Protein labelling and albumin binding characteristics of the near-IR Cy7 fluorophore, QuatCy

Thavornpradit, Sopida; Usama, Syed Muhammad; Lin, Chen‐Ming; Burgess, Kevin

doi:10.1039/c9ob01184f

Cited by 15 publications

(19 citation statements)

References 12 publications

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“…34,35 Reaction of 5-Cl (QuatCy) 38 with albumin is much slower under physiological conditions, but it will eventually form an analogous covalent adduct. 39 This difference is related to the extra positive charge on the QuatCy core (5) relative to framework 1 which impacts the electrostatic affinity of the two dyes toward {protein-based} nucleophiles, their water solubilities, logP (reflecting partitioning of ions) and logD (partitioning of all neutral species and ions) values. 38 Derivatives of 1 wherein the meso-Cl is replaced by a phenyl group, i.e., 1-Ph and 5-Ph, are excellent controls because they have no chloride to be displaced by nucleophiles.…”

Section: Compounds Consideredmentioning

confidence: 99%

Role of Albumin in Accumulation and Persistence of Tumor-Seeking Cyanine Dyes

et al. 2020

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Some heptamethine cyanine dyes accumulate in solid tumors in vivo and persist there for several days. The reasons why they accumulate and persist in tumors were incompletely defined, but explanations based on uptake into cancer cells via organic anion transporting polypeptides (OATPs) have been widely discussed. All cyanine-based "tumor-seeking dyes" have a chloride centrally placed on the heptamethine bridge (a "meso-chloride"). We were intrigued and perplexed by the correlation between this particular functional group and tumor uptake, so the following study was designed. It features four dyes (1-Cl, 1-Ph, 5-Cl, and 5-Ph) with complementary properties. Dye 1-Cl is otherwise known as MHI-148, and 1-Ph is a close analog wherein the meso-chloride has been replaced by a phenyl group. Data presented here shows that both 1-Cl and 1-Ph form noncovalent adducts with albumin, but only 1-Cl can form a covalent one. Both dyes 5-Cl and 5-Ph have a methylene (CH 2 ) unit replaced by a dimethylammonium functionality (N + Me 2 ). Data presented here shows that both these dyes 5 do not form tight noncovalent adducts with albumin, and only 5-Cl can form a covalent one (though much more slowly than 1-Cl). In tissue culture experiments, uptake of dyes 1 is more impacted by the albumin in the media than by the pan-OATP uptake inhibitor (BSP) that has been used to connect uptake of tumor-seeking dyes in vivo with the OATPs. Uptake of 1-Cl in media containing fluorescein-labeled albumin gave a high degree of colocalization of intracellular fluorescence. No evidence was found for the involvement of OATPs in uptake of the dyes into cells in media containing albumin. In an in vivo tumor model, only the two dyes that can form albumin adducts (1-Cl and 5-Cl) gave intratumor fluorescence that persisted long enough to be clearly discerned over the background (~4 h); this fluorescence was still observed at 48 h. Tumors could be imaged with a higher contrast if 5-Cl is used instead of 1-Cl, because 5-Cl is cleared more rapidly from healthy tissues. Overall, the

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Section: Compounds Consideredmentioning

confidence: 99%

Role of Albumin in Accumulation and Persistence of Tumor-Seeking Cyanine Dyes

et al. 2020

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“…As a natural ligand carrier, albumin has shown remarkable promise as a carrier for anti-cancer agents to promote their accumulation within tumors [ 31 ]. In the presence of albumin, MHI-148 rapidly forms a non-covalent complex, and, like other HMCDs containing a meso -chlorine, over time the albumin-free thiol displaces the meso -chlorine to form a covalent adduct [ 14 ]. As the cell-based assays in our study were performed in the presence of 5% FBS (equating to an albumin concentration of ~19 µM in the culture medium), the albumin concentration was in excess when compared to the concentration of MHI-148 and MHI-palbociclib in all experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Initially explored for their use in imaging neoplasms, their tumor-targeting properties and their tumor selectivity is primarily attributed to their uptake by isoforms of organic anion transporting polypeptides (OATPs), which are overexpressed in cancer tissues [ 12 , 13 ]. A particular heptamethine cyanine dye (MHI-148) was reported to readily form an adduct with albumin [ 14 ], and MHI-148 can be imported via albumin receptors which are over-expressed on cancer cells [ 15 ]. MHI-148 has previously been conjugated to kinase inhibitors e.g., dasatinib [ 16 ] with the goal of selectively delivering them to solid tumors [ 13 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

et al. 2022

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The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

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“…41 In the presence of albumin, MHI-148 rapidly forms a non-covalent complex, and, like other HMCDs containing a meso-chlorine, over time the albumin free thiol displaces the meso-chlorine to form a covalent adduct. 13 As the cellbased assays in our study were performed in the presence of 5% FBS (equating to an albumin concentration of ~19 M in the culture medium), the albumin concentration was in excess compared to the concentration of MHI-148 and MHI-palbociclib in all experiments. Therefore the cell-based assays involving MHI-148 and MHI-palbociclib presumably contained a mixture of species including the parent drug, a noncovalent adduct, and a covalent adduct.…”

Section: Discussionmentioning

confidence: 99%

“…10 Initially explored for their use in imaging neoplasms, their tumor-targeting properties and their tumor selectivity is primarily attributed to their uptake by isoforms of organic anion transporting polypeptides (OATPs) which are overexpressed in cancer tissues. 11,12 A particular heptamethine cyanine dye (MHI-148) was reported to readily form an adduct with albumin, 13 and MHI-148 can be imported via albumin receptors which are over-expressed on cancer cells. 14 MHI-148 has previously been conjugated to kinase inhibitors (e.g.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

Leung

Tomek

Tercel

et al. 2021

Preprint

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The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative as well as estrogen receptor positive breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells suggesting the mechanism of action differed from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

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Protein labelling and albumin binding characteristics of the near-IR Cy7 fluorophore, QuatCy

Abstract: “QuatCy” selectively labels Cys side-chains, and proteins with exposed Cys residues over albumin.

Cited by 15 publications

References 12 publications

Role of Albumin in Accumulation and Persistence of Tumor-Seeking Cyanine Dyes

Role of Albumin in Accumulation and Persistence of Tumor-Seeking Cyanine Dyes

Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

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