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Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action.

ABSTRACT: Doxil, a liposomal formulation of the chemotherapeutic drug doxorubicin, is FDA-approved for multiple indications. Doxil liposomes are designed to retain doxorubicin in circulation, minimize clearance by the mononuclear phagocyte system, and limit uptake in healthy tissue. Although pharmacokinetic data and survival statistics from clinical trials provide insight into distribution and efficacy, many details of the mechanism of action remain unresolved, despite the importance in translating liposome-based drug delivery systems to other molecules and cargo. Therefore, the objective of this study is to quantitatively assess the kinetics of doxorubicin leakage from Doxil liposomes. In contrast to previous studies, we consider three processes: dissolution of solid doxorubicin, protonation/deprotonation of soluble doxorubicin, and passive transport of neutral doxorubicin across the lipid bilayer of the liposomes. Experiments were performed for Doxil, Doxil-like liposomes, and Doxil-like liposomes with reduced cholesterol and pegylation. To mimic physiological conditions, we also performed experiments in serum and under slightly acidic conditions at pH5. We show that crystalline doxorubicin dissolution can be described by a first order rate constant of 1.0×10-9cms-1 at 37°C. Doxorubicin leakage can be described by first order rate constant for transport across the lipid bilayer with values in the range from 1 to 3×10-12cms-1 at 37°C. Based on these results we discuss implications for the mechanism of action, taking Doxil pharmacokinetics into account.

SUBMITTER: Russell LM

PROVIDER: S-EPMC5748343 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action.

Russell Luisa M LM Hultz Margot M Searson Peter C PC

Journal of controlled release : official journal of the Controlled Release Society 20171107

Doxil, a liposomal formulation of the chemotherapeutic drug doxorubicin, is FDA-approved for multiple indications. Doxil liposomes are designed to retain doxorubicin in circulation, minimize clearance by the mononuclear phagocyte system, and limit uptake in healthy tissue. Although pharmacokinetic data and survival statistics from clinical trials provide insight into distribution and efficacy, many details of the mechanism of action remain unresolved, despite the importance in translating liposo ...[more]

PMID: 29122661

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Project description:Scale mineral deposition is a critical problem that hinders the daily production of oil and gas fields. Chemical removal of these scales, based on the scale type, is common. In this paper, borax and diethylene tremaine penta acetic (DTPA) acid-based formulations are used for the removal of sulfides, carbonates, and sulfate scales. In particular, the dissolution rates of sulfide (pyrite, pyrrhotite, and galena), sulfate (celestite and barite), and carbonate (calcite) scales were investigated in a rotating disc apparatus at typical well conditions. Scanning electron microscopy-energy-dispersive X-ray and X-ray diffraction analyses were performed for characterizing scale composition and type. The effect of temperature, scale type, and formulation on the dissolution rate is studied. Even though borax formulation has been developed for the sulfide scale removal, it showed a high dissolution rate for the carbonate scale (7.23 × 10-7 mol·L-1·s-1·cm-2). For the sulfide scale, the highest dissolution in borax formulation was obtained with galena (lead sulfide, PbS), followed by pyrrhotite, and the lowest dissolution was reported for pyrite (1.55 × 10-8 mol·L-1·s-1·cm-2). Borax formulation was found to be inefficient in the removal of sulfate scales with a dissolution rate lower than carbonate and sulfide scales by 3 and 2 orders of magnitude, respectively. Similarly, DTPA-based formulation has yielded the highest dissolution for the carbonate scale (7.98 × 10-6 mol·L-1·s-1·cm-2). However, for sulfate, DTPA-based formulation showed better performance than borax. The increase in temperature leads to an increase in the dissolution rate for almost all types of scales; however, DTPA-based formulation showed improved performance with temperature. Both formulations are efficient in removing sulfate- and sulfide-rich scales. The experimental results of DTPA have been validated by density functional theory calculations of binding energies between DTPA and metal ions present in the mixed scale.

Dataset Information

Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action.

Publications

Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action.

Similar Datasets

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