Hows and Whys of Tumor-Seeking Dyes

Abstract

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.

Near‐Infrared Fluorescent Heptamethine Cyanine Dyes for COX‐2 Targeted Photodynamic Cancer Therapy

“…The uptake of Hcyanines in cancer cells is aided by hypoxia and activation of HIF1α/OATPs signalling leading to enhance dye uptake compared to normal cells which express lower OATPs level [7] . In addition to OATPs, albumin mediated Cy7 cell internalization was also proposed recently [8] . Hcyanines with a Cl atom on the meso ‐position could form noncovalent adduct with albumin and dissociated to form covalent bond after a prolonged period [9] .…”

“…[7] In addition to OATPs, albumin mediated Cy7 cell internalization was also proposed recently. [8] Hcyanines with a Cl atom on the meso-position could form noncovalent adduct with albumin and dissociated to form covalent bond after a prolonged period. [9] This could be the reason to support persistence tumour localization in vivo of Cy7.…”

Targeted Dual-Modal PET/SPECT-NIR Imaging: From Building Blocks and Construction Strategies to Applications

“…The C4’-chloro-containing cyanine named MHI-148 ( Figure 3 a) specifically localizes and persists for days in several preclinical solid tumor models (i.e., kidney, lung, brain, breast, and prostate) [ 122 , 123 , 124 ]. This targeting property has been attributed to organic anion transporting polypeptide (OATP) transporters [ 125 , 126 , 127 , 128 ]. A more hydrophilic version, with a quaternary amine in the cyclohexyl core, was reported by Burgess and coworkers (QuatCy) [ 129 ].…”

Shortwave Infrared Absorptive and Emissive Pentamethine-Bridged Indolizine Cyanine Dyes

“…(4-Bromopyridin-2-yl)(4-(dimethylamino)phenyl)methanol (10). To a flask equipped with a stir bar were added Mg turning (0.38 g, 15.60 mmol), tetrahydrofuran (38 mL, 0.40 M), two drops of 1,2dibromoethane, and 4-bromo-N,N-dimethylaniline (3.00 g, 15.0 mmol) under N 2 .…”

“…Cyanines are well-known as an exceptionally strong absorbing and emitting class of materials with high molecular brightness (MB, where MB = ε × ϕ, with ε being molar absorptivity and ϕ being the emission quantum yield) values in the near-infrared (NIR) region. , MB values are related to the amount of the emissive probe that is needed to rapidly generate a high-quality image with higher MB value materials allowing for the use of lower probe quantities. Additionally, cyanines are often relatively nontoxic compared to many emissive materials in the NIR and SWIR regions, with cellular component level targeting possible. ,− …”