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An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism.

ABSTRACT: PURPOSE:Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo. METHODS:First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs. Second, to further investigate the mechanism of CLDI formation, we asked whether specific accumulation of CFZ hydrochloride crystals in lysosomes could be explained as a passive, thermodynamic equilibrium phenomenon. A cellular pharmacokinetic model was constructed, simulating CFZ accumulation driven by pH-dependent ion trapping of the protonated drug in the acidic lysosomes, followed by the precipitation of CFZ hydrochloride salt via a common ion effect caused by high chloride concentrations. RESULTS:While lower loads of CFZ were mostly accommodated in lung macrophages, increased CFZ loading was accompanied by organ-specific changes in macrophage numbers, size and intracellular membrane architecture, maximizing the cargo storage capabilities. With increasing loads, the total cargo mass and concentrations of CFZ in different organs diverged, while that of individual macrophages converged. The simulation results support the notion that the proton and chloride ion concentrations of macrophage lysosomes are sufficient to drive the massive, cell type-selective accumulation and growth of CFZ hydrochloride biocrystals. CONCLUSION:CLDIs effectively function as an expandable mechanopharmaceutical device, revealing the coordinated response of the macrophage population to an increasingly massive, whole-organism endophagolysosomal cargo load.

SUBMITTER: Rzeczycki P

PROVIDER: S-EPMC6501569 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism.

Rzeczycki Phillip P Woldemichael Tehetina T Willmer Andrew A Murashov Mikhail D MD Baik Jason J Keswani Rahul R Yoon Gi Sang GS Stringer Kathleen A KA Rodriguez-Hornedo Nair N Rosania Gus R GR

Pharmaceutical research 20181112 1

<h4>Purpose</h4>Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo.<h4>Methods</h4>First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune c ...[more]

PMID: 30421091

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Project description:Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.

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An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism.

Publications

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism.

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