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Molecular Pharmaceutics Apr 2020The efflux of anticancer agents mediated by P-glycoprotein (P-gp) is one of the main causes of multidrug resistance (MDR) and eventually leads to chemotherapy failure....
The efflux of anticancer agents mediated by P-glycoprotein (P-gp) is one of the main causes of multidrug resistance (MDR) and eventually leads to chemotherapy failure. To overcome this problem, the delivery of anticancer agents in combination with a P-gp inhibitor using nanocarrier systems is considered an effective strategy. On the basis of the physiological compatibility and excellent drug loading ability of erythrocytes, we hypothesized that nanoerythrocytes could be used for the codelivery of an anticancer agent and a P-gp inhibitor to overcome MDR in breast cancer. Herein, a folic acid-modified nanoerythrocyte system (PTX/TQR NPs@NanoRBC-PEG/FA) was prepared to simultaneously transport paclitaxel and tariquidar, and the in vitro and in vivo characteristics of this delivery system were evaluated through several experiments. The results indicated that the average diameter and surface potential of this nanocarrier system were 159.8 ± 1.4 nm and -10.98 mV, respectively. Within 120 h, sustained release of paclitaxel was observed in both pH 6.5 media and pH 7.4 media. Tariquidar release from this nanocarrier suppressed the P-gp function of MCF-7/Taxol cells and significantly increased the intracellular paclitaxel level ( < 0.01 versus the PTX group). The results of the MTT assay indicated that the simultaneous transportation of paclitaxel and tariquidar could significantly inhibit the growth of MCF-7 cells or MCF-7/Taxol cells. After 48 h of incubation with PTX/TQR NPs@NanoRBC-PEG/FA, the viability of MCF-7 cells and MCF-7/Taxol cells decreased to 7.37% and 30.2%, respectively, and the IC values were 2.49 μM and 6.30 μM. Pharmacokinetic results illustrated that, compared with free paclitaxel, all test paclitaxel nanoformulations prolonged the drug release time and showed similar plasma concentration-time profiles. The peak concentration (), area under the curve (AUC), and half-life () of PTX/TQR NPs@NanoRBC-PEG/FA were 3.33 mg/L, 6.02 mg/L·h, and 5.84 h, respectively. Moreover, this active targeting nanocarrier dramatically increased the paclitaxel level in tumor tissues. Furthermore, compared with those of the other paclitaxel formulations, the cellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels of the PTX/TQR NPs@NanoRBC-PEG/FA group increased by 1.38-fold ( < 0.01) and 1.36-fold ( < 0.01), respectively, and the activities of superoxide dismutase (SOD) and catalase (CAT) decreased to 67.8% ( < 0.01) and 65.4% ( < 0.001), respectively. More importantly, in vivo antitumor efficacy results proved that the PTX/TQR NPs@NanoRBC-PEG/FA group exerted an outstanding tumor inhibition effect with no marked body weight loss and fewer adverse effects. In conclusion, by utilizing the inherent and advantageous properties of erythrocytes and surface modification strategies, this biomimetic targeted drug delivery system provides a promising platform for the codelivery of an anticancer agent and a P-gp inhibitor to treat MDR in breast cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Breast Neoplasms; Catalase; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Erythrocytes; Female; Folic Acid; Humans; MCF-7 Cells; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Paclitaxel; Particle Size; Quinolines; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 32176509
DOI: 10.1021/acs.molpharmaceut.9b01148 -
Pharmaceuticals (Basel, Switzerland) Feb 2023The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC)...
