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Colloidal vesicles for drug detoxification

English title Colloidal vesicles for drug detoxification
Applicant Leroux Jean-Christophe
Number 124882
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Pharmacology, Pharmacy
Start/End 01.01.2010 - 31.12.2012
Approved amount 415'000.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Biomedical Engineering

Keywords (8)

Liposomes; Polymersomes; Detoxification; Nanotechnology; Cardio-vascular drugs; Pharmaceutical sciences; Intoxication; Overdose

Lay Summary (English)

Lead
Lay summary
Hospitals are confronted with poisoned patients on a routine basis, with clinical scenarios ranging from drug overdose to illicit drug use, suicide attempts, or accidental toxic exposures. Unfortunately, for many life-threatening intoxications, specific antidotes are not available. One possible strategy for the management of overdose consists in administering systemically particulate carriers which could reduce the bioavailable drug concentration in the body by acting as a sink for the toxin/drug. To be useful in drug detoxification, particulate carriers should exhibit the following properties: physical stability, mean diameter in the 70 - 150 nm size range, long circulation time after intravenous administration, high affinity for the toxic compound, biocompatibility, and biodegradability. To the best of our knowledge, no such system has been described to date in the literature. Our laboratory is currently developing long circulating lipid and polymeric vesicle formulations, which we believe combine all required features for the treatment of overdoses, including overexposure to the antihypertensive drug diltiazem, which is commonly involved in voluntary or unintentional intoxications. The proposed system will be tailored to maximize drug removal from the affected peripheral tissues and restore normal physiological functions in a timely fashion. These novel vesicles may not only be useful for the prevention and/or treatment of drug acute toxicities but could also treat poisoning to other toxins, such as pesticides and chemical weapons.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Transmembrane pH-gradient liposomes to treat cardiovascular drug intoxication
Bertrand N, Bouvet C, Moreau P, Leroux J-C, Transmembrane pH-gradient liposomes to treat cardiovascular drug intoxication, in ACS Nano, 4(12), 7552-7558.
Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes
Forster Vincent, Luciani Paola, Leroux Jean-Christophe, Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes, in Biomaterials, 33, 3578-3585.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Phospholipids in Pharmaceutical Research Poster 16.09.2013 Heidelberg, Germany Forster Vincent;
Globalization of Pharmaceutics Education Network Meeting 2012 Poster 28.11.2012 Melbourne, Australia Forster Vincent;
Emulsion days 2011 Talk given at a conference 17.11.2012 Zurich, Switzerland Leroux Jean-Christophe;
Seminars of the Helmholtz Institute of Saarbrücken Talk given at a conference 13.11.2012 Saarbrücken, Germany Leroux Jean-Christophe;
Pharma/Tox Poster day Poster 04.10.2012 Zurich, Switzerland Forster Vincent;
Nanomedicine: from molecules to diagnosis and therapy Talk given at a conference 01.10.2012 Rome, Italy Leroux Jean-Christophe;
ETH Industry day Poster 07.09.2012 Zurich, Switzerland Forster Vincent;
Colloids and Nanomedicine Poster 15.07.2012 Amsterdam, Netherlands Luciani Paola;
7th Graduate Symposium of the Materials Research Center Talk given at a conference 07.06.2012 Zurich, Switzerland Forster Vincent;
19th local drug delivery meeting and cardiovascular course on revascularization & molecular strategies Poster 04.02.2012 Geneva, Switzerland Forster Vincent;
8th Swiss Experimental Surgery Symposium Poster 19.01.2012 Geneva, Switzerland Forster Vincent;
18th International Symposium on Microencapsulation Talk given at a conference 12.09.2011 Antalya, Turkey Leroux Jean-Christophe;
1st Bilateral workshop MRC ETH/Chalmers University Talk given at a conference 21.06.2011 Göteborg, Sweden Luciani Paola;
Zurich Pharma/Tox Poster day Talk given at a conference 06.06.2011 Zürich, Switzerland Forster Vincent;
Liposome Jerusalem Talk given at a conference 15.03.2011 Jerusalem, Israel Forster Vincent;
Doktorandentag Talk given at a conference 16.02.2011 Zürich, , Switzerland Forster Vincent;
7th Swiss Experimental Surgery Symposium Talk given at a conference 20.01.2011 Fribourg, Switzerland Forster Vincent;
Globalization of Pharmaceutics Education Network 2010 Talk given at a conference 10.11.2010 Chapel Hill, NC, United States of America Leroux Jean-Christophe;
Zürich Pharma/Tox Poster day Poster 08.10.2010 Zürich, Switzerland Forster Vincent;
3rd International NanoBio Conference Poster 24.08.2010 Zurich, Switzerland Forster Vincent;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Mise au point de vecteurs particulaires pour le traitement d'intoxications médicamenteuses International 2010

