Chemical synthesis and biological properties of novel fluorescent antifolates in pgp- and mrp-overexpressing tumour cell lines

Robson, Claire; Wright, KarenA; Twentyman, Peter R.; Lambert, Peter A.; Griffin, R. J.

doi:10.1016/s0006-2952(98)00068-9

Cited by 6 publications

(4 citation statements)

References 33 publications

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“…As another way to compare the effectiveness of these formulations, the antiproliferative effects of doxorubicin were measured for all formulations with H69/LX4 cells and H69 cells. While such sensitization studies have been conducted for parenteral formulations, − this is the first study of its kind where drug sensitization studies are being conducted with orally deliverable nanoparticle formulations to understand their interactions with P-gp receptors. Formulations were compared for their capacities to facilitate the antiproliferative effect of doxorubicin on the multidrug resistant cell lines.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Evaluation of pH-Responsive Nanoscale Hydrogels for the Oral Delivery of Hydrophobic Therapeutics

Puranik

Pao

White

et al. 2016

Ind. Eng. Chem. Res.

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About 70% of pharmaceutical drug candidates are poorly soluble and suffer from low oral bioavailability. Additionally, a large number of therapeutics are also substrates for P-glycoprotein (P-gp) receptors present on the intestinal cell lining and undergo efflux that further reduces their oral bioavailability drastically. Nanoscale hydrogels are promising candidates for oral delivery of hydrophobic therapeutics as they hold immense potential in improving solubility and increasing intestinal permeability of such therapeutics. In this report, we describe the in vitro evaluation and comparison of four novel, pH-responsive poly(methacrylic acid-g-polyethylene glycol-co-hydrophobic monomer) nanoscale hydrogels for their capacity to load and release chemotherapeutic doxorubicin, as well as their ability to modulate permeability in vitro for improving doxorubicin transport. The resulting nanoscale formulations showed appreciable loading, and in vitro release studies demonstrated excellent pH-triggered release kinetics. These nanoscale hydrogels can serve as carriers for oral delivery of doxorubicin, achieving drug loading efficiencies of 56−70%, and releasing up to 95% of drug within 6 h. Powder X-ray diffraction studies revealed a change from the crystalline nature of doxorubicin to an amorphous form when encapsulated within formulations, illustrating their potential of enhancing solubility and stability for oral delivery of the hydrophobic therapeutic. Furthermore, their ability to modulate in vitro intestinal permeability was also studied using transport studies with Caco-2 cells, and was complemented by assessing their antitumor activity against P-gp overexpressing, DOXresistant H69/LX4 cancer cells. In vitro cell culture tests demonstrated up to 50% reduction in cellular proliferation in the case of poly(methacrylic acid-g-polyethylene glycol-co-methyl methacrylate), suggesting that these carriers are most suitable as hydrophobic drug carriers that can potentially overcome solubility and permeability limitations typically faced by hydrophobic therapeutics in the gastrointestinal (GI) tract.

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Section: Resultsmentioning

confidence: 99%

In Vitro Evaluation of pH-Responsive Nanoscale Hydrogels for the Oral Delivery of Hydrophobic Therapeutics

Puranik

Pao

White

et al. 2016

Ind. Eng. Chem. Res.

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“…Thus, new substrates, inhibitors and chemosensitizers can be identified directly or by evaluating their interactions with known transported substrates [43]. Compiled from [59,60,70,[76][77][78][79]134,[144][145][146][147][148][149][150] The system requires that the elements that are essential for ATP-binding and hydrolysis (such as ATP, phosphocreatine, magnesium and creatine phosphokinase) be incubated with the insideout membrane vesicles and the possible labeled substrate. At the preferred temperature and following the appropriate time frame, the reaction is terminated.…”

Section: Vesicular Uptake Assaymentioning

confidence: 99%

ABC Drug Transporters as Molecular Targets for the Prevention of Multidrug Resistance and Drug-Drug Interactions

Calcagno¹,

Kim²,

Wu³

et al. 2007

CDD

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ABC transporters play an important role in mediating the cytoplasmic concentration of endogenous and xenobiotic substances. They therefore influence the pharmacokinetic profile of a variety of drugs. By virtue of their localization to plasma membranes in the intestine, liver, blood-brain and other vital biological barriers, a majority of ABC drug transporters cause drug-drug interactions, decreased drug efficacy and multidrug resistance for chemotherapeutic agents. Thus, elucidating which drug entities are substrates for ABC drug transporters is a crucial step in the drug development and treatment process. Here, we review the current status of methodology used to categorize drug compounds as substrates or modulators for the major ABC drug transporters including ABCB1, ABCC1 and ABCG2.

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“…The analysis of cytotoxicity by novel folic acid antagonists on the NCI-H69/P SCLC cell line and its multidrug-resistant subline NCI-H69/LX4, which overexpresses MDR1, as well as on COR-L23/P large cell line and its subline COR-L23/R overexpressing MRP, demonstrated that H69/LX4 and COR-L23/R sublines both showed clear cross-resistance to a number of folic acid antagonists associated with a marked reduction in cellular drug accumulation (Robson et al, 1998). Verapamil, as a drug-resistance modifier, showed little activity, whereas cyclosporin A was more active and partially restored drug accumulation in H69/LX4 overexpressing P-gp.…”

Section: Ink4amentioning

confidence: 99%

“…Verapamil, as a drug-resistance modifier, showed little activity, whereas cyclosporin A was more active and partially restored drug accumulation in H69/LX4 overexpressing P-gp. Hence, novel antifolates appear to be substrates for both the P-gp and MRP resistance mechanisms (Robson et al, 1998).…”

Section: Ink4amentioning

confidence: 99%

Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

Danesi

Braud

Fogli

et al. 2003

Pharmacological Reviews

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Chemical synthesis and biological properties of novel fluorescent antifolates in pgp- and mrp-overexpressing tumour cell lines

Cited by 6 publications

References 33 publications

In Vitro Evaluation of pH-Responsive Nanoscale Hydrogels for the Oral Delivery of Hydrophobic Therapeutics

In Vitro Evaluation of pH-Responsive Nanoscale Hydrogels for the Oral Delivery of Hydrophobic Therapeutics

ABC Drug Transporters as Molecular Targets for the Prevention of Multidrug Resistance and Drug-Drug Interactions

Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

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