The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC) functionalized with PEG and RIPL peptide (PRN) (D^T-PRN) was compared with that of a physically mixed dual-carrier system of DTX-loaded PRN (D-PRN) and TRQ-loaded PRN (T-PRN) to overcome DTX mono-administration-induced multidrug resistance. NLC samples were prepared using the solvent emulsification evaporation technique and showed homogeneous spherical morphology, with nano-sized dispersion (<220 nm) and zeta potential values of -15 to -7 mV. DTX and/or TRQ was successfully encapsulated in NLC samples (>95% encapsulation efficiency and 73-78 µg/mg drug loading). In vitro cytotoxicity was concentration-dependent; D^T-PRN exhibited the highest MDR reversal efficiency, with the lowest combination index value, and increased the cytotoxicity and apoptosis in MCF7/ADR cells by inducing cell-cycle arrest in the G2/M phase. A competitive cellular uptake assay using fluorescent probes showed that, compared to the dual nanocarrier system, the single nanocarrier system exhibited better intracellular delivery efficiency of multiple probes to target cells. In the MCF7/ADR-xenografted mouse models, simultaneous DTX and TRQ delivery using D^T-PRN significantly suppressed tumor growth as compared to other treatments. A single co-loaded system for PRN-based co-delivery of DTX/TRQ (1:1, /) constitutes a promising therapeutic strategy for drug-resistant breast cancer cells.
PubMed: 36986449
DOI: 10.3390/ph16030349 -
Journal of Nuclear Medicine : Official... Aug 2016(11)C-elacridar and (11)C-tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member... (Clinical Trial)
Clinical Trial
UNLABELLED
(11)C-elacridar and (11)C-tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans.
METHODS
Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either (11)C-elacridar or (11)C-tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms.
RESULTS
Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 ± 0.06 μSv/MBq for (11)C-elacidar and 3.62 ± 0.11 μSv/MBq for (11)C-tariquidar.
CONCLUSION
Our data indicate that both (11)C-elacridar and (11)C-tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.
Topics: Acridines; Adult; Carbon Radioisotopes; Humans; Metabolic Clearance Rate; Organ Specificity; Positron-Emission Tomography; Quinolines; Radiation Dosage; Radiopharmaceuticals; Tetrahydroisoquinolines; Tissue Distribution; Whole-Body Counting
PubMed: 27081167
DOI: 10.2967/jnumed.116.175182 -
ACS Chemical Neuroscience Feb 2011Tariquidar was developed as a specific inhibitor of the efflux transporter ABCB1. Recent positron emission tomographic brain imaging studies using [(11)C]tariquidar to...
Tariquidar was developed as a specific inhibitor of the efflux transporter ABCB1. Recent positron emission tomographic brain imaging studies using [(11)C]tariquidar to measure ABCB1 (P-gp, P-glycoprotein) density in mice indicate that the inhibitor may not be as specific as previously thought. We examined its selectivity as an inhibitor and a substrate for the human transporters P-gp, breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance protein 1 (MRP1, ABCC1). Our results show that at low concentrations, tariquidar acts selectively as an inhibitor of P-gp and also as a substrate of BCRP. At much higher concentrations (≥100 nM), tariquidar acts as an inhibitor of both P-gp and BCRP. Thus, the in vivo specificity of tariquidar depends on concentration and the relative density and capacity of P-gp vs BCRP.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Female; HEK293 Cells; Humans; Neoplasm Proteins; Quinolines; Substrate Specificity
PubMed: 22778859
DOI: 10.1021/cn100078a -
PloS One 2013Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a...
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently discovered member of the ATP-binding cassette (ABC) family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR). We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
Topics: Cell Line; Drug Resistance, Multiple; Humans; Multidrug Resistance-Associated Proteins; Quinolines
PubMed: 23393594
DOI: 10.1371/journal.pone.0055576 -
Journal of Controlled Release :... Feb 2021Multidrug resistance (MDR) of cancer stem cells (CSCs) is a major hurdle to chemotherapy, and it is very important to develop CSCs-specific targeted nanocarriers for the...
Novel dendritic polyglycerol-conjugated, mesoporous silica-based targeting nanocarriers for co-delivery of doxorubicin and tariquidar to overcome multidrug resistance in breast cancer stem cells.
