On the Mechanisms of Uptake of Tumor-Seeking Cyanine Dyes

Abstract

Molecular entities that localize in tumor tissue are clinically important for targeted delivery of diagnostic, imaging, and therapeutic reagents. Often these targeting entities are designed for specific receptors (e.g., EGFR or integrin receptors). However, there is a subset of cyanine-7 dyes that apparently localize in every type of solid tumor tissue (at least, no exceptions have been reported so far), and they persist there for several days. Consequently, these dyes can be used for near-IR optical imaging of tumors in animal studies, they can be conjugated with cytotoxic species to give experimental theranostics, and there is potential for expanding their use into the development of clinically useful derivatives. Data presented in the literature and in this work indicate that the half-lives of these compounds in serum at 37 °C is on the order of minutes to a few hours, so what accounts for the persistent fluorescence of these dyes in tumor tissue over periods of several days? Literature, solely based on tissue culture experiments featuring a particular receptor blocker, indicates that uptake of these dyes is mediated by the organic anion transporter proteins (OATPs). Data presented in this paper agrees with that conclusion for short-term uptake, but significantly expands understanding of the likely reasons for long-term uptake and persistent tumor localization in vivo.

Conjugation of Dasatinib with MHI‐148 Has a Significant Advantageous Effect in Viability Assays for Glioblastoma Cells

“…[17] Conjugate 1 was designed to conform to several criteria. Second, the meso-chloro group of fluorophore A was not used to form conjugate 1.T he role of the meso-chloro functionality in the tumor-seeking properties of these dyes remainst ob ef ully elucidated, but we [21] and others [22] have shown that it is displaced by S-nucleophiles under physiological conditions, including the free cysteine residue in serum albumin.W eh ave also shown that the mesochloridec an be displaced to form ac ovalent albumin adduct that permeates into cancer cells. Second, the meso-chloro group of fluorophore A was not used to form conjugate 1.T he role of the meso-chloro functionality in the tumor-seeking properties of these dyes remainst ob ef ully elucidated, but we [21] and others [22] have shown that it is displaced by S-nucleophiles under physiological conditions, including the free cysteine residue in serum albumin.W eh ave also shown that the mesochloridec an be displaced to form ac ovalent albumin adduct that permeates into cancer cells.…”

“…First, complexes of dasatinib with kinases [18][19][20] showt he nucleoside-like heterocyclic fragment buried in the active side of the enzyme, with its hydroxyethylene group projected into the aqueous medium ( Figure 1and Figure S1);t his indicates that A could be connected to the hydroxyethylene group without impeding the binding. Second, the meso-chloro group of fluorophore A was not used to form conjugate 1.T he role of the meso-chloro functionality in the tumor-seeking properties of these dyes remainst ob ef ully elucidated, but we [21] and others [22] have shown that it is displaced by S-nucleophiles under physiological conditions, including the free cysteine residue in serum albumin.W eh ave also shown that the mesochloridec an be displaced to form ac ovalent albumin adduct that permeates into cancer cells. [21b] Fluorophore A was conjugated with dasatinib (das) as described in the Supporting Information (selection of the amine base in this procedure proved critical).…”

“…Data in Figure 2a was compared with ac ontrol conjugate featuring ac yanine dye without a meso-chloro group,i .e.,t he only clinically approved near-IRd ye indocyanineg reen (ICG). Dye A in compound 1 forms ac ovalenta dduct with albumin [21,22] that is retained in cancer cells, hence it hasa higheri mpact on viability than 2 (based on B)w here the dye cannotform ac ovalent albumin adduct. [24] Syntheses of conjugates to sulfonic acids are less convenient than to carboxylic acids, so ICG derivative( B)a nd dasatinib conjugate 2 were used.…”

“…These data indicate conjugate 1 was % 4.7-fold more cytotoxic than dasatinib in this assay.W ei nfer the differencei nc ell viabilityo fc onjugates 1 and 2 is duet o the dye used. Dye A in compound 1 forms ac ovalenta dduct with albumin [21,22] that is retained in cancer cells, hence it hasa higheri mpact on viability than 2 (based on B)w here the dye cannotform ac ovalent albumin adduct.…”

Research progress of near-infrared fluorescence probes based on indole heptamethine cyanine dyes in vivo and in vitro

“…The probe MHI-148 ( Fig. 53, Probe 81) was used to label free Cys residues, such as vimentin and serum albumin [102]. Other Cy-7 dyes containing meso-Cl (Fig.…”