Organic Anion Transporting Polypeptides as Drug Targets

Kotsampasakou, Eleni; Ecker, Gerhard

doi:10.1002/9783527679430.ch12

Cited by 7 publications

(10 citation statements)

References 148 publications

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“…Some class B dyes are known to localize in solid tumor tissue (e.g., prostate, gastric, kidney, lung, glioblastoma, , and liver tumor tissues) but not in normal cells and tissue. ,− Evidence from several studies suggests this is because those particular fluors are uptaken by the organic anion transporter proteins (OATPs). , These OATP cell surface receptors are overexpressed on solid tumors; their natural function is to influx organic anions (and some neutral materials), which are important to cells (e.g., bile salts, steroids, bilirubin, and thyroid hormones), and to balance this ion influx. OATP receptors efflux intracellular bicarbonate, glutathione, and glutathione adducts.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Figure 7 compares the fluorescence uptake by HepG2 cells treated with 2ac alone (i.e., no blocking, Figure 7a), with the fluorescence when the same cell type but treated first with paninhibitor OATPs (which there are several subtypes within this category, but the inhibitor is believed to inhibit all; Figure 7b), 45,46 and finally (Figure 7c) with HepG2 cells treated with an agent to induce hypoxia and therefore to promote expression of HIF1α, leading to an enhance expression of OATPs. 36,47 Data in Figure 7 shows there is less uptake of 2ac when the OATPs are inhibited and more when their overexpression is enhanced.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Optimized Heptamethine Cyanines for Photodynamic Therapy

Usama

Thavornpradit

Burgess

2018

ACS Appl. Bio Mater.

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Over 10 near-IR fluorescent sensitizers were prepared to explore their properties relevant to potential applications in photodynamic therapy (PDT). Key properties of these compounds are that they can be excited around 800 nm, (i) are hydrophilic, (ii) generate singlet oxygen with acceptable quantum yields, and (iii) are imported into cancer cells via the organic anion transporter proteins (OATPs). (This is crucial to tumor localization.) The N-substituents of these cyanines were varied to adjust their charges and polarities and to accommodate conjugation to other entities (e.g., biomolecules or fragments to expand their theranostic modalities). Thus, it was possible to optimize their photocytotoxicities without compromising their other desirable characteristics for PDT. Overall, sensitizers like this have superior characteristics relative to clinically approved sensitizers for PDT insofar as they can be excited at greater depths in tissue.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Optimized Heptamethine Cyanines for Photodynamic Therapy

Usama

Thavornpradit

Burgess

2018

ACS Appl. Bio Mater.

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“…Many reports (for example ,,,− ,, ) explain the “tumor-seeking” characteristics of fluors 1 -Cl and B – D in terms of uptake via the Organic Anion Transporter Proteins (OATPs). , Hypoxia (common in compressed solid tumors) triggers activation of HIF1α, and promotes OATPs overexpression in cancer tissue relative to levels found in normal cells. , The natural role of OATPs is to mediate influx of organic anions and some neutral materials that are important to cells (e.g., bile salts, steroids, bilirubin, and thyroid hormones). This diversity of substrates means OATPs are not particularly selective and, coincidentally, these receptors also import some drug structures and fluors 1 -Cl, B – D . − To balance this ion influx, OATPs efflux intracellular bicarbonate, glutathione, and glutathione adducts.…”

Section: Introductionmentioning

confidence: 99%

“…Many reports (for example 8,10,11,[13][14][15][16]19,30 ) explain the "tumor-seeking" characteristics of fluors 1-Cl and B−D in terms of uptake via the Organic Anion Transporter Proteins (OATPs). 31,32 Hypoxia (common in compressed solid tumors) triggers activation of HIF1α, and promotes OATPs overexpression in cancer tissue relative to levels found in normal cells. 9,30 The natural role of OATPs is to mediate influx of organic anions and some neutral materials that are important to cells (e.g., bile salts, steroids, bilirubin, and thyroid hormones).…”

Section: ■ Introductionmentioning

confidence: 99%

On the Mechanisms of Uptake of Tumor-Seeking Cyanine Dyes

2018

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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.

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“…They can transport many clinically important drugs, including widely prescribed lipidlowering statins, anti-diabetic, antibiotics, and anticancer agents, from blood into the liver (3). Tissue targeting of therapeutic molecules mediated by transporters, including liver targeting via liverspecific OATP1B1 and OATP1B3, is an emerging area in drug development (4)(5)(6). There is a need to develop a screening tool that can simultaneously assess OATP1B3-mediated hepatic uptake and hepatocellular accumulation of drug candidates in vitro.…”

Section: Introductionmentioning

confidence: 99%

Development of a Rat Sandwich-Cultured Hepatocytes Model Expressing Functional Human Organic Anion Transporting Polypeptide (OATP) 1B3: A Potential Screening Tool for Liver-Targeting Compounds

Farasyn

Yue

2021

J Pharm Pharm Sci

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Purpose: Organic anion transporting polypeptide (OATP) 1B3 transports many clinically important drugs, including statins, from blood into the liver. It exclusively expresses in human liver under normal physiological conditions. There is no rodent ortholog of human OATP1B3. Tissue targeting of therapeutic molecules mediated by transporters, including liver-targeting via liver-specific OATPs, is an emerging area in drug development. Sandwich-cultured primary hepatocytes (SCH) are a well characterized in vitro model for assessment of hepatic drug uptake and biliary excretion. The current study was designed to develop a novel rat SCH model expressing human OATP1B3 to study the hepatic disposition of OATP1B3 substrates. Methods: Primary rat hepatocytes transduced with adenoviral vectors expressing FLAG-tagged OATP1B3 (Ad-OATP1B3), a control vector Ad-LacZ, or that were non-transduced were cultured in a sandwich configuration. FLAG immunoblot and immunofluorescence-staining determined expression and localization of OATP1B3. Uptake of [3H]-cholecystokinin octapeptide (CCK-8), a specific OATP1B3 substrate, was determined. Taurocholate (TC) is a substrate routinely used in SCH to assess biliary excretion via bile canaliculi (BC) and is also a substrate of OATP1B3. [3H]-TC accumulation in cells+BC, cells, biliary excretion index (BEI) and in vitro Clbiliary were determined using B-CLEAR® technology. Results: OATP1B3 protein was extensively expressed and primarily localized on the plasma membrane in day 4 Ad-OATP1B3-transduced rat SCH. [3H]-CCK-8 accumulation in cells+BC was significantly greater (~5-13 folds, p<0.001) in day 4 SCH with vs. without Ad-OATP1B3-transduction. Expressing OATP1B3 in rat SCH significantly increased [3H]-TC accumulation in cells+BC and cells, without affecting BEI and in vitro Clbiliary. Conclusions: Rat SCH expressing human OATP1B3-is a novel in vitro model allowing simultaneous assessment of hepatic uptake, hepatocellular accumulation and biliary excretion process of a human OATP1B3 substrate. This model could be a potential tool for screening for liver-targeting compounds mediated by OATP1B3.

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Organic Anion Transporting Polypeptides as Drug Targets

Cited by 7 publications

References 148 publications

Optimized Heptamethine Cyanines for Photodynamic Therapy

Optimized Heptamethine Cyanines for Photodynamic Therapy

On the Mechanisms of Uptake of Tumor-Seeking Cyanine Dyes

Development of a Rat Sandwich-Cultured Hepatocytes Model Expressing Functional Human Organic Anion Transporting Polypeptide (OATP) 1B3: A Potential Screening Tool for Liver-Targeting Compounds

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