Awards

Title Year
Best abstract / Pharma/Tox Poster day
Best oral presentation award - Doktorandentag
Best poster award - 19th Local drug delivery meeting and cardiovascular course on revascularization
Best poster award - Pharma/Tox Poster day
Best poster award - Swiss Experimental Surgery Symposium

Associated projects

Number Title Start Funding scheme
138342 Functional nanomedicines for improved anticancer chemotherapy 01.05.2012 Project funding (Div. I-III)
135732 Celiac disease - Improving enzymatic oral therapies via polymer conjugation 01.11.2011 Project funding (Div. I-III)

Abstract

Acute drug intoxication, whether intentional or accidental, remains a major health problem worldwide. In particular, calcium channel blockers (CCBs) overdose may lead to serious morbidity, even more so when older agents such as verapamil or diltiazem are concerned, due to their action on both cardiac and vascular tissues. To this date the management of CCB toxicity remains empirical at best and consists in a combination of support measures (when advisable) and treatment of visible signs and symptoms. However, this course of treatment may not be sufficient to prevent the quick deterioration of the patient’s state. An increasingly attractive approach consists in using colloids for drug detoxification. Such nanosized particulate carriers are hypothesized to reduce drug toxicity by acting as sinks for the toxin. We have previously shown that nanometric transporters could successfully be employed to take up and extract various potent therapeutic agents such as docetaxel and amytriptyline, from peripheral tissues. Both lipid vesicles and lipid nanocapsules have demonstrated such abilities. Here, we propose the use of vesicular carriers, namely transmembrane pH-gradient unilamellar liposomes and polymersomes to mitigate diltiazem toxicity. These systems are bilayered structures and comprise a liquid aqueous center. The latter will be acidified to ease the capture and retention of diltiazem, a weakly basic drug. To demonstrate that both liposomes and polymersomes are potent diltiazem detoxifying agents, we have defined the following objectives:1) Confirm that vesicular carriers bearing a pH-gradient can efficiently sequester a weakly basic drug under physiological conditions (Years 1 and 2).1.1. Prepare and characterize pH-gradient liposomes and polymersomes 1.2. Evaluate the ability of both carriers to capture diltiazem in vitroExperimental plan: Transmembrane pH-gradient liposomes and polymersomes of various compositions will be prepared and thoroughly characterized. Parameters such as physical and chemical stabilities and capacity to maintain a transmembrane pH-gradient over time will be investigated. The ability of both systems to sequester diltiazem will be studied in vitro under physiological conditions (isotonic buffer, 37°C) and in the presence of serum proteins. 2) Determine whether long-circulating lipidic or polymeric vesicles can influence the distribution of orally-administered diltiazem and thus, reduce the tissue concentrations to sub-toxic levels (Years 2 and 3).2.1. Study the pharmacokinetics and distribution of empty liposomes and polymersomes2.2. Study the pharmacokinetics and distribution of orally-administered diltiazem2.3. Study the pharmacokinetics and distribution of orally-administered diltiazem in the presence of liposomes and polymersomes.Experimental plan: Liposomes and polymersomes bearing a transmembrane pH-gradient will be injected intravenously to healthy animals at a lipid/polymer dose that would typically be used to treat an overdose. In this experiment, the pharmacokinetics and distribution of both colloidal vesicles will be characterized and used to identify the formulations exhibiting the longest circulation time. Then, the pharmacokinetics and distribution of diltiazem will be evaluated in the presence and absence of the optimized detoxification vehicles. Here the diltiazem dose will be administered in the form of an aqueous solution to establish the proof of principle. This experiment is aimed at determining whether pH-gradient vesicles can modulate the distribution profile of diltiazem in a live animal model.3) Confirm that the administration of vesicular carriers can prevent the adverse effects brought about by a diltiazem overdose on live animals (Year 3).3.1. Determine the "toxic" diltiazem dose3.2. Study the ability of liposomes/polymersomes to mitigate symptomatic diltiazem toxicityExperimental plan: First, diltiazem will be administered at various doses to determine the one which will produce a 30% decrease in the mean arterial blood pressure. Changes in heart rate will also be measured. Then, in a separate experiment, liposomes/polymersomes will be administered 1 h after the drug at the selected dose, and their ability to revert the cardiovascular effects of diltiazem will be monitored.If successful the proposed approach may prove useful not only in the prevention and/or treatment of acute toxicities to diltiazem but may also to a number of weakly basic drugs, poisons and chemical weapons for which there exists no commercial antidotes.
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