Multidrug resistance (MDR) of cancer stem cells (CSCs) is a major hurdle to chemotherapy, and it is very important to develop CSCs-specific targeted nanocarriers for the treatment of drug resistant CSCs. In this work, we developed CSCs-specific targeted mSiO-dPG nanocarriers simultaneous delivery chemotherapy drug DOX along with the P-glycoprotein (P-gp) inhibitor tariquidar (Tar) for enhanced chemotherapy to overcome MDR in breast CSCs. The mSiO-dPG nanocarriers possess a high loading capability, excellent pH stimuli-responsive performance, and good biocompatibility. With the help of CSCs-specific targeting and P-gp inhibitor Tar, the accumulation of DOX delivered by the mSiO-dPG nanocarriers could be greatly increased in drug resistant three-dimensional mammosphere of breast CSCs, and the chemotherapeutic efficacy against breast CSCs was enhanced. Moreover, the expression of stemness-associated gene and tumorspheres' formation ability was also significantly suppressed, which indicates the excellent capability for overcoming MDR of breast CSCs. Taken together, we developed a CSCs-specific targeted mSiO-dPG nanocarriers for co-delivery DOX and Tar, which provide a promising approach to effectively eliminate the CSCs and overcome the MDR of breast CSCs.
Topics: Breast Neoplasms; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Glycerol; Humans; MCF-7 Cells; Nanoparticles; Neoplastic Stem Cells; Polymers; Quinolines; Silicon Dioxide
PubMed: 33189788
DOI: 10.1016/j.jconrel.2020.11.015 -
ChemMedChem Oct 2013Tariquidar and elacridar are among the most potent inhibitors of the multidrug resistance transporter P-glycoprotein (P-gp), but how they interact with the protein is...
Tariquidar and elacridar are among the most potent inhibitors of the multidrug resistance transporter P-glycoprotein (P-gp), but how they interact with the protein is yet unknown. In this work, we describe a possible way in which these inhibitors interact with P-gp. We rely on structure-activity relationship analysis of a small group of tariquidar and elacridar analogues that was purposefully selected, designed, and tested. Structural modifications of the compounds relate to the presence or absence of functional groups in the tariquidar and elacridar scaffolds. The activity of the compounds was evaluated by their effects on the accumulation of P-gp substrates rhodamine 123 and Hoechst 33342 in resistant tumor cells. The data allow estimation of the ability of the compounds to interact with the experimentally proposed R- and H-sites to which rhodamine 123 and Hoechst 33342 bind, respectively. Using an inward-facing homology model of human P-gp based on the crystallographic structure of mouse P-gp, we demonstrate that these binding sites may overlap with the binding sites of the QZ59 ligands co-crystallized with mouse P-gp. Based on this SAR analysis, and using flexible alignment and docking, we propose possible binding modes for tariquidar and elacridar. Our results suggest the possibility for the studied compounds to bind to sites that coincide or overlap with the binding sites of rhodamine 123 and Hoechst 33342. These results contribute to further understanding of structure-function relationships of P-gp and can help in the design of selective and potent P-gp inhibitors with potential clinical use.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Acridines; Animals; Benzimidazoles; Binding Sites; Cell Line, Tumor; Drug Resistance, Multiple; Humans; Mice; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Quinolines; Rhodamine 123; Structure-Activity Relationship; Substrate Specificity; Tetrahydroisoquinolines
PubMed: 23943604
DOI: 10.1002/cmdc.201300233 -
Neurotoxicology Sep 2018Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) has been shown to...
Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) has been shown to enhance the efficacy of nerve agent treatment in soman exposed rats. In the present study, the promising effects of the PgP inhibitor tariquidar were investigated in more detail in rats s.c. exposed to 150 μg/kg soman. Treatment with HI-6 and atropine sulfate (125 and 3 mg/kg i.m respectively) was administered 1 min after exposure. Diazepam (0.5 mg/kg i.m.) and/or tariquidar (7.5 mg/kg i.v.) were included either at 1 min or 40 min following onset of seizures. Animals that received tariquidar, in addition to HI-6 and atropine, at 1 min, displayed a rapid normalization of EEG activity and cessation of seizure-associated behaviour. This improvement by addition of tariquidar was even more substantial in animals that also received diazepam, either immediately or delayed. Animals exhibiting lower intensity seizures displayed less severe neuropathology (neuronal loss, microglia activation and astrogliosis), primarily in the piriform cortex, and to a lesser extent amygdala and entorhinal cortex. The present findings suggest that the interaction of tariquidar with atropine may be the decisive factor for enhanced treatment efficacy, given that atropine was previously found to be a PgP substrate. A more thorough understanding of the interactions of nerve agent antidotes, in particular the actions of central anticholinergics with benzodiazepines, could contribute to a future optimization of treatment combinations, particularly those aimed at later stage medical interventions.
