems that bedevil low molecular mass drugs.
Small molecule imaging agents and drugs attached to tumor-seeking
dyes have high therapeutic indices and long residence times in cancer
cells and tumor tissue. All this sounds too good to be true. We believe
most of this is true, but the controversy is associated
with how and why these characteristics arise. Prior to our studies,
the prevailing hypothesis, often repeated, was that tumor seeking
dyes are uptaken by organic anion transporting polypeptides (OATPs)
overexpressed on cancer cells. This Account summarizes evidence indicating
tumor seeking Cy-7 dyes have exceptional accumulation and persistence
properties because they covalently bind to albumin in vivo. That adduct formation provides a convenient way to form albumin-bound
pharmaceuticals labeled with near-IR fluorophores which can be tracked in vivo. This understanding may facilitate more rapid developments
of generally applicable actively targeted reagents.