Topics: Animals; Anticonvulsants; Astrocytes; Atropine; Brain; Cholinesterase Reactivators; Cholinesterases; Diazepam; Male; Microglia; Neurons; Neuroprotective Agents; Oximes; Pyridinium Compounds; Quinolines; Rats, Wistar; Seizures; Soman
PubMed: 30130561
DOI: 10.1016/j.neuro.2018.08.005 -
Seizure May 2024P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp...
PURPOSE
P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp inhibitor tariquidar (TQD) has been shown to effectively inhibit P-gp at the human blood-brain barrier, improving brain entry of several ASMs. A potential strategy to overcome drug-resistance is the co-administration of P-gp inhibitors such as TQD to ASMs. Here we present data on the tolerability of single-dose TQD as a potential add-on medication to ASMs.
METHODS
We performed a multi-centre cohort study including drug-resistant epilepsy patients and healthy controls from the United Kingdom and Austria. TQD was administered intravenously at five different doses (2 mg/kg or 3 mg/kg of TQD were given to drug-resistant epilepsy patients and healthy controls, higher doses of TQD at 4 mg/kg, 6 mg/kg and 8 mg/kg as well as a prolonged infusion aiming at a dose of 6 mg/kg were only given to healthy controls). Adverse events were recorded and graded using the Common Terminology Criteria (CTCAE) scale. Additionally, TQD plasma concentration levels were measured and compared between drug-resistant patients and healthy controls.
RESULTS
In total, 108 participants received TQD once at variable doses and it was overall well tolerated. At doses of 2 or 3 mg/kg TQD, only two of the 19 drug-resistant epilepsy patients and a third of the healthy controls (n = 14/42) reported adverse events probably related to TQD. The majority of those adverse events (96 %) were reported as mild. One drug-resistant epilepsy patient reported adverse events 24-hours after TQD administration possibly related to TQD-induced increased ASMs levels in the brain.
CONCLUSIONS
TQD is an effective and well tolerated P-gp inhibitor as a single dose and could potentially be used intermittently in conjunction with ASMs to improve efficacy. This promising strategy to overcome drug-resistance in epilepsy should be investigated further in clinical randomised controlled trials.
PubMed: 38776617
DOI: 10.1016/j.seizure.2024.05.007 -
European Journal of Medicinal Chemistry Nov 2023New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug...
New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug resistance (MDR) reversers. Their behaviour on the three ABC transporters P-gp, MRP1 and BCRP was investigated. All compounds inhibited the P-gp transport activity in MDCK-MDR1 cells overexpressing P-gp, showing EC values even in the low nanomolar range (compounds 15, 22). Oxadiazole derivatives were able to increase the antiproliferative effect of doxorubicin in MDCK-MDR1 and in HT29/DX cells confirming their nature of P-gp modulators, with derivative 15 being the most potent in these assays. Compound 15 also displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. A computational study suggested a common interaction pattern on P-gp for most of the potent compounds. The bioisosteric substitution of the amide group of lead compounds allowed identifying a new set of potent oxadiazole derivatives that modulate MDR through inhibition of the P-gp efflux activity. If compared to previous amide derivatives, the introduction of the heterocycle rings greatly enhances the activity on P-gp, introduces in two compounds a moderate inhibitory activity on MRP1 and maintains in some cases the effect on BCRP, leading to the unveiling of dual inhibitor 15.
Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Resistance, Neoplasm; Structure-Activity Relationship; Neoplasm Proteins; Drug Resistance, Multiple; Tetrazoles; Amides
PubMed: 37573829
DOI: 10.1016/j.ejmech.2023.115716